Genetics of Breast and Ovarian Cancer

Summary Type: Genetics
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the genetics of breast and ovarian cancer, including information about specific genes and family cancer syndromes. The summary also contains information about interventions that may influence the risk of developing breast and ovarian cancer in individuals who may be genetically susceptible to these diseases. Psychosocial issues associated with genetic testing are also discussed.

Genetics of Breast and Ovarian Cancer

Introduction

General Information

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. In 2007, an estimated 180,510 new cases will be diagnosed, and 40,910 deaths from breast cancer will occur. Ovarian cancer is the seventh most common cancer, with an estimated 22,430 new cases in 2007, but is the fourth most deadly, with an estimated 15,280 deaths in 2007.¹ (Refer to the PDQ summary on Breast Cancer Treatment and Ovarian Epithelial Cancer Treatment for more information on breast cancer and ovarian cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer and the Family History as a Risk Factor for Ovarian Cancer sections below), and by the observation of rare families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with autosomal dominant inheritance of cancer susceptibility. Formal studies of families (linkage analysis ) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many cancer-prone families. (Refer to the PDQ summary Cancer Genetics Overview for more information on linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Family History as a Risk Factor for Breast Cancer

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative or a second-degree relative with breast cancer.^2,^3,^4,⁵ The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.⁶ In a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).⁶ Risk increases with the number of affected relatives and age at diagnosis.^3,^4,^6,

Family History as a Risk Factor for Ovarian Cancer

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one first-degree relative with ovarian cancer.^7,

Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.

Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. Those most strongly associated with these 2 cancers are BRCA1 or BRCA2 mutation syndromes, but breast cancer is also associated with Li-Fraumeni syndrome due to TP53 mutations, and Cowden syndrome due to PTEN mutations.⁸ Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

Other genetic syndromes that may include breast cancer as an associated feature include ataxia telangiectasia (AT) and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 (MEN1), and hereditary nonpolyposis colon cancer (HNPCC).⁸ The specific phenotypic characteristics are discussed later in this section.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).

Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual).

Cases of male breast cancer.

Possible increased risk of other selected cancers and benign features for males and females. (Refer to the Major Genes section of this summary for more information.)

Based on typical histopathological characteristics, breast and ovarian cancers occurring in BRCA1/2 mutation carriers generally do not differ dramatically from sporadic cases occurring in noncarriers and thus far have no known pathognomonic features. [Refer to the Pathology/Prognosis of Breast Cancer and Pathology/Prognosis of Ovarian Cancer sections for more information.]

Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk

When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.^9,^10,

Other Risk Factors for Breast Cancer

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) These factors are considered in more detail in numerous reviews,^11,¹² including among BRCA1/BRCA2 mutation carriers.¹³ Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (More information about their effects in BRCA1/BRCA2 mutation carriers can be found in the section on Interventions later in this document.)

Age

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.¹⁴ In women with a genetic susceptibility , breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

Reproductive and menstrual history

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.^13,

Oral contraceptives

Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer.^15,

Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.^16,^17,¹⁸

Hormone Replacement Therapy

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a relative risk of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause.¹⁹ The Women's Health Initiative (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and 2 trials of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits.^20,²¹ One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P <.001) in women randomized to receive estrogen and progestin.²¹ HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.^21,

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.^22,^23,^24,^25,²⁶ ¹⁹ The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.²¹ Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.^19,²⁷ The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has only been studied in the context of bilateral prophylactic oophorectomy, where short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.^28,

Radiation exposure

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations,^29,^30,^31,³² and in association with germline ATM and TP53 mutations.^33,³⁴ Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene.

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers.³⁵ Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results.^36,^37,

Alcohol intake

The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population.^38,³⁹ One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.⁴⁰

Physical Activity and Anthropometry

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor.⁴¹ These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.^42,

Benign breast disease and mammographic density

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer).⁴³ There may also be an association between benign breast disease and family history of breast cancer.^44,

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,^43,^45,⁴⁶ and breast density may have a genetic component to its etiology.^47,^48,^49,

Other factors

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in subgroups of women defined according to genotype. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer.⁵⁰ One study ⁵¹ found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.⁵²

Other Risk Factors for Ovarian Cancer

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and oral contraceptives.^53,⁵⁴ (Refer to the PDQ summary on Prevention of Ovarian Cancer for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Risk Modification section for more information.)

Age

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote; even in hereditary cancer families.^55,

Reproductive

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.⁵⁶ Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.^53,⁵⁷ Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.^58,^59,^60,^61,

Surgical History

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,^53,^62,⁶³ including in BRCA1/BRCA2 mutation carriers.⁶⁴ Ovarian cancer risk is reduced >90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.^65,⁶⁶ For further information on these studies refer to the Risk-Reducing Salpingo-Oophorectomy section of this summary.

Oral Contraceptives

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.⁵³ ⁵⁴ A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.^56,^67,^68,^69,^70,

Models for Prediction of Breast Cancer Risk

Models to predict an individual’s lifetime risk for developing breast cancer are available. In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. For further information on these models refer to the Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation section of this summary. Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to the study population on which the model was based. The table, Characteristics of the Gail and Claus Models, summarizes the salient aspects of the risk assessment models and is designed to aid in choosing the one that best applies to a particular individual.

Two models for predicting breast cancer risk, the Claus model ⁷¹ and the Gail model,⁷² are widely used in research studies and clinical counseling . Both have limitations, and the risk estimates derived from the 2 models may differ for an individual patient. These models, however, represent the best methods currently available for individual risk assessment.

It is important to note that these models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. In those cases, Mendelian risks would apply. A 3-generation cancer family history is taken before applying any model. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for more information on Taking a Family History.) Generally, the Claus or Gail models should not be used for families with 1 of the following characteristics:

Three individuals with breast or ovarian cancer (especially when 1 or more breast cancers are diagnosed before age 50 years).

A woman who has both breast and ovarian cancer.

Ashkenazi Jewish ancestry with at least 1 case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

Table 1. Characteristics of the Gail and Claus Models*
Gail ModelClaus Model*Adapted from Domchek et al.,⁷³ Rubenstein et al.,⁷⁴ and Rhodes.^75,Data derived from Breast Cancer Detection Demonstration Project (BCDDP) Study Cancer and Steroid Hormone (CASH) Study Study population 2,852 cases, age ≥35 years 4,730 cases, age 20-54 years In situ and invasive cancer Invasive cancer 3,146 controls 4,688 controls Caucasian Caucasian Annual breast screening Not routinely screened Family history characteristics First-degree relatives with breast cancer First-degree or second-degree relatives with breast cancer Age of onset in relatives Other characteristics Current age Current age Age at menarche Age at first live birth Number of breast biopsies Atypical hyperplasia in breast biopsy Race (included in the most current version of the Gail model) Strengths Incorporates: Incorporates: Risk factors other than family history Paternal as well as maternal history Age at onset of breast cancer Family history of ovarian cancer Limitations Underestimates risk in hereditary families May underestimate risk in hereditary families Number of breast biopsies without atypical hyperplasia may cause inflated risk estimates May not be applicable to all combinations of affected relatives Does not include risk factors other than family history Does not incorporate: Paternal family history of breast cancer or any family history of ovarian cancer Age at onset of breast cancer in relatives All known risk factors for breast cancer ⁷⁵ Best application For individuals with no family history of breast cancer or 1 first-degree relative with breast cancer at ≥age 50 years For individuals with 0, 1, or 2 first-degree or second-degree relatives with breast cancer For determining eligibility for chemoprevention studies

The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography.^76,^77,^78,^79,⁸⁰ While the model is reliable in predicting the number of breast cancer cases expected in a group of women from the same age-risk strata, it is less reliable in predicting risk for individual patients. Risk can be overestimated in:

Noncompliant women (i.e., not compliant with screening).^76,^77,

Women in the highest risk strata.^79,

Risk could be underestimated in the lowest risk strata.⁷⁹ Earlier studies ^76,⁷⁷ suggested risk was overpredicted in younger women and underpredicted in older women. More recent studies ^78,⁷⁹ using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations.^80,

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk.⁸¹ The 2 models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.

The Gail model is the basis for the Breast Cancer Risk Assessment Tool, a computer program that is available from the NCI by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237, or TTY at 1-800-332-8615). This version of the Gail Model estimates only the risk of invasive breast cancer.

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⁶¹ Anderson GL, Judd HL, Kaunitz AM, et al.: Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 290 (13): 1739-48, 2003.

⁶² Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.

⁶³ Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270 (23): 2813-8, 1993.

⁶⁴ Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.

⁶⁵ Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.

⁶⁶ Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.

⁶⁷ Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.

⁶⁸ Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.

⁶⁹ Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.

⁷⁰ McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.

⁷¹ Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.

⁷² Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.

⁷³ Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003.

⁷⁴ Rubinstein WS, O'Neill SM, Peters JA, et al.: Mathematical modeling for breast cancer risk assessment. State of the art and role in medicine. Oncology (Huntingt) 16 (8): 1082-94; discussion 1094, 1097-9, 2002.

⁷⁵ Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.

⁷⁶ Bondy ML, Lustbader ED, Halabi S, et al.: Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst 86 (8): 620-5, 1994.

⁷⁷ Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.

⁷⁸ Rockhill B, Spiegelman D, Byrne C, et al.: Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93 (5): 358-66, 2001.

⁷⁹ Costantino JP, Gail MH, Pee D, et al.: Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 91 (18): 1541-8, 1999.

⁸⁰ Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.

⁸¹ McTiernan A, Kuniyuki A, Yasui Y, et al.: Comparisons of two breast cancer risk estimates in women with a family history of breast cancer. Cancer Epidemiol Biomarkers Prev 10 (4): 333-8, 2001.

Major Genes

Introduction

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. In most cases an extensive family history (more than 4 relatives in the same biologic line affected) is not present. In some families, however, inherited factors are clearly the major component of an individual’s cancer risk. We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes . The recent isolation of several of these genes associated with a significantly increased risk of breast/ovarian cancer make it possible to identify families who carry mutations in these genes . Mutation carriers who have a risk of developing breast cancer that may exceed 50% comprise no more than 5% to 10% of all breast cancer cases.

Hereditary breast cancer is characterized by early age at onset (on average 5-15 years earlier than in sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and familial association with tumors of other organs, particularly the ovary and prostate gland.^1,^2,³

The clinical evidence of an autosomal dominant inherited predisposition to breast cancer has been supported by segregation analysis, a statistical genetics method to determine whether a particular trait follows a Mendelian pattern of inheritance. (For more information on criteria of autosomal dominant inheritance, refer to the Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition section of this summary.)

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.⁴ When segregation analysis was applied to the Cancer and Steroid Hormone (CASH) data set, goodness-of-fit tests of genetic models provided additional evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.^5,

The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by the study of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11.

BRCA1

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.⁶ The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.¹ The BRCA1 gene (OMIM: 113705) was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. BRCA1 appears to be responsible for disease in 45% of families with multiple cases of breast cancer only, and in up to 90% of families with both breast and ovarian cancer.^7,

BRCA2

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM: 600185) are thought to account for approximately 35% of multiple case breast cancer families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.^8,⁹ BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.¹⁰ While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene, with loss of the unmutated allele found in tumor specimens.

BRCA1 and BRCA2 Function

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on 1 copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, however, the normal allele is deleted, resulting in loss of all function. This finding strongly suggests that BRCA1 and BRCA2 are in the class of tumor suppressor genes, i.e., genes whose loss of function can result in neoplastic growth.^11,^12,

Additional evidence that BRCA1 is a tumor suppressor gene is that overexpression of the BRCA1 protein leads to tumor growth suppression in vitro and in a mouse model, in a fashion similar to the tumor suppressor gene TP53 and the retinoblastoma (RB) gene.¹³ While this provides a conceptual framework for understanding the role of mutations in cancer progression, it does little to indicate how these genes normally function to prevent cancer.

However, a variety of evidence now points to BRCA1 and BRCA2 being directly involved in the DNA repair process. Several strategies are used to evaluate gene function. These include comparing the sequence and structure of the protein product to other known genes; determining the tissues, cell types, and stages of the cell cycle in which the protein is expressed; and identifying other proteins with which the protein interacts. Animal models also provide an important tool; in particular, knockout mice provide a way to study the effects of different gene mutations. In this approach, the normal mouse gene coding for the analogous function has been removed, and normal or mutated human genes are then inserted to assess their biological effects. Epidemiological studies can provide important evidence for other factors, both genetic and nongenetic, that modify the effect of BRCA1 and BRCA2 gene mutations. New technical tools for study of gene function are now being developed; for example, microarray techniques that permit the assessment of gene variants or gene expression at multiple gene sites may allow the identification of other gene proteins that interact with or modify the effect of the BRCA1 and BRCA2 protein products.

Taken together, current data suggest that the BRCA1 and BRCA2 protein products interact with each other and with RAD51 and other proteins known to be involved in DNA repair. Loss of DNA repair function is assumed to lead to the accumulation of additional mutations and ultimately to carcinogenesis. Several review articles are available in the literature on BRCA1 and BRCA2 gene function.^14,^15,

Mutations in BRCA1 and BRCA2

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.¹⁶ The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.¹⁷ In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.^18,^19,^20,

Variants of uncertain significance

Germline deleterious (disease-associated) mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, classifying deleterious nucleotide changes to predict their functional impact relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial problems in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, as well as the likelihood that the VUS is significant.

African Americans appear to have a higher rate of VUS.²¹ A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a three-year period.²² Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of individuals had sequence alterations that were once considered VUS, but were reclassified, usually as a polymorphism though occasionally as a deleterious mutation. As additional information is accumulated, VUS are reclassified and such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development.^23,²⁴ Genetics clinics should make all efforts to track the VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. Parents and all affected family members should be tested for the variant (which is generally covered by Myriad Genetic Laboratory). The Myriad Genetic Laboratory typically provides additional information when a VUS is reported, including available data on cosegregation and whether the VUS has been seen in conjunction with a known deleterious mutation. In general, a VUS observed in subjects who also have a deleterious mutation, especially when it occurs with different mutations, is not felt to be in itself deleterious, although there are rare exceptions. Models based on sequence conservation and the biochemical properties of amino acid changes exist ^23,^25,^26,^27,²⁸ and are an adjunct to the clinical information. An attempt at further refining such models has also incorporated information on pathologic characteristics of BRCA1- and BRCA2- related tumors (such as the fact that BRCA1-related breast cancers are usually estrogen receptor negative).²⁹ Functional studies that measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 have been employed as well.^30,³¹ When attempting to interpret a VUS, all available information should be examined.

Prevalence and Founder Effects

Approximately 1 in 800 individuals in the general population may carry a pathogenic mutation in BRCA1. The frequency of carriers in selected groups has been measured. Among cases identified from the Cancer Surveillance System of Western Washington, the frequency of BRCA1 mutations was highest in cases diagnosed before age 30 years (23% carriers, 95% confidence interval (CI), 5.0-53.8), and in those with more than 3 relatives with breast cancer (20%, 95% CI, 6%-44%). A family history of ovarian cancer in a first-degree relative was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI, 3.2%-65.1%).³² In a second study, 263 women with familial breast cancer were analyzed.³³ BRCA1 mutations were found in 7% (95% CI, 0.3%-39%) of families with site-specific breast cancer, 18% of families with bilateral breast cancer, and 40% (95% CI, 1.7%-80.0%) of families with both breast and ovarian cancer. In a population-based series of incident cases of ovarian cancer in Canada, the overall prevalence of BRCA1/2 mutations was 11.7%; among women with a first-degree relative with breast or ovarian cancer, it was 19%. Of note, 6.5% of women with no affected first-degree relative carried a mutation, suggesting a higher overall prevalence of mutations in women with a diagnosis of ovarian cancer than in those with breast cancer.^34,^35,^36,

In some cases the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect. This occurs when a contemporary population can be traced back to a small, isolated group of founders. Most notably, 2 specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews (those tracing their roots to Central and Eastern Europe). Carrier frequencies for these mutations have been determined in the general Jewish population: 0.9% (95% CI, 0.7%-1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%-0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%-1.5%) for the BRCA2 6174delT mutation.^37,^38,^39,⁴⁰ Altogether, the frequency of these 3 mutations approximates 1 in 40 among Ashkenazi Jews; they account for 25% of early-onset breast cancer, and up to 90% of families with multiple cases of both breast and ovarian cancer in this population.^41,⁴² Additional founder mutations have been described in the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 999del5), and Sweden (BRCA1, 3171ins5).^43,^44,^45,⁴⁶

The presence of these founder mutations has practical implications for genetic testing . Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without pitfalls. It is estimated that 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.^22,

Penetrance of Mutations

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance . For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 14% to 87% for breast cancer and 10% to 68% for ovarian cancer.^7,^34,^36,^39,^47,^48,^49,^50,^51,^52,^53,^54,^55,^56,^57,^58,^59,^60,^61,^62,^63, Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.^7,^47,^48, For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% at ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.^47,^48, For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than 4 affected relatives in the same biologic lineage). Thus, the penetrance figures derived from the BCLC may not provide a high level of accuracy for individual patients seeking genetic counseling and testing.

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype . Epidemiologic evidence points to an increased risk of early-onset breast and/or ovarian cancer among first-degree relatives of women with fallopian tube cancers.⁶⁴ Histopathologic examination of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.^65,⁶⁶ A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.⁶⁷ While the true incidence of fallopian tube tumors in BRCA carriers is not known, there is a growing consensus that risk-reducing oophorectomy should be accompanied by prophylactic removal of the fallopian tubes.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,^7,^47,^48,^50,^52,^56,^62,^68, at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.^34,^36,^39,^51,^53,^54,^55,^56,^57,^58,^59,^60,^61, Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,^39,^49,^51,^54,^57,^58,⁶⁰ compared with complete sequencing of the 2 genes required in most populations. The first study of a community-based series was carried out in the Washington, D.C., area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.³⁹ Study participants were tested for 3 founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% CI, 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%-28%). These values were lower than most prior risk estimates. Men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately 2-fold increased risk of prostate cancer in BRCA2 mutation carriers.^54,^69,^70,.

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. Most studies have done molecular testing on the proband only and have done no,^34,^39,^49,^51,^54,^55,^56,^57,^58,^60,^61, or limited,^53,⁶² testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one half of first-degree relatives of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known.³⁶ These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history.⁶¹ Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%-78%) for BRCA1 and 45% (95% CI, 31%-56%) for BRCA2. The penetrances for ovarian cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are average risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings.⁷¹ Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.^61,^72,^73,⁷⁴ Risk of breast cancer appears increased in more recent birth cohorts.^36,^72,

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors, such as differing rates of oophorectomy.^36,^61,^75,^76,^77,⁷⁸ While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are very high, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

The tables titled “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer” and “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Table 2. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer
Cumulative Incidence of Breast Cancer to Given Age# - Outcome is breast OR ovarian cancer * - Incidence to age 55 years& - Incidence to age 75 years@ - Incidence to age 80 yearsBRCA1 BRCA2 BRCA1/2 Population 50 yr 70 yr 50 yr 70 yr 50 yr 70 yr Linkage analysis-maximization of logarithm of the odd (LOD) score —214 breast-ovary families (BCLC) ⁷ 59%82%—BRCA1-linked families (BCLC) ^48,51%85%—237 breast and breast-ovarian cancer families (BCLC) ⁵⁰ 49%71%28%84%Incidence of second cancers after breast cancer —33 BRCA1-linked families (BCLC) ⁴⁷ 73%87%—BRCA1-linked families (BCLC) ⁴⁸ 50%65%Analysis of family members —Jewish ovarian cancer cases, 7 BRCA1, 3 BRCA2 ^49,30%#50%#16%#23%#—Jewish breast-ovary families, 16 BRCA1, 9 BRCA2 ^49,37%#64%#18%#49%#Kin cohort using family and cancer registries —Unselected Icelandic breast cancer patients, 56 female and 13 male BRCA2 995del5 ⁵¹ 17%37%Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes —173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) ^52,37%52%Modified segregation analysis - all available relatives tested (MENDEL) —Australian population-based breast cancer age <40 years, 9 BRCA1, 9 BRCA2 ^53,10%40%Kin cohort —Community-based Washington area Jews, 61 BRCA1, 59 BRCA2 ³⁹ 38%59%26%51%33%56%—Jewish women with breast cancer, 34 BRCA1, 15 BRCA2 ⁵⁴ 60%28%—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 ⁵⁷ 31%*44%&6%*37%&—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 ³⁴ 68%@14%@Modified segregation analysis (MENDEL) —Breast cancer cases age <55 years, 8 BRCA1, 16 BRCA2 ^55,32%47%18%56%21%54%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 ⁵⁶ 39%72%19%71%—Unselected cases ovarian cancer, 12 BRCA1 ^56,34%50%—164 BRCA2-positive families from BCLC ⁵⁹ 41%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^61,38%65%15%45%—Australian multiple-case families, 28 BRCA1, 23 BRCA2 ⁶² 48%74%Relative risk times population rates —Jewish hospital-based ovarian cancer patients, 103 BRCA1, 44 BRCA2 founder mutations ^58,18%59%6%38%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive —Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 ^36,39%69%34%74%Mendelian retrospective likelihood approach —U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 ^63,46%43%

Table 3. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer
Cumulative Incidence of Ovarian Cancer to Given Age & - Incidence to age 75 years@ - Incidence to age 80 yearsBRCA1 BRCA2 BRCA1/2 Population 50 yr 70 yr 50 yr 70 yr 50 yr 70 yr Incidence of second cancers after breast cancer —33 BRCA1-linked families (BCLC) ^47,29%44%—BRCA1-linked families (BCLC) ^48,29%44%Linkage analysis - maximization of LOD score —BRCA1-linked families (BCLC) ^48,23%63%—237 breast and breast-ovarian cancer families (BCLC) ^50,0%27%Kin cohort —Community-based Washington area Jews, 61 BRCA1, 59 BRCA2 ^39,8%16%5%18%7%16%—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 ^34,36%@10%@Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes —173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) ^52,3%16%Modified segregation analysis (MENDEL) —Breast cancer cases age <55 years, 8 BRCA1, 16 BRCA2 ^55,11%36%3%10%4%16%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 ^56,17%53%1%31%—Unselected cases ovarian cancer, 12 BRCA1 ^56,21%68%—164 BRCA2-positive families from BCLC ^59,14%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^61,13%39%1%11%Relative risk times population rates —Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 ^57,>40%&20%&—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^60,11%37%3%21%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive —Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 ^36,21%46%2%12%Mendelian retrospective likelihood approach —U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 ^63,40%22%

Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation

Statistics regarding the percentage of women found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing, but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

General non-Ashkenazi Jewish population: 1 in 500 (.002%).^79,

Women with breast cancer (all ages): 1 in 50 (2%).^80,

Women with breast cancer (younger than 40 years): 1 in 11 (9%).^81,

Men with breast cancer (regardless of age): 1 in 20 (5%).^82,

Women with ovarian cancer (all ages): 1 in 10 (10%).^34,^83,

Among Ashkenazi Jewish individuals (likelihood of having one of 3 founder mutations):

General Ashkenazi Jewish population: 1 in 40 (2.5%).^39,

Women with breast cancer (all ages): 1 in 10 (10%).^36,

Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).^36,^84,^85,

Men with breast cancer (regardless of age): 1 in 5 (19%).^86,

Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).^57,^67,^87,

Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. These studies have used populations derived from clinical referral centers.^33,^88,^89,^90,^91,^92,⁹³ Personal characteristics associated with an increased likelihood of a BRCA1 or BRCA2 mutation include the following:

Breast cancer diagnosed at an early age.

Bilateral breast cancer.

A history of both breast and ovarian cancer.

The presence of breast cancer in 1 or more male family members.^33,^88,^89,^90,^93,

Family history characteristics associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation include the following:

Multiple cases of breast cancer in the family.

Both breast and ovarian cancer in the family.

One or more family members with 2 primary cancers.

Ashkenazi Jewish background.^33,^88,^89,^90,

The likelihood of having a BRCA mutation can vary from one individual to the next based on their country of origin, ethnicity, and family history of cancer. The models outlined in the table titled Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation take these factors into account and assist in providing tailored risk assessments . Another model, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), was developed in 2004 to assess both breast and ovarian cancer risks and the probabilities of carrying a BRCA1/2 mutation.⁹⁴ This model appears to perform well, particularly in the situation of a family history of breast cancer, compared to the Claus and BRCAPRO models, but because of its complexity, it is not readily applied in a clinical setting and is not included in the following table.

Table 4. Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation
Couch ^33,Shattuck-Eidens ^88,Frank ^90,Parmigiani ^93,CSGE = conformation sensitive gel electrophoresis Gene BRCA1BRCA1BRCA1 and BRCA2BRCA1 and BRCA2Study population 169 women with breast cancer and family history of breast cancer and/or ovarian cancer 798 women with either early-onset breast cancer or ovarian cancer, or with family history of breast or ovarian cancer 238 women with breast cancer diagnosed at age <50 years or with ovarian cancer, with at least 1 first-degree or second-degree relative with breast cancer <50 years or ovarian cancer Statistical model (BRCAPRO) Proband characteristics Proband may or may not have breast or ovarian cancer Proband must be affected with breast cancer and/or ovarian cancer Proband must be affected with breast cancer <50 years or ovarian cancer Proband may or may not have breast or ovarian cancer Takes into account bilateral breast cancer and age of onset of proband Takes into account probands with bilateral breast cancer and those with both breast and ovarian cancer Consideration of proband’s current age or age at diagnosis of breast or ovarian cancer Special consideration for probands with breast cancer <40 years Takes into account: - Bilateral breast cancer and those with breast cancer, ovarian cancer, or breast and ovarian cancer at any age - Male breast cancer - BRCA1/2 mutation status Family history characteristics Family must have >2 cases of breast cancer May or may not have affected relatives Must have first-degree relative with breast cancer <50 years or ovarian cancer Includes all first-degree relatives and second-degree relatives with and without cancer Takes into account proband or relatives with breast and/or ovarian cancer Takes into account relatives with breast and/or ovarian cancer Takes into account additional relatives with breast cancer <50 years or ovarian cancer Takes into account:Uses average age at diagnosis of breast cancers Does not take into account age of onset of cancer or bilateral breast cancer in relatives - Relatives with male or female breast cancer Takes into account Ashkenazi Jewish ancestry Takes into account Ashkenazi Jewish ancestry - Female relatives with ovarian cancer or breast and ovarian cancer - Current age or age at death and age at diagnosis of breast cancer and ovarian cancer - Ashkenazi Jewish ancestry - BRCA1/2 mutation status Provides risk estimate for Composite family probability Proband (who has breast or ovarian cancer) Proband (who has breast cancer <50 years or ovarian cancer) Any affected or unaffected family member Limitations Does not estimate likelihood of BRCA2 mutation Does not estimate likelihood of BRCA2 mutation Not applicable to women diagnosed with breast cancer at ≥ 50 years Requires computer software and time-consuming data entryNot applicable to families with site-specific ovarian cancer Further calculation required for unaffected relatives Further calculation required for unaffected relatives Incorporates only first-degree relatives and second-degree relatives; may need to change proband to best capture risk Does not take into account bilaterality or male breast cancer Underestimates risk with multiple affected members Combined data for Ashkenazi Jewish and non-Jewish families so it may overestimate risk for non-Jewish probands and underestimate risk for Jewish probands Has been validated in a high-risk genetic counseling clinic ^95,Some estimates are based on small sample size Validity in moderate family histories unknown Further calculation required for unaffected relatives Because testing used CSGE, may underestimate mutation likelihood Best application Families with 1 or more cases of breast cancer, Ashkenazi Jewish families, and families with multiple affected members Families with small number of affected members Families with 2 first-degree relatives with breast cancer <50 years or ovarian cancer Widely applicable. Performs equally well in African American families as in Caucasian families.^21,Provides likelihood of either BRCA1 or BRCA2 mutation Only model to incorporate unaffected relatives, male breast cancer, bilateral breast cancer, and age at diagnosis for all affected individuals Provides likelihood of either BRCA1 or BRCA2 mutation Program also provides Couch, Shattuck-Eidens and Frank risk estimates

Genetic testing for BRCA1 and BRCA2 has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This in turn gives providers better data to estimate an individual patient’s risk of carrying a mutation. There remains an art to risk assessment in practitioners’ selection of the best model to fit their individual patient’s circumstances and consideration of factors that might limit the ability to provide an accurate risk assessment (i.e., small family size or paucity of women).

Role of BRCA1 and BRCA2 in Sporadic Cancer

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. To date, only weak connections have been made between these genes and sporadic breast and ovarian cancer. Studies of tumor tissue from sporadic breast cancers have detected no somatic BRCA1 mutations and a very low frequency of BRCA2 mutations.^96,^97,^98,^99,¹⁰⁰ In ovarian cancer tumor tissue, however, BRCA1 mutations appear to occur with some frequency. In an unselected series of 103 ovarian cancers, 7 disease-causing mutations in BRCA1 were found that were not present in normal tissue of these patients.¹⁰¹ Another series of 221 ovarian cancers analyzed for mutations in BRCA1 identified 15 somatic mutations and 18 tumors with evidence of BRCA1 dysfunction due to hypermethylation.^102,

Since few somatic BRCA1 and BRCA2 mutations are seen in sporadic breast tumors, other mechanisms for the inactivation of these tumor suppressor genes have been investigated. In particular, decreased expression of wild-type BRCA1 may occur on an epigenetic basis, i.e., as a result of DNA methylation or other physiological change that results in loss of gene expression, an event that in turn leads to cancer. In support of this hypothesis, artificially decreasing expression of BRCA1 using antisense oligonucleotides resulted in accelerated growth of mammary epithelial cells in culture.¹⁰³ Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.^103,^104,^105,^106,¹⁰⁷ Similar findings have not been reported for BRCA2, though the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.^108,^109,

Taken together, current pathologic, cytogenetic, and gene expression data suggest not only that inactivation of BRCA1 and BRCA2 plays a role in sporadic cancer, but also that there are biologic differences between BRCA1-related, BRCA2-related, and sporadic breast cancers. A clear understanding of these differences (and similarities) has not yet been reached.^110,^111,^112,^113,^114,

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.^9,⁵⁰ This is the region of the gene containing the BRC repeats, which have been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region.^59, In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401-4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191.¹¹⁵ These observations have generally been confirmed in subsequent studies.^61,^62,¹¹⁶ Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene.^60,¹¹⁷ The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 in BRCA2:6174delT mutation carriers.^60,¹¹⁷ None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management.

Additional evidence exists that this region of BRCA2 contains a specific functional domain. Of the 5 different homozygous BRCA2 knockout mice constructed by independent laboratories, 3 lead to embryonic lethality during the first 10 days of gestation.^118,^119,¹²⁰ The other 2 knockouts yield viable full-term mice that can survive to adulthood.^121,¹²² The dramatic difference in phenotype correlates with the position of the BRCA2 mutation. The mice that die in utero contain a truncation in the BRCA2 gene before a series of repeated sequences in the large exon 11, while in those mice that can come to term, some copies of these repeats are retained. The repeats themselves have been shown to be the site of interaction of the Rad51 protein, suggesting that Rad51 binding is critical in determining the function of BRCA2 both during development and neoplasia.¹²³

Genetic changes associated with BRCA1- and BRCA2-related cancers are just beginning to be examined. Mutations in TP53 seem to be much more frequent in BRCA1 breast cancers (20/26) and somewhat more frequent in BRCA2-associated breast cancers (10/22) than in grade-matched sporadic cancers (7/20).¹²⁴ BRCA mutation-associated cancers contain TP53 mutations not typically found in sporadic breast cancer, and 12 individual hereditary breast cancers were shown to contain more than a single TP53 mutation. This raised the issue that mutations of BRCA1 and BRCA2 may confer a mutator phenotype allowing the general accumulation of a high rate of genetic abnormalities. Analysis of the coding sequence from the I-ran and Pancho oncogenes and the a-globin gene revealed no increase in mutations in BRCA mutation-associated breast cancers. In addition, no evidence was seen of the microsatellite instability characteristic of HNPCC associated cancers. Therefore, TP53 inactivation (or perhaps gain of function mutations) may be specifically selected for during BRCA1 and BRCA2 tumor progression.

A genome-wide screening for chromosomal gains or losses was performed on BRCA1 and BRCA2 breast cancers to determine the presence of other associated genetic hot-spots.¹¹¹ On the whole, BRCA-associated cancers had more regions that were amplified or deleted compared with controls (not stage matched and grade matched), suggesting a generalized increase in large-scale genomic instability. Specifically, chromosomes 5q, 4q, and 4p had very frequent LOH in BRCA1 tumors, while BRCA2 tumors were characterized by losses at 13q (near the BRCA2 locus itself) and 6q and chromosomal gains at 17q (outside of the HER2/neu locus) and 20q. LOH of both chromosomes 13 and 17 have been found simultaneously in a series of sporadic ovarian cancers, suggesting a synergistic mechanism.¹²⁵ In addition, the oncogene MYC on chromosome 8q24 was found to be amplified in 48% of 60 BRCA1-related breast cancers versus 14% of non-BRCA1 tumors.^126,

Pathology/Prognosis of Breast Cancer

BRCA1

Pathology

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, though historically, medullary, tubular, and lobular histologies have been associated with familial breast cancer.¹²⁷ Other studies have noted an excess of medullary histology in multicase families.^128,¹²⁹ Since the identification of the BRCA1 and BRCA2 genes, several studies have evaluated the distinct pathologic patterns seen in known hereditary breast cancers. Medullary histology was significantly more common (19% vs. 0%) in a series of BRCA1-associated breast cancer compared with sporadic cases in a study from France,¹³⁰ in carriers from the Breast Cancer Linkage Consortium,^131,, in a Swedish population-based study of breast cancer cases from high-risk families,¹³² and among women with early-onset breast cancer in a population-based study,¹³³ suggesting that medullary histology itself may be an indication for BRCA1 testing.

The Breast Cancer Linkage Consortium reported a relative lack of an in situ component in BRCA1-associated breast cancers.¹³¹ Data from the Mayo Clinic cohort of women undergoing mastectomy, however, found a significantly lower prevalence of hyperplastic lesions in BRCA1/2 mutations, but no difference in the prevalence of in situ lesions.¹³⁴ A population-based case-control study of ductal carcinoma in situ patients also found the prevalence of BRCA mutations to be similar in these women, as previously reported in studies of invasive breast cancer patients.¹³⁵ Therefore, it appears that ductal carcinoma in situ is a component of the hereditary breast ovarian cancer syndrome.

The recent development of gene-expression technology has created the potential to increase the specificity of the classification of breast cancer at the molecular level. Global gene expression profiles of tumors with BRCA1 and BRCA2 mutations and sporadic tumors differed significantly from each other in one small series.¹³⁶ Using comparative genomic hybridization (CGH), investigators from the Netherlands were able to develop a profile of distinct somatic genetic alterations, which can identify BRCA1-associated tumors with an accuracy of 84%.¹³⁷ Another study using tissue microarray technology to compare BRCA1, BRCA2, and sporadic tumors found that BRCA1 tumors were more likely to be BCL2-negative and to express high levels of P-cadherin.^138,

One potentially unifying hypothesis is that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. These tumors characteristically exhibit higher-grade features, areas of necrosis, and frequent TP53 mutations.¹³⁹ They are typically estrogen receptor–negative, are HER2-negative, and they stain positive for cytokeratin 5/6, 14, or 17, which are markers of basal epithelium.^140,^141,¹⁴² A study of 76 estrogen receptor–negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely (88% vs. 45% in BRCA1-negative subjects) to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.¹³⁹ Two additional studies of invasive breast cancers occurring in BRCA1 mutation carriers not selected for estrogen receptor status found that 78% of 27 tumors ¹⁴² and 61% of 182 tumors ¹⁴³ were positive for basal epithelial markers. Among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype.¹⁴⁴ If, in fact, the basal epithelial cells of the breast represent the breast stem cells, the sugg