Abstract
Mutated germline alleles in the DNA damage repair (DDR) genes “breast cancer gene 1” (BRCA1) and BRCA2 have originally been identified as major susceptibility genes in breast and ovarian cancers. With the establishment and approval of more cost-effective gene sequencing methods, germline and somatic BRCA mutations have been detected in several cancers. Since the approval of poly (ADP)-ribose polymerase inhibitors (PARPi) for BRCA-mutated cancers, BRCA mutations gained rising therapeutic implications. The impact and significance of BRCA mutations have been evaluated extensively in the last decades. Moreover, other genes involved in the DDR pathway, such as ATM, ATR, or CHK1, have emerged as potential new treatment targets, as inhibitors of these proteins are currently under clinical investigation. This review gives a concise overview on the emerging clinical implications of mutations in the DDR genes in gastrointestinal cancers with a focus on BRCA mutations.
Highlights
The breast and ovarian cancer susceptibility genes “breast cancer gene” (BRCA)1 and BRCA2 have been thoroughly investigated in the last decades
Besides breast and ovarian cancer, Poly-(ADP) ribose polymerase inhibitors (PARPi) have been recently evaluated for the treatment of BRCA-mut pancreatic cancer implicating a possible further use in other BRCA-mut gastrointestinal (GI) cancers
For hepatocellular carcinoma (HCC), risks seem comparable, and for colorectal cancer (CRC), evidence is unclear if gBRCA1mut carriers have a higher lifetime risk for CRC compared with gBRCA2-mut carriers [68, 102]
Summary
The breast and ovarian cancer susceptibility genes “breast cancer gene” (BRCA) and BRCA2 have been thoroughly investigated in the last decades. It is estimated, that one out of 400 to 800 individuals (0.125%–0.25%) in the USA may harbor a germline loss-of-function mutation in BRCA1 or BRCA2 (gBRCA-mut) [1, 2]. That one out of 400 to 800 individuals (0.125%–0.25%) in the USA may harbor a germline loss-of-function mutation in BRCA1 or BRCA2 (gBRCA-mut) [1, 2] This is associated with an approximately 60% lifetime risk for breast cancer and a 15% to 40% lifetime risk for ovarian cancer development [3,4,5]. The frequency of BRCA1 and BRCA2 mutations in GI cancers varies between tumor entities (see Table 1)
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