BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian

Abstract

Objective: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects.

Data sources, data extraction, data synthesis: The author collected data published in > 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data were extracted and used directly as published whenever possible with a minimum of statistical manipulation.

Conclusions: Although mutations target breast and ovary, a broader spectrum of cancers also occur with statistically significant elevated frequencies. Risks for "all cancers except breast or ovary" are elevated, with some population subgroups differing with regard to how frequently elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate, and colon. The increased risk ranged from about 20% to 60%, with the greatest increases in risk in stomach and pancreas. The collected data show BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.

Figure 1

A. Significant relative risks for cancers other than breast/ovarian in mutation carriers or likely mutation carriers found in various subgroups by different studies. Sites are arranged in descending frequency that statistically significant cancers were reported in different publications. Brackets indicate reports from the same publication for different groups. Gallbladder/bile duct cancers are grouped together as are leukemias and lymphomas. Population groups are listed along the bottom of the graph with references in parentheses. B. Relative risks for any cancer other than breast or ovarian cancer in mutation carriers or populations eligible for mutation testing.

Figure 1

A. Significant relative risks for cancers other than breast/ovarian in mutation carriers or likely mutation carriers found in various subgroups by different studies. Sites are arranged in descending frequency that statistically significant cancers were reported in different publications. Brackets indicate reports from the same publication for different groups. Gallbladder/bile duct cancers are grouped together as are leukemias and lymphomas. Population groups are listed along the bottom of the graph with references in parentheses. B. Relative risks for any cancer other than breast or ovarian cancer in mutation carriers or populations eligible for mutation testing.

Figure 2

A. Relative risks of stomach/gastric cancer based on data in different population studies. B. Relative risks for prostatic cancer. C. Relative risks for pancreatic cancer. D. Relative risks for colon and for rectal cancer.

Figure 2

A. Relative risks of stomach/gastric cancer based on data in different population studies. B. Relative risks for prostatic cancer. C. Relative risks for pancreatic cancer. D. Relative risks for colon and for rectal cancer.

Figure 2

A. Relative risks of stomach/gastric cancer based on data in different population studies. B. Relative risks for prostatic cancer. C. Relative risks for pancreatic cancer. D. Relative risks for colon and for rectal cancer.

Figure 2

A. Relative risks of stomach/gastric cancer based on data in different population studies. B. Relative risks for prostatic cancer. C. Relative risks for pancreatic cancer. D. Relative risks for colon and for rectal cancer.

Figure 3

Examples of interactions involving BRCA1 and BRCA2 proteins stressing the general nature of their functions and some interactions with BRCA1. The exact order of events and understanding of these interactions are still evolving.