Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version
SECTIONS
- Executive Summary
- Introduction
- Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers
- Multigene (Panel) Testing
- High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes
- Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer
- Low-Penetrance Genes and Loci
- Clinical Management of Carriers of BRCAPathogenic Variants
- Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes
- Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes
- Changes to This Summary (10/07/2016)
- About This PDQ Summary
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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 RiskFactors 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 SyndromesBreast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline pathogenic variants inBRCA1 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 ManagementBreast 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 ofBRCA1 and BRCA2 pathogenic variants. Chemoprevention strategies, including the use of tamoxifen and oral contraceptives, have also been examined in this population.Tamoxifen use has been shown to reduce the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2 pathogenic 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 BRCA2pathogenic variants, with no association of increased risk of breast cancer when using formulations developed after 1975.
- Psychosocial and Behavioral IssuesPsychosocial 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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