Mutational Signature Points to Ways, in Addition to BRCA1 and BRCA2 Mutations, That DNA Repair Mechanism Can Be Shut Off in Breast Cancer

A mutation pattern or “signature” linked to defects in two genes points to other ways an important DNA repair mechanism can be shut off in breast cancer. Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base exchanges -- e.g., T's for G's, C's for A's -- throughout a genome) known in cancer genomics as "Signature 3." But not all breast tumor cells exhibiting Signature 3 have BRCA1 or BRCA2 mutations. Therefore, some consider Signature 3 a biomarker for "BRCAness," a sign of a breakdown in BRCA-related DNA repair (a process called homologous recombination, or HR) in general and not BRCA damage in particular. The question is, what else might deactivate HR and give rise to Signature 3? And beyond that, might Signature 3 have a role in the clinic? To find out, an international team led by Drs. Paz Polak, Jaegil Kim, Lior Braunstein, and Gad Getz of the Broad Institute's Cancer Program, and Dr. William Foulkes of McGill University reanalyzed data from nearly 1,000 breast cancer tumors collected by The Cancer Genome Atlas (TCGA). Their findings, reported online on August 21, 2017 in Nature Genetics, hint that mutational signatures like Signature 3 might fuel a precision medicine approach that uses a tumor's full scope of mutations to guide risk and treatment decisions, instead of focusing on individual genes.