위암에서 병원성 BRCA 유전자 돌연변이와 백금기반 항암화학요법에의 반응성 및 분자 아형과의 관련성에 대한 연구

Abstract

Background Homologous recombination defect is an important biomarker of chemotherapy in certain tumor types and the presence of pathogenic or likely pathogenic mutations involving BRCA1 or BRCA2 (pBRCA) mutations is the most well-established marker for the homologous recombination defect. Gastric cancer, one of the most prevalent tumor types in Asia, also harbors pBRCA mutations.

Methods 366 cases of gastric cancer from 1820 cases analyzed through next-generation sequencing (NGS) and investigated whether the presence of biallelic or heterozygous pBRCA mutations is associated with certain molecular subtypes, and responsiveness to platinum-based chemotherapy. Chi-square test and Wilcoxon signed-rank test were performed for pairwise comparisons. For non-parametric analysis between groups and variants, Kruskal-Wallis test was used. The Kaplan-Meier method was performed for survival analyses and the Mantel-Cox log-rank (MC) test was used to evaluate whether certain factors affect survivals.

Results The presence of pBRCA mutations was enriched in the chromosomal instability subtype, which was detected by the proportion of copy-number altered genomic segments, and microsatellite instability subtype. Although patients with gastric cancer harboring pBRCA mutations demonstrated no better response, gastric cancer harboring biallelic pBRCA mutations showed a better response to platinum-based chemotherapy.

Conclusions Gastric cancers with biallelic pBRCA mutations are associated with platinum-based chemotherapy. Patients with gastric cancer harboring biallelic pBRCA mutations could be considered candidates for poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor therapy, and screening for pBRCA mutations is advised in gastric cancers of chromosomal instability subtype.