A mutational signature in gastric cancer suggests therapeutic strategies

Abstract

Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.

When Genome Maintenance Goes Badly Awry

“…However, somatic loss of function has been found to occur at significant frequency through epigenetic BRCA1 silencing (Cancer Genome Atlas Research, 2011), and clinically-relevant somatic mutations in BRCA1, BRCA2, and other HR genes are now being detected. Together germline and somatic mutations in HR genes have been found in a significant fraction of some tumor types (10–20%), e.g., high-grade serous ovarian carcinomas, the most malignant epithelial ovarian cancer subtype (Cancer Genome Atlas Research, 2011), other ovarian, fallopian tube, and peritoneal carcinomas (Norquist et al, 2016; Pennington et al, 2014), gastric tumors (Alexandrov et al, 2015b), and metastatic castration-resistant prostate cancers (Robinson et al, 2015). Interestingly, this latter case is a larger fraction than previously observed in primary prostate cancers (Barbieri et al, 2012; Cancer Genome Atlas Research, 2015), suggestive of tumor evolution.…”

“…A mutational signature associated with defective HR was first identified in BRCA1 or BRCA2 germline mutant breast cancers (Nik-Zainal et al, 2012), and later in ovarian, pancreatic, and gastric cancers (Alexandrov et al, 2015b; Alexandrov et al, 2013; Patch et al, 2015; Waddell et al, 2015). This signature consists of elevated numbers of indels (>3 bp) associated with microhomology at the breakpoint junctions (Figure 1A).…”

Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer

“…Based upon enrichment of HR mutations in our discovery cohort and a recent report showing multiple intestinal, diffuse and mixed histology gastric tumors with a somatic HR deficiency signature 8 , our validation cohort included both HDGC and non-HDGC cases of diffuse and non-diffuse histology (Supplementary methods). Targeted sequencing identified four additional mutation carriers: two sharing a known Hispanic BRCA1 founder mutation (p.Gln1111Asnfs) 9 and two with novel PALB2 mutations (p.Pro918Gln and p.Lys628_Cys630del) with predicted deleterious effects.…”

“…Further characterizations of the GC histology in HR gene mutation carriers are also needed as we found instances where the same mutation was found in cases with different histologies (CG-12 and CG-008 with PALB2 p.Arg414ter and CG-039 and CG-028 with PALB2 p.Lys628_Cys630del, Table 1). CDH1 mutation negative families might benefit from HR gene testing and increased endoscopic surveillance and targeted therapies, such as PARP inhibitors 8 .…”

“…Members of the Latin American Gastric Cancer Genetics Collaborative Group: Magdalena Echeverry 1 , Mabel Bohorquez 1 , Rodrigo Prieto 1 , John Suarez 1 , Gilbert Mateus 2 , Maria Mercedes Bravo 3 , Fernando Bolaños 4 , Alejandro Vélez 5 , Alejandro Corvalan 6 , Pilar Carvallo 7 , Javier Torres 8 , Luis Carvajal-Carmona 9 .…”