Genetics of Breast and Gynecologic Cancers (PDQ®)

Health Professional Version

PDQ Cancer Genetics Editorial Board.

Published online: October 7, 2016.

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).

Executive Summary

This executive summary reviews the topics covered in this PDQ summary on the genetics of breast and gynecologic cancers, with hyperlinks to detailed sections below that describe the evidence on each topic.

Inheritance and Risk
Factors suggestive of a genetic contribution to both breast cancer and gynecologic cancer include 1) an increased incidence of these cancers among individuals with a family history of these cancers; 2) multiple family members affected with these and other cancers; and 3) a pattern of cancers compatible with autosomal dominant inheritance. Both males and females can inherit and transmit an autosomal dominant cancer predisposition gene.
Additional factors coupled with family history—such as reproductive history, oral contraceptive and hormone replacement use, radiation exposure early in life, alcohol consumption, and physical activity—can influence an individual’s risk of developing cancer.
Risk assessment models have been developed to clarify an individual's 1) lifetime risk of developing breast and/or gynecologic cancer; 2) likelihood of having a pathogenic variant in BRCA1 or BRCA2; and 3) likelihood of having a pathogenic variant in one of the mismatch repair genes associated with Lynch syndrome (LS).

Associated Genes and Syndromes
Breast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline pathogenic variants in BRCA1 and BRCA2. Other genes, such as PALB2, TP53 (associated with Li-Fraumeni syndrome), PTEN (associated with Cowden syndrome), CDH1(associated with diffuse gastric and lobular breast cancer syndrome), and STK11 (associated with Peutz-Jeghers syndrome), confer a risk to either or both of these cancers with relatively high penetrance.
Inherited endometrial cancer is most commonly associated with LS, a condition caused by inherited pathogenic variants in the highly penetrant mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. Colorectal cancer (and, to a lesser extent, ovarian cancer and stomach cancer) is also associated with LS.
Additional genes, such as CHEK2, BRIP1, RAD51, and ATM, are associated with breast and/or gynecologic cancers with moderate penetrance. Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast and gynecologic cancers, but the clinical utility of these findings remains uncertain.

Clinical Management
Breast cancer screening strategies, including breast magnetic resonance imaging and mammography, are commonly performed in carriers of BRCA pathogenic variants and in individuals at increased risk of breast cancer. Initiation of screening is generally recommended at earlier ages and at more frequent intervals in individuals with an increased risk due to genetics and family history than in the general population. There is evidence to demonstrate that these strategies have utility in early detection of cancer. In contrast, there is currently no evidence to demonstrate that gynecologic cancer screening using cancer antigen 125 testing and transvaginal ultrasound leads to early detection of cancer.
Risk-reducing surgeries, including risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy(RRSO), have been shown to significantly reduce the risk of developing breast and/or ovarian cancer and improve overall survival in carriers of BRCA1 and BRCA2 pathogenic variants. Chemoprevention strategies, including the use of tamoxifen and oral contraceptives, have also been examined in this population. Tamoxifenuse has been shown to reduce the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2pathogenic variants after treatment for breast cancer, but there are limited data in the primary cancer prevention setting to suggest that it reduces the risk of breast cancer among healthy female carriers of BRCA2 pathogenic variants. The use of oral contraceptives has been associated with a protective effect on the risk of developing ovarian cancer, including in carriers of BRCA1 and BRCA2 pathogenic variants, with no association of increased risk of breast cancer when using formulations developed after 1975.

Psychosocial and Behavioral Issues
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic testing varies widely across studies. Psychological factors that have been associated with testing uptake include cancer-specific distress and perceived risk of developing breast or ovarian cancer. Studies have shown low levels of distress after genetic testing for both carriers and noncarriers, particularly in the longer term. Uptake of RRM and RRSO also varies across studies, and may be influenced by factors such as cancer history, age, family history, recommendations of the health care provider, and pretreatment genetic education and counseling. Patients' communication with their family members about an inherited risk of breast and gynecologic cancer is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.

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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: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a genetic difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

[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 2016, an estimated 249,260 new cases will be diagnosed, and 40,890 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 22,280 new cases of ovarian cancer are expected in 2016, with an estimated 14,240 deaths. Ovarian cancer is the fifth most deadly cancer in women.[1] An estimated 60,050 new cases of endometrial cancer are expected in 2016, with an estimated 10,470 deaths.[1] (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.) Pathogenic variants 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.

Family history including inherited cancer genes

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.[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, the occurrence of bilateral or multiple ipsilateral breast cancers in a family member, and the number of affected male relatives.[4,5,7-9] 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.[9] (Refer to the Penetrance of BRCA pathogenic variants section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 pathogenic variants who themselves test negative for the family pathogenic variant.)