The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma.
The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma.
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种系/体细胞DNA损伤修复基因突变调节中国晚期胰腺导管腺癌患者的治疗反应
DOI：
10.1186/s12967-021-02972-6
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发表时间：
2021-07-12
影响因子：
7.4
通讯作者：
Cao D
中科院分区：
文献类型：
--
作者：
Shui L;Li X;Peng Y;Tian J;Li S;He D;Li A;Tian B;Li M;Gao H;An N;Yi C;Cao D
背景胰腺导管腺癌（pancreatic ductal adenocarcinoma，PDAC）是一种具有分子异质性、生物学行为和治疗策略差异的致死性疾病。在中国PDAC人群中，NGS谱的致病性改变是有限的。我们进行了一项回顾性研究，探讨DNA损伤修复（DDR）突变的预测作用，在精准medicine.MethodsNGS配置文件进行切除组织从195中国PDAC患者。收集基线临床或遗传特征和生存状态。采用Kaplan-Meier生存分析软件R version 3.6.1进行生存分析。结果KRAS、TP53、CDKN 2A和SMAD 4是主要的生存驱动基因。晚期KRAS突变患者的OS比KRAS野生型患者差（p = 0.048）。DDR致病缺陷30例（15.38%），主要涉及BRCA2基因9例（4.62%）、ATM基因8例（4.10%）和RAD50基因3例（1.54%）。有或无DDR突变的患者之间OS无显著性差异（p = 0.88）。但DDR突变是晚期PDAC患者生存分析的独立预后因素（p = 0.032）。对于DDR突变患者，分别使用铂类化疗（p = 0.0096）或奥拉帕尼（p = 0.018）治疗可改善总生存期。肿瘤突变负荷（TMB）和DDR突变之间没有统计学差异。PD-1阻断治疗并没有带来显着改善OS DDR突变患者比幼稚DDR group.ConclusionsIn这项回顾性研究中，我们显示了生殖细胞和体细胞DDR突变的作用，在预测奥拉帕尼和铂类化疗的疗效在中国患者。然而，DDR突变在预测高突变状态和对PD-1阻断剂的敏感性方面的价值需要进一步研究。
BackgroundPancreatic 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.MethodsThe 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.ResultsThe 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).ConclusionsIn 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.
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影响因子：
29.4
作者：
Haraldsdottir S;Hampel H;Tomsic J;Frankel WL;Pearlman R;de la Chapelle A;Pritchard CC
通讯作者：
Pritchard CC
DOI：
10.1001/jama.2018.6228
发表时间：
2018-06-19
期刊：
JAMA
影响因子：
--
作者：
Hu C;Hart SN;Polley EC;Gnanaolivu R;Shimelis H;Lee KY;Lilyquist J;Na J;Moore R;Antwi SO;Bamlet WR;Chaffee KG;DiCarlo J;Wu Z;Samara R;Kasi PM;McWilliams RR;Petersen GM;Couch FJ
通讯作者：
Couch FJ
DOI：
10.1158/1078-0432.ccr-17-3099
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu ZI;Shia J;Stadler ZK;Varghese AM;Capanu M;Salo-Mullen E;Lowery MA;Diaz LA Jr;Mandelker D;Yu KH;Zervoudakis A;Kelsen DP;Iacobuzio-Donahue CA;Klimstra DS;Saltz LB;Sahin IH;O'Reilly EM
通讯作者：
O'Reilly EM
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
20.4
作者：
Park, Sehhoon;Lee, Hayoon;Park, Keunchil
通讯作者：
Park, Keunchil