Genetics of Breast and Ovarian Cancer (PDQ®) - National Cancer Institute

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Genetics of Breast and Ovarian Cancer (PDQ®) - National Cancer Institute

Table of Contents

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         Physical activity and anthropometry         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

High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes

BRCA1 and BRCA2         Introduction         BRCA1         BRCA2         BRCA1 and BRCA2 function         Mutations in BRCA1 and BRCA2         Population estimates of the likelihood of having a BRCA1 or BRCA2 mutation         Clinical criteria and models for prediction of the likelihood of a BRCA1 or BRCA2 mutation         Penetrance of mutations         Role of BRCA1 and BRCA2 in sporadic cancer         Genotype-phenotype correlations         Pathology of breast cancer         Pathology of ovarian cancer         Clinical management of BRCA mutation carriers Other High-Penetrance Syndromes Associated with Breast and/or Ovarian Cancer         Lynch syndrome         Li-Fraumeni syndrome         Cowden syndrome         Peutz-Jeghers syndrome (PJS)         De novo mutation rate

Low- and Moderate-Penetrance Genes Associated With Breast and/or Ovarian Cancer

Background Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches         CHEK2         ATM         BRIP1         PALB2         CASP8 and TGFB1         RAD51         Abraxas Genome-Wide Searches

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction Uptake of Genetic Counseling and Genetic Testing         Degree of uptake of genetic counseling and genetic testing         Factors influencing uptake of genetic counseling and genetic testing         Uptake of genetic counseling and genetic testing in diverse populations         Factors associated with declining genetic counseling and testing         Genetic counseling and testing in children 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         Children         Prenatal diagnosis and preimplantation genetic diagnosis Cultural/Community Effects Ethical Concerns Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer         Decision aids for persons considering risk management options for hereditary breast and ovarian cancer         Uptake of cancer risk management options         Cancer screening and risk-reducing behaviors Psychosocial Outcome Studies         Risk-reducing mastectomy         Risk-reducing salpingo-oophorectomy Interventions: Psychological Behavioral Outcomes

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Introduction

General Information

 [Note: 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.]

 [Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2014, an estimated 235,030 new cases will be diagnosed, and 40,430 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptor–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Women’s Health Initiative (WHI).[2] An estimated 21,980 new cases of ovarian cancer are expected in 2014, with an estimated 14,270 deaths. Ovarian cancer is the fifth most deadly cancer in women.[1] (Refer to the PDQ summaries on Breast Cancer Treatment and Ovarian Epithelial Cancer Treatment for more information about 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 some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant 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 families. (Refer to the PDQ summary Cancer Genetics Overview for more information about 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 (FDR) or a second-degree relativewith breast cancer.[3-6] The risk conferred by a family history of breast cancer has been assessed in 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 an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2).[7] Risk increases with the number of affected relatives, age at diagnosis, and the number of affected male relatives.[4,5,7,8] (Refer to the Penetrance of mutations section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 mutations who themselves test negative for the family mutation.)

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 of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.[9]

Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancerpredisposition 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 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 the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and ofCowden syndrome due to PTEN mutations.[10] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene andPeutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (OMIM).[10] Germlinemutations in the genes responsible for those syndromes 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:

• Multiple cancers within a family.
• 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 cancer and ovarian cancer in the same individual).
• Cases of male breast cancer.

Figure 1 and Figure 2 depict some of the classic inheritance features of a deleterious BRCA1 andBRCA2 mutation, respectively. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)

Enlarge

Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA1 mutation across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

Enlarge

Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA2 mutation across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor–negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary 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%.[11,12]

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 Breast Cancer Prevention for more information.) These factors, including their role in the etiology of breast cancer among BRCA1/BRCA2 mutation carriers, are considered in more detail in other reviews.[13-15] Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (Refer to the Clinical management of BRCA mutation carriers section of this summary for more information about their effects in BRCA1/BRCA2 mutation carriers.)

Age

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[16] 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

In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. In BRCA1 and BRCA2 mutation carriers, results have been conflicting and may be gene dependent. No consistent significant associations have been observed.[15,17-19] Evidence suggests that reproductive history may be differentially associated with breast cancer subtype (i.e., triple-negative vs. ER-positive breast cancers). In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.[20]

Oral contraceptives

Oral contraceptives (OCs) 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 OC use did not vary in relationship to a family history of breast cancer.[21]

OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers.[22] However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04).[22] (Refer to the Reproductive factors section in the Clinical management of BRCA mutation carriers section of this summary for more information.)

Hormone replacement therapy

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal 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.[23] The WHI, a randomized controlled trial (NCT00000611) of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[24,25] 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.[26] 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.[27]

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.[28-32,23] 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.[32] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested forBRCA1/BRCA2 mutations.[25] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[23,33] 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.[34] (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)

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 or BRCA2 mutations,[35-38] and in association with germline ATM and TP53mutations.[39,40]

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 BRCA2mutation 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.[41] Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results.[42-46] A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years.[46] (Refer to the Mammography section in the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section of this summary for more information about radiation.)

Alcohol intake

The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population.[47,48] Prior studies of BRCA1/BRCA2mutation carriers have found no increased risk associated with alcohol consumption.[49,50]

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.[51] 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.[52]

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).[53] There may also be an association between BBD and family history of breast cancer.[54]

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[53,55,56] and breast density is likely to have a genetic component in its etiology.[57-59]

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 women who are in specific genotypically defined subgroups. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer.[60] One study [61] found a reduced risk of breast cancer amongBRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.[62]

Other Risk Factors for Ovarian Cancer

Factors that increase risk of ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of OCs.[63,64] (Refer to the PDQ summary onPrevention 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 theReproductive factors section of this summary 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.[65]

Reproductive history

Nulliparity is consistently associated with an increased risk of ovarian cancer, including amongBRCA1/BRCA2 mutation carriers.[66] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[63,67] 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.[68-71]

Surgical history

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[63,72,73] including in BRCA1/BRCA2 mutation carriers.[74] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[75,76] (Refer to the Risk-reducing salpingo-oophorectomysection of this summary for more information about these studies.)

Oral contraceptives

Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[63,64] A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers.[66,77-80] A meta-analysis of 18 studies including 13,627 BRCA mutation carriers reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use.[22] (Refer to the Oral contraceptives section in theChemoprevention section of this summary for more information.)

Models for Prediction of Breast Cancer Risk

Models to predict an individual’s lifetime risk of developing breast cancer are available.[81,82] In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about these models.) 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. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models.[82,83] Table 1 summarizes the salient aspects of two of the common risk assessmentmodels and is designed to aid in choosing the model that best applies to a particular individual.

The Claus model [84,85] and the Gail model [86] are widely used in research studies and clinicalcounseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models, which include more detailed family history information, are also in use and are discussed below.

Table 1. Characteristics of the Gail and Claus Models^a