Multi-omics characterization of molecular features of gastric cancer correlated with response to neoadjuvant chemotherapy

• Published in: Science advances Vol. 6; no. 9; p. eaay4211
• Main Authors: Li, Ziyu, Gao, Xiangyu, Peng, Xinxin, May Chen, Mei-Ju, Li, Zhe, Wei, Bin, Wen, Xianzi, Wei, Baoye, Dong, Yu, Bu, Zhaode, Wu, Aiwen, Wu, Qi, Tang, Lei, Li, Zhongwu, Liu, Yiqiang, Zhang, Li, Jia, Shuqin, Zhang, Lianhai, Shan, Fei, Zhang, Ji, Wu, Xiaojiang, Ji, Xin, Ji, Ke, Wu, Xiaolong, Shi, Jinyao, Xing, Xiaofang, Wu, Jianmin, Lv, Guoqing, Shen, Lin, Ji, Xuwo, Liang, Han, Ji, Jiafu
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.02.2020
• Subjects: Biomarkers, Tumor - genetics; Cancer; Carrier Proteins - genetics; Female; Human Genetics; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Neoadjuvant Therapy; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-myc - genetics; RNA-Seq; SciAdv r-articles; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach Neoplasms - therapy; Whole Genome Sequencing
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aay4211

Neoadjuvant chemotherapy is a common treatment for patients with gastric cancer. Although its benefits have been demonstrated, neoadjuvant chemotherapy is underutilized in gastric cancer management, because of the lack of biomarkers for patient selection and a limited understanding of resistance mechanisms. Here, we performed whole-genome, whole-exome, and RNA sequencing on 84 clinical samples (including matched pre- and posttreatment tumors) from 35 patients whose responses to neoadjuvant chemotherapy were rigorously defined. We observed increased microsatellite instability and mutation burden in nonresponse tumors. Through comparisons of response versus nonresponse tumors and pre- versus posttreatment samples, we found that mutations were associated with treatment resistance, which was supported by drug response data and potentially through inhibition of cell cycle, and that amplification correlated with treatment sensitivity, whereas amplification showed the opposite pattern. Neoadjuvant chemotherapy also reshapes tumor-immune signaling and microenvironment. Our study provides a critical basis for developing precision neoadjuvant regimens.