Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Gut. 2021 Oct;70(10):1894-1903. doi: 10.1136/gutjnl-2020-320730. Epub 2020 Sep 15.
To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).
We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).
12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like and , but more likely to have mutations in genes that drive cancers with microsatellite instability like and . MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.
MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.
描述具有 DNA 错配修复缺陷（MMRD）和功能（MMRP）的胰腺癌的临床、病理和基因组特征。
我们在临床队列（N=1213，519 例进行了基因检测，53 例进行了免疫组织化学（IHC））和基因组队列（N=288 例进行了全基因组测序（WGS））中鉴定了 MMRD 和 MMRP 胰腺癌患者。
在临床队列中，1213 例中有 12 例（1.0%）通过 IHC 或 WGS 为 MMRD。在 14 例林奇综合征患者中，3 例（21.4%）IHC 为 MMRP 胰腺癌，4 例（28.6%）因组织不可用而排除。手术后 MMRD 癌症的总生存期更长（粗化精确匹配后加权 HR 为 0.11，95%CI 为 0.02 至 0.78，p=0.001）。1 例不可切除的 MMRD 癌症患者在开始接受 PD-L1/CTLA-4 抑制治疗 3 年后仍有部分缓解。该肿瘤没有 MMRD 肿瘤的典型组织病理学特征。288 例肿瘤中有 9 例（3.1%）WGS 为 MMRD。尽管肿瘤突变负担和新抗原负荷明显更高，但 MMRD 癌症不太可能发生通常的胰腺癌驱动基因如 和 突变，但更可能发生导致微卫星不稳定癌症的基因如 和 突变。MMRD 肿瘤更可能具有基底样转录程序和升高的免疫原性转录标志物。
MMRD 胰腺癌具有独特的临床、病理和基因组特征。应考虑对 MMRD 胰腺癌患者进行篮式试验，以靶向增强的免疫原性或这些恶性肿瘤中独特的基因组驱动因素。
