High overall copy number variation burden by genome-wide methylation profiling holds negative prognostic value in surgically treated pancreatic ductal adenocarcinoma

Sönke Detlefsen; Henning Bünsow Boldt; Mark Burton; Mikkel Marschall Thomsen; Lukas Gammelgaard Rasmussen; Siri Vreim Ørbeck; Per Pfeiffer; Michael Bau Mortensen; Karin de Stricker

doi:10.1016/j.humpath.2023.11.002

High overall copy number variation burden by genome-wide methylation profiling holds negative prognostic value in surgically treated pancreatic ductal adenocarcinoma

Hum Pathol. 2023 Dec:142:68-80. doi: 10.1016/j.humpath.2023.11.002. Epub 2023 Nov 17.

Authors

Sönke Detlefsen¹, Henning Bünsow Boldt², Mark Burton³, Mikkel Marschall Thomsen², Lukas Gammelgaard Rasmussen⁴, Siri Vreim Ørbeck⁵, Per Pfeiffer⁶, Michael Bau Mortensen⁷, Karin de Stricker⁸

Affiliations

¹ 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. Electronic address: Sonke.Detlefsen@rsyd.dk.
² Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
³ Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
⁴ Department of Pathology, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark.
⁵ 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.
⁶ 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 Oncology, Odense University Hospital, Odense, Denmark.
⁷ 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 Surgery, Upper GI and HPB Section, Odense University Hospital, Odense, Denmark.
⁸ Department of Pathology, Odense University Hospital, Odense, Denmark.

PMID: 37977512
DOI: 10.1016/j.humpath.2023.11.002

Abstract

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.

Keywords: Copy number variation (CNV); Next-generation sequencing; Pancreatic cancer; Prognosis; Subtyping.

MeSH terms

Adenocarcinoma* / pathology
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / surgery
Chromosome Aberrations
DNA Copy Number Variations
DNA Methylation
Humans
Mutation
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / surgery
Prognosis
Proto-Oncogene Proteins p21(ras) / genetics

Substances

Proto-Oncogene Proteins p21(ras)