Department of Pathology, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Hum Pathol. 2023 Dec;142:68-80. doi: 10.1016/j.humpath.2023.11.002. Epub 2023 Nov 17.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with an overall 5-year survival of around 10 %. New prognostic tools to stratify patients are needed. Our main aim was to evaluate the prognostic value of overall copy number variation (CNV) burden in surgically treated PDAC. DNA extracted from 108 surgical PDAC specimens was examined to collect data on the genome-wide DNA methylation status of >850,000 CpG sites in promoter, gene body, and enhancer regions (Illumina Infinium Methylation EPIC BeadChip Kit). CNV profiles were obtained and all PDACs were stratified into one of three groups: Low, moderate, or high overall CNV burden. Tumors histologically showing a dominant conventional and/or tubulopapillary pattern in 60 %-100 % and 0-59 % were categorized as Group A and Group B as per Kalimuthu. We also performed targeted next-generation sequencing (NGS) and immunohistochemistry. High overall CNV burden held independent negative prognostic value with poor survival (HR 4.01 (95%CI 1.96-8.19), p = 0.00014) and was more frequent in Group B (p = 0.0003). Most frequent chromosomal arm-level aberrations were gains of 8q (29 %) and 1q (19 %) and losses of 17p (55 %), 18q (43 %), 6q (37 %), 9p (36 %), 6p (26 %), 19p (26 %), and 8p (25 %). Most frequent mutations found were in KRAS (95 %), TP53 (62 %), CDKN2A (24 %), SMAD4 (23 %), ATM (9 %), ARID1A (7 %), RNF43 (7 %), GNAS (6 %), and KDM6A (6 %). Group A PDACs showed more frequently KRAS variants other than Gly12Val and Gly12Asp (p = 0.012). Our data indicate that overall CNV burden using genome-wide methylation profiling may be a useful prognostic tool in surgically treated PDAC. Importantly, our approach, using data from genome-wide methylation profiling for analysis of overall CNV burden, can be performed on formalin-fixed and paraffin embedded PDAC tissues. Future studies should examine the prognostic value of overall CNV burden in unresectable PDAC.
胰腺导管腺癌（PDAC）是一种侵袭性癌症，总体 5 年生存率约为 10%。需要新的预后工具来对患者进行分层。我们的主要目的是评估手术治疗的 PDAC 中总拷贝数变异（CNV）负担的预后价值。从 108 例手术 PDAC 标本中提取的 DNA 用于收集启动子、基因体和增强子区域中 >850,000 个 CpG 位点的全基因组 DNA 甲基化状态的数据（Illumina Infinium Methylation EPIC BeadChip Kit）。获得 CNV 图谱，并根据 Kalimuthu 的方法将所有 PDAC 分为三组之一：低、中或高总体 CNV 负担。组织学上显示在 60%-100%和 0-59%之间占主导地位的传统和/或小管状乳头状模式的肿瘤被归类为 A 组和 B 组。我们还进行了靶向下一代测序（NGS）和免疫组织化学检测。高总体 CNV 负担与不良生存相关，具有独立的负预后价值（HR 4.01（95%CI 1.96-8.19），p=0.00014），并且在 B 组中更为常见（p=0.0003）。最常见的染色体臂水平异常是 8q（29%）和 1q（19%）的增益以及 17p（55%）、18q（43%）、6q（37%）、9p（36%）、6p（26%）、19p（26%）和 8p（25%）的缺失。发现的最常见突变是 KRAS（95%）、TP53（62%）、CDKN2A（24%）、SMAD4（23%）、ATM（9%）、ARID1A（7%）、RNF43（7%）、GNAS（6%）和 KDM6A（6%）。A 组 PDAC 中更频繁地发现除 Gly12Val 和 Gly12Asp 以外的 KRAS 变体（p=0.012）。我们的数据表明，使用全基因组甲基化谱进行的总体 CNV 负担可能是手术治疗 PDAC 的一种有用的预后工具。重要的是，我们的方法使用来自全基因组甲基化谱分析的总体 CNV 负担的数据，可以在福尔马林固定和石蜡包埋的 PDAC 组织上进行。未来的研究应检查不可切除的 PDAC 中总体 CNV 负担的预后价值。
