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

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.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.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.BRCA1 and BRCA2 proteins are thought to be essential to prevent breast/ovarian cancer largely because of the high lifetime risks faced by carriers of mutations in the corresponding genes. More modest increases in risk for other cancers have also been noted [1-5]. Basic science studies find multiple biologic functions for BRCA1 and BRCA2 proteins [6-15], including participating within a pathway that mediates error-free repair of DNA double strand breaks by homologous recombination [15].Fig. 1 summarizes a mo