控制DNA修复的基因中的突变组合和高突变负荷在胰腺导管腺癌（PDAC）中具有预后作用：一项针对撒丁岛人群的回顾性现实研究。

Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population.

作者信息

Sini Maria Cristina, Doro Maria Grazia, Frogheri Laura, Zinellu Angelo, Paliogiannis Panagiotis, Porcu Alberto, Scognamillo Fabrizio, Delogu Daniele, Santeufemia Davide Adriano, Persico Ivana, Palomba Grazia, Maestrale Giovanni Battista, Cossu Antonio, Palmieri Giuseppe

机构信息

Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy.

Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

出版信息

J Transl Med. 2024 Jan 27;22(1):108. doi: 10.1186/s12967-024-04923-3.

DOI:10.1186/s12967-024-04923-3

PMID:38280995

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10821545/

Abstract

BACKGROUND

Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia.

METHODS

A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms.

RESULTS

Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival.

CONCLUSIONS

The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.

摘要

背景

携带错配修复机制受损的胰腺导管腺癌（PDCA）患者在接受传统化疗时似乎预后更佳，而肿瘤突变负荷对预后的作用仍存在争议。在本研究中，我们以医院为基础，对撒丁岛北部一家主要机构收治的一系列PDAC患者进行了评估，以确定参与基因组损伤修复的突变基因在预后中的作用，该机构负责此类疾病的手术治疗。

方法

对55例连续的PDAC患者进行队列研究，这些患者患有潜在可切除/边界可切除的PDAC（IIB-III期）或寡转移疾病（IV期），且有肿瘤组织可供使用，使用包含驱动癌基因、肿瘤抑制基因以及控制DNA修复机制的基因的面板进行基于二代测序（NGS）的分析。

结果

分别在17例（31%）和15例（27%）病例中发现参与基因组损伤修复（DR）和DNA错配修复（MMR）的基因发生突变。四分之一的PDAC病例（14/55；25.5%）携带的肿瘤存在修复基因（DR和MMR）突变组合以及最高的突变负荷率（MLR-H）。在对混杂因素（手术、辅助治疗、T分期和转移）进行校正后，多因素Cox回归分析表明，DR基因的突变（HR = 3.0126，95% CI 1.0707至8.4764，p = 0.0367）和MLR（HR = 1.0018，95%CI 1.0005至1.0032，p = 0.009）与较差的生存率显著相关。