Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives

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.

Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms

“…BRCA mutations and ATM alterations. BRCA mutations are extremely rare in digestive adenocarcinomas (0.5-2%) [39], but its incidence among digestive HG-NEN has not been reported prior. Our findings of BRCA 1/2 mutations in 5.3% of NEC and 14.6% of NET G3 seem higher than for adenocarcinoma.…”

Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective

“…DNA damage repair (DDR) genes are essential for preserving the function of cells [143]. Several genes are involved in maintaining the stability of the DDR system, including BRCA1, BRCA2 and PALB2 [144]. Deficiencies in DDR genes via homologous recombination (HR) can cause genetic instability leading to increased rates of somatic genetic alterations [145,146].…”

“…Alterations in BRCA and in other DDR genes are found in a significant subset of gastrointestinal cancers (15-20%) [149]. Moreover, mutated DDR genes are detectable in approximately 22% of CRCs [144]. While the results of a first clinical trial investigating the efficacy of a monotherapy with the PARP inhibitor olaparib were disappointing [150], combining a PARP inhibitor with classical cytotoxic regimens yielded promising response rates [151,152].…”

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

“…BRCA and other DDR complex genes are considered drug targets and treatment regimens in the majority of CRC patients [ 16 ]. Despite blocking molecular pathways by targeted drugs that have been used as adjunct to chemotherapy, CRC patients have not yet reaped significant benefits.…”