BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian

Abstract and Introduction

Please note that on June 29, 2005 the incorrect text was posted for the article, "BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian". The text has been corrected.

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.

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Some female carriers of inherited mutations in BRCA1 or BRCA2 genes have lifetime risks for breast cancer exceeding 80%.

BRCA-related pathways safeguard genetic content, and a very large fraction of human cancers have abnormal genetic content. BRCA1 and/or BRCA2 are involved in pathways important for DNA damage recognition, double-strand break repair, checkpoint control, transcription regulation, and chromatin remodeling. These functions are essential and important for all cell types. Despite the general nature of BRCA functions, tumors in mutation carriers predominantly target breast and ovary. A major problem is that the broad theoretical importance of BRCA-related pathways conflicts with the specific targeting of cancers to breast and ovary. Some observational studies report elevations of the risk for certain cancers besides breast or ovarian cancer in BRCA1 or BRCA2 mutation carriers, but other studies conflict.

Although mutations in BRCA-related pathways may increase risk for sporadic or hereditary cancers other than breast or ovarian, the risks for these additional cancers may be smaller than those for breast or ovarian cancer; they may show wider variation; they may require large populations to measure; and they may involve proteins elsewhere in the pathways.

Carriers of mutations in BRCA1 and BRCA2 are relatively infrequent in the general population, and BRCA mutations are thought to be involved in at most 5% to 10% of all breast cancers. Mutations of genes encoding ATM and CHEK2 or mutations leading to EMSY amplification also affect BRCA pathways. These changes occur more frequently than BRCA1 or BRCA2 mutations in the general population, suggesting inactivation of BRCA-related pathways is probably associated with significantly higher percentages of cancers. Fortunately, data exist from many thousands of high-risk individuals who were not identified mutation carriers but who were eligible for mutation testing. These data would include all mutations that affect BRCA pathways, and some studies provide a built-in control because they also include those who were not eligible for mutation testing.

I collected data published in more than 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers or in large populations eligible for mutation testing. Results of meta-analyses show that the loss of BRCA gene function provides growth or survival advantages to a broader spectrum of tumors, including stomach, pancreas, prostate, and colon.

Thus, BRCA pathways function at multiple sites throughout the body, not just in breast or ovary. This does much to resolve a major conflict between the mechanisms of BRCA pathways participation in tumor suppression and clinical observations. The data suggest there ought to be increased clinical awareness for those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to tumors in those with BRCA pathway deficits may provide helpful targets for chemotherapy or chemoprevention.

© 2005  Medscape

Cite this: BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian - Medscape - Jun 29, 2005.