The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

Abstract

Background: The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias.

Methods: Literature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products.

Results: Deleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers.

Conclusion: An important function of the BRCA pathway is to prevent a subgroup of human leukemias and lymphomas that may involve non-random, characteristic gene rearrangements. Here, the genetic defect in BRCA pathway deficiencies is a chromosomal misrepair syndrome that may facilitate this subgroup of somatic cancers. Inactivation of a single gene within the pathway can increase risks for multiple cancers and inactivation of a different gene in the same pathway may have similar effects. The results presented here may have clinical implications for surveillance and therapy.

Figure 1

Schematic model for the "error-free" BRCA double strand break repair pathway Brief overview of components within the BRCA pathway used here as a working model that was tested here. The model is based largely on reference 16. BRCA2 is the same as FANCD1 and the interaction between BRCA1 and Fanconi anemia protein J is shown. While the gene products shown represent the over-all pathway, "error-free" double strand break repair by homologous recombination undoubtedly involves other proteins but the discussion is limited to those shown. Not shown are details of the 13 Fanconi anemia gene products and additional components including EMSY, a whole family of RAD51 related proteins, DCC, cohesins and accessory proteins. Deficiency states may be rare or unknown for these additional proteins and large epidemiologic studies are uncommon. Other protein kinases related to ATM carry out similar functions in response to other genotoxic stresses, and some of them collaborate with ATM. Proteins within the pathway also interact with other branches of the DNA damage response and with further proteins.