癌症易感性种系突变与胰腺导管腺癌 (PDAC) 相关。然而，亚洲人群中 PDAC 的遗传状况及其对生存的影响很大程度上未知。对 PDAC 个体的 527 份血液样本进行了外显子组测序，并分析了 80 个致癌基因的突变。根据 ACMG 变异分类类别诊断致病性和可能致病 (P/LP) 种系变异。在 III/IV 期疾病患者中探讨种系同源重组基因突变（gHRmut，包括 BAP1、BRCA1、BRCA2、PALB2、ATM、BLM、BRIP1、CHEK2、NBN、MUTYH、FANCA 和 FANCC）与治疗结果之间的关联采用一线 (1L) 含铂化疗与无铂化疗进行比较。总体而言，527 名患者中有 104 名 (19.7%) 携带种系 P/LP 变异。最常见的突变基因是BRCA2（3.60%），其次是ATR（2.66%）和ATM（1.9%）。中位随访时间为 38.3 个月（95% 置信区间，95% CI 35.0-43.7）后，gHRmut、非 HR 种系突变或无突变患者的中位总生存期 (OS) 没有显着差异（P = 0.43）。在接受 1L 联合化疗的 320 名 III/IV 期疾病患者中，32 名（10%）患有 gHRmut。其中，接受 1L 铂类化疗的患者与无铂化疗的患者相比，中位 OS 显着延长，分别为 26.1 个月 (95% CI 12.7-33.7) 和 9.6 个月 (95% CI 5.9-17.6)，P = 0.001 。然而，对于没有 gHRmut 的患者，接受 1L 含铂化疗和无铂化疗的患者的中位 OS 分别为 14.5 个月 (95% CI 13.2-16.9) 和 12.6 个月 (95% CI 10.8-14.7) (P = 0.22) 。在多变量 Cox 回归分析中调整了年龄、肿瘤分期、体能状态和基线 CA 19.9 等潜在混杂因素后，这些结果是一致的。我们的研究表明，近 20% 的台湾 PDAC 患者携带种系 P/LP 变异。在接受 1L 铂类化疗的 gHRmut 患者中观察到的较长生存期凸显了所有晚期 PDAC 诊断时进行种系检测的重要性。© 2024。作者。

Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.© 2024. The Author(s).