National Cancer Institute


Posted Date: Jan 26, 2016

Expert-reviewed information summary about the genetics of breast and gynecologic cancers, 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 gynecologic cancers in individuals who may be genetically susceptible to these diseases. Psychosocial issues associated with genetic testing are also discussed.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and gynecologic cancers. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Genetics of Breast & Gynecologic Cancers

Genetics of Breast and Gynecologic Cancers

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.

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 2015, an estimated 234,190 new cases will be diagnosed, and 40,730 deaths from breast cancer will occur. 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). An estimated 21,290 new cases of ovarian cancer are expected in 2015, with an estimated 14,180 deaths. Ovarian cancer is the fifth most deadly cancer in women. An estimated 54,870 new cases of endometrial cancer are expected in 2015, with an estimated 10,170 deaths. (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial 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 (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), 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.

Risk Factors for Breast Cancer

Refer to the PDQ summary on Breast Cancer Prevention for information about risk factors for breast cancer in the general population.

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 relative with breast cancer. 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. 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). Risk increases with the number of affected relatives, age at diagnosis, the occurrence of bilateral or multiple ipsilateral breast cancers in a family member, and the number of affected male relatives. A large population-based study from the Swedish Family Cancer Database confirmed the finding of a significantly increased risk of breast cancer in women who had a mother or a sister with breast cancer. The hazard ratio (HR) for women with a single breast cancer in the family was 1.8 (95% CI, 1.8–1.9) and was 2.7 (95% CI, 2.6–2.9) for women with a family history of multiple breast cancers. For women who had multiple breast cancers in the family, with one occurring before age 40 years, the HR was 3.8 (95% CI, 3.1–4.8). However, the study also found a significant increase in breast cancer risk if the relative was aged 60 years or older, suggesting that breast cancer at any age in the family carries some increase in risk. (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.)

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

In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. There may be an increased risk of breast cancer in BRCA1 and BRCA2 mutation carriers with pregnancy at a younger age (before age 30 years), with a more significant effect seen for BRCA1 mutation carriers. Likewise, breast feeding can reduce breast cancer risk in BRCA1 (but not BRCA2) mutation carriers. Regarding the effect of pregnancy on breast cancer outcomes, neither diagnosis of breast cancer during pregnancy nor pregnancy after breast cancer seems to be associated with adverse survival outcomes in women who carry a BRCA1 or BRCA2 mutation. Parity appears to be protective for BRCA1 and BRCA2 mutation carriers, with an additional protective effect for live birth before age 40 years.

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.

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. 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). (Refer to the Reproductive factors section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information.)

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, and in association with germline ATM and TP53 mutations.

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. 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. 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. (Refer to the Mammography section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information about radiation.)

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. Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.

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. 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.

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

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

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. One study found a reduced risk of breast cancer among BRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.

Risk Factors for Ovarian Cancer

Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information about risk factors for ovarian cancer in the general population.

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.

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.

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers, yet a meta-analysis could only identify risk-reduction in women with four or more live births. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid. Several studies have reported a risk reduction in ovarian cancer after OC pill use in BRCA1/BRCA2 mutation carriers; a risk reduction has also been shown after tubal ligation in BRCA1 carriers, with a statistically significant decreased risk of 22% to 80% after the procedure. On the other hand, 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.

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. 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. (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)

Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population. A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers. 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. (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)

Risk Factors for Endometrial Cancer

Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.

Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a woman’s risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause, with the main hereditary endometrial cancer syndrome being Lynch syndrome ( LS), an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals. (Refer to the LS section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years. Women with LS tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.

Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.

Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome (PCOS), and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use. Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer. In contrast, oral contraceptives, the levonorgestrel-releasing intrauterine system, and combination estrogen-progesterone hormone replacement therapy all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.

Autosomal Dominant Inheritance of Breast and Gynecologic Cancer Predisposition

Autosomal dominant inheritance of breast and gynecologic cancers 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 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 of Cowden syndrome due to PTEN mutations. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with LS, basal cell nevus (Gorlin) syndrome ( OMIM), and multiple endocrine neoplasia type 1 (OMIM). LS is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).

Germline mutations in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary 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 or endometrial and colon cancer in the same individual).
  • Cases of male breast cancer. The inheritance risk for autosomal dominant genetic conditions is 50% for both males and females, but the differing penetrance of the genes may result in some unaffected individuals in the family.

Figure 1 and Figure 2 depict some of the classic inheritance features of a deleterious BRCA1 and BRCA2 mutation, respectively. Figure 3 depicts a classic family with LS. (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.)

Pedigree showing some of the classic features of a family with a deleterious BRCA1 mutation across three generations, including transmission occurring through maternal and paternal lineages. The unaffected female proband is shown as having an affected mother (breast cancer diagnosed at age 42 y), female cousin (breast cancer diagnosed at age 38 y), maternal aunt (ovarian cancer diagnosed at age 53 y), and maternal grandmother (ovarian cancer diagnosed at age 49 y).
Figure 1. pedigree. This pedigree shows some of the classic features of a family with a deleterious mutation across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Pedigree showing some of the classic features of a family with a deleterious BRCA2 mutation across three generations, including transmission occurring through maternal and paternal lineages. The unaffected female proband is shown as having an affected brother (breast cancer diagnosed at age 52 y), mother (breast cancer diagnosed at age 45 y and pancreatic cancer diagnosed at age 55 y), maternal aunt (ovarian cancer diagnosed at age 58 y), and maternal grandfather (prostate cancer diagnosed at age 55 y).
Figure 2. pedigree. This pedigree shows some of the classic features of a family with a deleterious 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. families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Pedigree showing some of the classic features of a family with Lynch syndrome across three generations, including transmission occurring through maternal and paternal lineages and the presence of both colon and endometrial cancers.
Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be ER-negative, progesterone receptor–negative, HER2/neu receptor–negative (i.e., triple-negative breast cancers), 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.)

Some pathologic features distinguish LS mutation carriers from noncarriers. The hallmark feature of endometrial cancers occurring in LS is mismatch repair (MMR) defects, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.

Considerations in Risk Assessment and in Identifying a Family History of Breast and Ovarian Cancer Risk

The accuracy and completeness of family histories must be taken into account when they are used to assess risk. 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 does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared 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%. Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Models for Prediction of Breast and Gynecologic Cancer Risk

Models to predict an individual’s lifetime risk of developing breast and/or gynecologic cancer are available. In addition, models exist to predict an individual’s likelihood of having a mutation in BRCA1, BRCA2, or one of the MMR genes associated with LS. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about some of these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to those of 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.

In general, breast cancer risk assessment models are designed for two types of populations: 1) women without a predisposing mutation or strong family history of breast or ovarian cancer; and 2) women at higher risk because of a personal or family history of breast cancer or ovarian cancer. Models designed for women of the first type (e.g., the Gail model, which is the basis for the Breast Cancer Risk Assessment Tool [BCRAT]) , and the Colditz and Rosner model ) require only limited information about family history (e.g., number of first-degree relatives with breast cancer). Models designed for women at higher risk require more detailed information about personal and family cancer history of breast and ovarian cancers, including ages at onset of cancer and/or carrier status of specific breast cancer-susceptibility alleles. The genetic factors used by the latter models differ, with some assuming one risk locus (e.g., the Claus model ), others assuming two loci (e.g., the International Breast Cancer Intervention Study [IBIS] model and the BRCAPRO model ), and still others assuming an additional polygenic component in addition to multiple loci (e.g., the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA] model ). The models also differ in whether they include information about nongenetic risk factors. Three models (Gail/BCRAT, Pfeiffer, and IBIS) include nongenetic risk factors but differ in the risk factors they include (e.g., the Pfeiffer model includes alcohol consumption, whereas the Gail/BCRAT does not). These models have limited ability to discriminate between individuals who are affected and those who are unaffected with cancer; a model with high discrimination would be close to 1, and a model with little discrimination would be close to 0.5; the discrimination of the models currently ranges between 0.56 and 0.63). The existing models generally are more accurate in prospective studies that have assessed how well they predict future cancers.

In the United States, BRCAPRO, the Claus model, and the Gail/BCRAT are widely used in clinical counseling. Risk estimates derived from the models differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.

Two risk predictions models have been developed for ovarian cancer. The Rosner model included age at menopause, age at menarche, oral contraception use, and tubal ligation; the concordance statistic was 0.60 (0.57–0.62). The Pfeiffer model included oral contraceptive use, menopausal hormone therapy use, and family history of breast cancer or ovarian cancer, with a similar discriminatory power of 0.59 (0.56–0.62). Although both models were well calibrated, their modest discriminatory power limited their screening potential.

The Pfeiffer model has been used to predict endometrial cancer risk in thegeneral population. For endometrial cancer, the relative risk model included BMI, menopausal hormone therapy use, menopausal status, age at menopause, smoking status, and oral contraceptive pill use. The discriminatory power of the model was 0.68 (0.66–0.70); it overestimated observed endometrial cancers in most subgroups but underestimated disease in women with the highest BMI category, in premenopausal women, and in women taking menopausal hormone therapy for 10 years or more.

In contrast, MMRpredict, PREMM1,2,6, and MMRpro are three quantitative predictive models used to identify individuals who may potentially have LS. MMRpredict incorporates only colorectal cancer patients but does include MSI and immunohistochemistry (IHC) tumor testing results. PREMM1,2,6 accounts for other LS-associated tumors but does not include tumor testing results. MMRpro incorporates tumor testing and germline testing results, but is more time intensive because it includes affected and unaffected individuals in the risk-quantification process. All three predictive models are comparable to the traditional Amsterdam and Bethesda criteria in identifying individuals with colorectal cancer who carry MMR mutations. However, because these models were developed and validated in colorectal cancer patients, the discriminative abilities of these models to identify LS are lower among individuals with endometrial cancer than among those with colon cancer. In fact, the sensitivity and specificity of MSI and IHC in identifying mutation carriers are considerably higher than the prediction models and support the use of molecular tumor testing to screen for LS in women with endometrial cancer.

Table 1 summarizes salient aspects of breast and gynecologic cancer risk assessment models that are commonly used in the clinical setting. These models differ by the extent of family history included, whether nongenetic risk factors are included, and whether carrier status and polygenic risk are included (inputs to the models). The models also differ in the type of risk estimates that are generated (outputs of the models). These factors may be relevant in choosing the model that best applies to a particular individual.

High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes

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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. 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 in an apparent autosomal dominant pattern of transmission (through either the maternal or the paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland. It is now known 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, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families. The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies 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, MSH2, MSH6, and PMS2, 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. 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. The BRCA1 gene ( OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1; 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) 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. (Refer to the Penetrance of mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids. 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 (nonmutated) 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.

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, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described. Approximately 1 in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2. 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 analysis and conformation-sensitive gel electrophoresis, miss nearly a third of the mutations that are detected by DNA sequencing. In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish (AJ) descent. Furthermore, studies have suggested that these rearrangements may be more frequently seen in Hispanic and Caribbean populations.

Statistics regarding the percentage of individuals 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 additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in AJs. However, other founder mutations have been identified in African Americans and Hispanics. 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 limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.

Among the general population, the likelihood of having any BRCA mutation is as follows:

  • General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
  • Women with breast cancer (any age): 1 in 50 (2%).
  • Women with breast cancer (younger than 40 years): 1 in 10 (10%).
  • Men with breast cancer (any age): 1 in 20 (5%).
  • Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).

Among AJ individuals, the likelihood of having any BRCA mutation is as follows:

  • General AJ population: 1 in 40 (2.5%).
  • Women with breast cancer (any age): 1 in 10 (10%).
  • Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
  • Men with breast cancer (any age): 1 in 5 (19%).
  • Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 and BRCA2 mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi whites, and 8.3% to 10.2% in Ashkenazi Jewish individuals. The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in whites.

A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of BRCA1 and BRCA2 mutations. Deleterious BRCA mutations were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2); 21 of the 189 (11%) deleterious BRCA mutations identified were large rearrangements, of which 13 (62%) were BRCA1 ex9-12 deletions. In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 ex9-12 deletion was found in three patients, suggesting that this mutation may be a Mexican founder mutation and may represent 10% to 12% of all BRCA1 mutations in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent mutations, which accounted for 53% of all mutations observed in this cohort, suggesting the existence of additional founder mutations in this population.

A retrospective review of 29 AJ patients with primary fallopian tube tumors identified germline BRCA mutations in 17%. Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall). Estimates of the frequency of fallopian tube cancer in BRCA mutation carriers are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

  • Breast cancer diagnosed at an early age. (Some studies use age 40 years as a cutoff, while others use age 50 years.)
  • Ovarian cancer.
  • Bilateral breast cancer.
  • A history of both breast and ovarian cancer.
  • Breast cancer diagnosed in a male at any age.
  • Triple-negative breast cancer diagnosed in women younger than 60 years.
  • AJ background.

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

  • Multiple cases of breast cancer.
  • Both breast and ovarian cancer.
  • One or more breast cancers in male family members.
  • AJ background.

Genetic testing for BRCA1 and BRCA2 mutations 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, but risk assessment continues to be an art. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 4. For adult-onset diseases, penetrance is usually described by the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years 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.

Numerous studies have estimated breast and ovarian cancer penetrance in BRCA1 and BRCA2 mutation carriers. Risk of both breast and ovarian cancer is consistently estimated to be higher in BRCA1 than in BRCA2 mutation carriers. Results from two large meta-analyses are shown in Table 3. One study analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 mutation–positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 mutation–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for BRCA1 and 45% to 47% for BRCA2 mutation carriers. Ovarian cancer risks were 39% for BRCA1 and 11% to 17% for BRCA2 mutation carriers.

While the cumulative risks of developing cancer by age 70 years are higher for BRCA1 than for BRCA2 mutation carriers, the relative risks (RRs) of breast cancer decline more with age in BRCA1 mutation carriers. Studies of penetrance for carriers of specific individual mutations are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder mutations have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder mutations from their larger meta-analyses and found that the estimated penetrance for the individual mutations was very similar to the corresponding estimates among all mutation carriers. A later study of 4,649 women with BRCA mutations reported significantly lower relative risks of breast cancer in those with the BRCA2 6174delT mutation than in those with other BRCA2 mutations (hazard ratio [HR], 0.35; confidence interval [CI], 0.18–0.69).

One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages. Nonetheless, making precise penetrance estimates in an individual carrier is difficult.

Data from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), comprising 19,581 BRCA1 mutation carriers and 11,900 BRCA2 mutation carriers, were analyzed to estimate HRs for breast cancer and ovarian cancer by mutation type, function, and nucleotide position. Breast cancer cluster regions and ovarian cancer cluster regions were found in both genes. Risks for incidence of breast cancer and ovarian cancer and age at diagnosis differed by mutation class. Further evaluation of these findings is needed before they can be translated into clinical practice.

Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk. (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other potentially modifiable reproductive and hormonal factors can also affect risk. Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time. (Refer to the Modifiers of Risk in BRCA1 and BRCA2 Mutation Carriers section for more information.) While the average breast cancer and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts, and additional studies will be required to further characterize potential modifying factors to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

Some genotype- phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. 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. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629. 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 with families with mutations on either side of this region. 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. These observations have generally been confirmed in subsequent studies. 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. 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 years in BRCA2:6174delT mutation carriers.

Ovarian cancers in women with BRCA1 and BRCA2 mutations are more likely to b

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