Purpose of This PDQ Summary
Introduction

General Information Family History as a Risk Factor for Breast Cancer Family History as a Risk Factor for Ovarian Cancer Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk Other Risk Factors for Breast Cancer         Age         Reproductive and menstrual history         Oral contraceptives         Radiation exposure         Alcohol intake         Benign breast disease and mammographic density         Other factors Other Risk Factors for Ovarian Cancer         Age         Reproductive history         Surgical history         Oral contraceptives Models for Prediction of Breast Cancer Risk

Major Genes

Introduction BRCA1 BRCA2 BRCA1 and BRCA2 Function Mutations in BRCA1 and BRCA2         Variants of uncertain significance Prevalence and Founder Effects Penetrance of Mutations Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation Role of BRCA1 and BRCA2 in Sporadic Cancer Genotype-Phenotype Correlations Pathology/Prognosis of Breast Cancer         BRCA1         BRCA2 Pathology/Prognosis of Ovarian Cancer         Pathology         Prognosis Other Rare Breast and Ovarian Cancer Associated Syndromes         Li-Fraumeni syndrome         Cowden syndrome         Peutz-Jeghers syndrome

Low Penetrance Predisposition to Breast and Ovarian Cancer

Background Confirmed Candidate Breast Cancer Susceptibility Genes         CHEK2         ATM         BRIP1         PALB2         CASP8 and TGFB1 Genome-Wide Searches

Interventions

Breast Cancer         Screening         Risk modification         Breast conservation therapy for BRCA1/2 mutation carriers         Role of BRCA1 and BRCA2 in response to chemotherapy Ovarian Cancer         Screening         Risk Modification

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction Interest in and Uptake of Genetic Testing What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics Genetic Counseling for Hereditary Predisposition to Breast Cancer Emotional Outcomes of Individuals Family Effects         Family communication about genetic testing and hereditary risk         Family functioning         Partners of high-risk women         At-risk males         Children         Reproductive issues Cultural/Community Effects Ethical Concerns Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer         Cancer screening and risk-reducing behaviors Psychosocial Outcome Studies         Risk-reducing mastectomy         Risk-reducing salpingo-oophorectomy Interventions: Psychological Behavioral Outcomes

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Changes to This Summary (09/15/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board ¹.

The following information is included in this summary:

• Family history and other risk factors for breast and ovarian cancer.
• Models for predicting breast cancer risk.
• Major genes associated with breast and ovarian cancer risk.
• Screening and risk modification for hereditary breast and ovarian cancer.
• Psychosocial issues associated with hereditary breast and ovarian cancer and genetic testing.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview ².

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary breast and ovarian cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

General Information

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms ³. 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 2008, an estimated 182,460 new cases will be diagnosed, and 40,480 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptor-positive cancers occurring after age 50 years, has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy following early reports from the Women’s Health Initiative.[2] Ovarian cancer is the eighth most common cancer, with an estimated 21,650 new cases in 2008, but is the fifth most deadly, with an estimated 15,520 deaths in 2008.[1] (Refer to the PDQ summary on Breast Cancer Treatment ⁴ and Ovarian Epithelial Cancer Treatment ⁵ 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 ⁶ and the Family History as a Risk Factor for Ovarian Cancer ⁷ 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 ² 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.

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.[3-6] 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.[7] In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).[7] Risk increases with the number of affected relatives and age at diagnosis.[4,5,7] Refer to the Penetrance of Mutations ⁸ section for a discussion of familial risk for women from families with BRCA1/2 mutations who themselves test negative for the family mutation.

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.[8]

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. The syndromes most strongly associated with both cancers are BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome ⁹ due to TP53 mutations; of Cowden syndrome ¹⁰ due to PTEN mutations; and with mutations in CHEK2 ¹¹ .[9] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene ¹² and Peutz-Jeghers syndrome ¹³. Ovarian cancer has also been associated with Lynch syndrome ¹⁴, basal cell nevus (Gorlin) syndrome (OMIM ¹⁵), and multiple endocrine neoplasia type 1 (MEN1) (OMIM ¹⁶).[9] Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

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 ¹⁷ section of this summary for more information.)

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers with those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are unlikely to be of mucinous or borderline histopathology. [Refer to the Pathology/Prognosis of Breast Cancer ¹⁸ and Pathology/Prognosis of Ovarian Cancer ¹⁹ sections for more information.]

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%.[10,11]

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 ²⁰ for more information.) These factors are considered in more detail in numerous reviews,[12,13] including among BRCA1/BRCA2 mutation carriers.[14] 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 ²¹ later in this document.)

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[15] 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.

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.[14,16]

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.[17]

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.[18-20]

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 RR 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.[21] The Women's Health Initiative ²² (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits 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.[22,23] Adverse outcomes prompting closure included 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) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom.[24] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[25]

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.[26-30,21] 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.[23] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[21,31] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[32]

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,[33-36] and in association with germline ATM and TP53 mutations.[37,38] 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.[39] 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.[40,41] (Refer to text on Radiation ²³ in the Interventions ²¹ section of this summary for more information.)

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.[42,43] One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.[44]

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.[45] 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.[46]

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).[47] There may also be an association between benign breast disease and family history of breast cancer.[48]

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[47,49,50] and breast density may have a genetic component in its etiology.[51-53]

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.[54] One study [55] 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.[56]

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and oral contraceptives.[57,58] (Refer to the PDQ summary on Prevention of Ovarian Cancer ²⁴ 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 ²⁵ section for more information.)

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.[59]

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.[60] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[57,61] 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.[62-65]

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[57,66,67] including in BRCA1/BRCA2 mutation carriers.[68] Ovarian cancer risk is reduced more than 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.[69,70] For further information on these studies refer to the Risk-Reducing Salpingo-Oophorectomy ²⁶ section of this summary.

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[57,58] A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.[60,71-74]

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 ²⁷ 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 ²⁸, 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 [75,76] and the Gail model,[77] are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two 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 ²⁹ for more information on Taking a Family History ³⁰.) Generally, the Claus or Gail models should not be the sole model used for families with one of the following characteristics:

• Three individuals with breast or ovarian cancer (especially when one 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 one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

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.[81-85] 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:

• Nonadherent women (i.e., does not adhere to screening recommendations).[81,82]
• Women in the highest risk strata.[84]

Risk could be underestimated in the lowest risk strata.[84] Earlier studies [81,82] suggested risk was overpredicted in younger women and underpredicted in older women. More recent studies [83,84] 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.[85]

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.[86] The two 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 ³², 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.

The Tyrer-Cuzick model incorporates both genetic and non-genetic factors.[87] A three generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The BOADICEA model examines family history to estimate breast cancer risk, and also incorporates both BRCA1/2 and non-BRCA1/2 genetic risk factors.[88]

Other models incorporating breast density have been developed, but are not ready for clinical use.[89,90] In the future, models may be developed or refined to include such factors as breast density and other biomarkers.

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41. Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.  [PUBMED Abstract]
    
    
42. Smith-Warner SA, Spiegelman D, Yaun SS, et al.: Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279 (7): 535-40, 1998.  [PUBMED Abstract]
    
    
43. Hamajima N, Hirose K, Tajima K, et al.: Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87 (11): 1234-45, 2002.  [PUBMED Abstract]
    
    
44. McGuire V, John EM, Felberg A, et al.: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 15 (8): 1565-7, 2006.  [PUBMED Abstract]
    
    
45. McTiernan A: Behavioral risk factors in breast cancer: can risk be modified? Oncologist 8 (4): 326-34, 2003.  [PUBMED Abstract]
    
    
46. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.  [PUBMED Abstract]
    
    
47. Chen J, Pee D, Ayyagari R, et al.: Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst 98 (17): 1215-26, 2006.  [PUBMED Abstract]
    
    
48. Dupont WD, Page DL, Parl FF, et al.: Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 331 (1): 10-5, 1994.  [PUBMED Abstract]
    
    
49. Boyd NF, Byng JW, Jong RA, et al.: Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87 (9): 670-5, 1995.  [PUBMED Abstract]
    
    
50. Byrne C, Schairer C, Wolfe J, et al.: Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87 (21): 1622-9, 1995.  [PUBMED Abstract]
    
    
51. Pankow JS, Vachon CM, Kuni CC, et al.: Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 89 (8): 549-56, 1997.  [PUBMED Abstract]
    
    
52. Boyd NF, Lockwood GA, Martin LJ, et al.: Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst 91 (16): 1404-8, 1999.  [PUBMED Abstract]
    
    
53. Vachon CM, King RA, Atwood LD, et al.: Preliminary sibpair linkage analysis of percent mammographic density. J Natl Cancer Inst 91 (20): 1778-9, 1999.  [PUBMED Abstract]
    
    
54. Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.  [PUBMED Abstract]
    
    
55. Brunet JS, Ghadirian P, Rebbeck TR, et al.: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90 (10): 761-6, 1998.  [PUBMED Abstract]
    
    
56. Ghadirian P, Lubinski J, Lynch H, et al.: Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer 110 (3): 413-6, 2004.  [PUBMED Abstract]
    
    
57. Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136 (10): 1184-203, 1992.  [PUBMED Abstract]
    
    
58. John EM, Whittemore AS, Harris R, et al.: Characteristics relating to ovarian cancer risk: collaborative analysis of seven U.S. case-control studies. Epithelial ovarian cancer in black women. Collaborative Ovarian Cancer Group. J Natl Cancer Inst 85 (2): 142-7, 1993.  [PUBMED Abstract]
    
    
59. Amos CI, Struewing JP: Genetic epidemiology of epithelial ovarian cancer. Cancer 71 (2 Suppl): 566-72, 1993.  [PUBMED Abstract]
    
    
60. Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.  [PUBMED Abstract]
    
    
61. Brinton LA, Lamb EJ, Moghissi KS, et al.: Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 103 (6): 1194-203, 2004.  [PUBMED Abstract]
    
    
62. Rodriguez C, Patel AV, Calle EE, et al.: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285 (11): 1460-5, 2001.  [PUBMED Abstract]
    
    
63. Riman T, Dickman PW, Nilsson S, et al.: Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 94 (7): 497-504, 2002.  [PUBMED Abstract]
    
    
64. Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.  [PUBMED Abstract]
    
    
65. 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.  [PUBMED Abstract]
    
    
66. Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.  [PUBMED Abstract]
    
    
67. 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.  [PUBMED Abstract]
    
    
68. 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.  [PUBMED Abstract]
    
    
69. 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.  [PUBMED Abstract]
    
    
70. 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.  [PUBMED Abstract]
    
    
71. 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.  [PUBMED Abstract]
    
    
72. 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.  [PUBMED Abstract]
    
    
73. 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.  [PUBMED Abstract]
    
    
74. 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.  [PUBMED Abstract]
    
    
75. Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.  [PUBMED Abstract]
    
    
76. Claus EB, Risch N, Thompson WD: The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 28 (2): 115-20, 1993.  [PUBMED Abstract]
    
    
77. 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.  [PUBMED Abstract]
    
    
78. 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.  [PUBMED Abstract]
    
    
79. 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.  [PUBMED Abstract]
    
    
80. Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.  [PUBMED Abstract]
    
    
81. 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.  [PUBMED Abstract]
    
    
82. 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.  [PUBMED Abstract]
    
    
83. 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.  [PUBMED Abstract]
    
    
84. 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.  [PUBMED Abstract]
    
    
85. Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.  [PUBMED Abstract]
    
    
86. 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.  [PUBMED Abstract]
    
    
87. Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004.  [PUBMED Abstract]
    
    
88. Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.  [PUBMED Abstract]
    
    
89. Barlow WE, White E, Ballard-Barbash R, et al.: Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst 98 (17): 1204-14, 2006.  [PUBMED Abstract]
    
    
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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 four relatives in the same biologic line affected) is not present. However, it has long been recognized that in some families, there is hereditary breast cancer which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations through either the maternal or paternal lines in an apparent autosomal dominant pattern of transmission and familial association with tumors of other organs, particularly the ovary and prostate gland.[1,2] We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, only 5% to10% of individuals who develop breast cancer are known to carry highly penetrant gene mutations.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[3] 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. Other genes, such as the mismatch repair genes MLH1 and MSH2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

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.[4] 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.[5] The BRCA1 gene (OMIM ³⁴) was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance section ⁸ for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in 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 ³⁵) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.[8-13] (Refer to the Penetrance section ⁸ for more information.) BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[14] 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. In tumors associated with both BRCA1 and BRCA2 mutations there is often loss of the wild-type (unmutated) allele.

Mutations in BRCA1 and BRCA2 appear 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.[15]

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one 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.[16,17]

In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in a myriad of functions within cells including homologous DNA repair, genomic stability, transcriptional regulation and cell cycle control.[18,19]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[20] 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.[21] 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.[22-24]

Germline deleterious 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.[25] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a 3-year period.[26] 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.[27,28] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. Variant tracking is accomplished by testing parents and all affected family members (these costs are 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 [27,29-32] 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).[33] Functional studies that measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 have been employed as well.[34,35] When attempting to interpret a VUS, all available information should be examined.

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 mo