The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma

作者全名："Shui, Lin; Li, Xiaofen; Peng, Yang; Tian, Jiangfang; Li, Shuangshuang; He, Du; Li, Ang; Tian, Bole; Li, Mao; Gao, Heli; An, Ning; Yi, Cheng; Cao, Dan"

作者地址："[Shui, Lin; Li, Xiaofen; Li, Shuangshuang; Yi, Cheng; Cao, Dan] Sichuan Univ, West China Hosp, Canc Ctr, Dept Abdominal Oncol, Chengdu, Peoples R China; [Peng, Yang] Chongqing Med Univ, Dept Breast Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Tian, Jiangfang] China Natl Nucl Corp 416 Hosp, Affiliated Hosp 2, Dept Oncol, Chengdu Med Coll, Chengdu, Peoples R China; [He, Du] Sichuan Univ, West China Hosp, Dept Pathol, Chengdu, Peoples R China; [Li, Ang; Tian, Bole; Li, Mao] Sichuan Univ, West China Hosp, Pancreat Surg, Chengdu, Peoples R China; [Gao, Heli] Fudan Univ, Dept Oncol, Canc Hosp, Shanghai, Peoples R China; [An, Ning] Sichuan Prov, Dept Oncol, Peoples Hosp, Chengdu, Peoples R China"

通信作者："Cao, D (corresponding author), Sichuan Univ, West China Hosp, Canc Ctr, Dept Abdominal Oncol, Chengdu, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000671755500001

JCR分区：Q1

影响因子：7.4

年份：2021

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Pancreatic ductal adenocarcinoma; DNA damage repair gene; Next generation sequencing; Chinese population

摘要："Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. Methods The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1. Results The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). Conclusions In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773097]

基金资助正文：This work was funded by the National Natural Science Foundation of China (No. 81773097).