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The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C

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The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C Published OnlineFirst August 3, 2016; DOI: 10.1158/0008-5472.CAN-16-0658 Cancer Molecular and Cellular Pathobiology Research The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C. Wedge3,4, Inger Marie Bowitz Lothe1,5, Knut Jørgen Labori6, Stefan C. Dentro3,4,Trond Buanes6,7, Martina L. Skrede1, Astrid M. Dalsgaard1, Else Munthe8, Ola Myklebost8, Ole Christian Lingjærde9, Anne-Lise Børresen-Dale1,7, Tone Ikdahl10,11, Peter Van Loo12,13, Silje Nord1, and Elin H. Kure1,2 Abstract Despite advances in diagnostics, less than 5% of patients with and Wnt signaling. By integrating genomics and transcrip- periampullary tumors experience an overall survival of five years tomics data from the same patients, we identified CCNE1 and or more. Periampullary tumors are neoplasms that arise in the ERBB2 as candidate driver genes. Morphologic subtypes of vicinity of the ampulla of Vater, an enlargement of liver and periampullary adenocarcinomas (i.e., pancreatobiliary or intes- pancreas ducts where they join and enter the small intestine. In tinal) harbor many common genomic aberrations. However, this study, we analyzed copy number aberrations using Affymetrix gain of 13q and 3q, and deletions of 5q were found specificto SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo the intestinal subtype. Our study also implicated the use of the University Hospital to identify genome-wide copy number aber- PAM50 classifier in identifying a subgroup of patients with a rations, putative driver genes, deregulated pathways, and poten- high proliferation rate, which had impaired survival. Further- tial prognostic markers. Results were validated in a separate cohort more, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 derived from The Cancer Genome Atlas Consortium (n ¼ 127). (19q13.2, 19q13.31-32) and subsequent overexpression of the In contrast to many other solid tumors, periampullary adeno- genes in these loci were associated with impaired survival. carcinomas exhibited more frequent genomic deletions than Our work identifies potential prognostic markers for periampul- gains. Genes in the frequently codeleted region 17p13 and lary tumors, the genetic characterization of which has lagged. 18q21/22 were associated with cell cycle, apoptosis, and p53 Cancer Res; 76(17); 5092–102. Ó2016 AACR. Introduction evolution is driven either by mutations or by copy number aberrations (CNA; ref. 2). CNAs play a critical role in activating Pancreatic cancer is the fourth most common cause of cancer- oncogenes and inactivating tumor suppressor genes, thereby related deaths in Western countries, and it is projected to be the targeting the hallmarks of cancer (3, 4). Studies have shown that second leading cause of cancer-related death by 2030 (1). The driver alterations in pancreatic cancer include both single-nucle- incidence and mortality rate for pancreatic cancer are almost equal otide variants and large-scale rearrangements (5, 6). In the field of and the 5-year survival rate is <5%. Across tumor types, tumor cancer genomics, the focus has been on identifying altered geno- mic regions and pathways by high-throughput technologies, and relating these to phenotypic effects. This knowledge has already 1Department of Cancer Genetics, Institute for Cancer Research, Oslo led to substantial advances in diagnostics and therapeutics in University Hospital, Oslo, Norway. 2Department for Environmental other cancers such as targeting the HER2 oncogene in breast cancer Health and Science, University College of Southeast Norway, Bø, Norway. 3Wellcome Trust Sanger Institute, Hinxton, United Kingdom. patients using the mAb trastuzumab (7). 4Department of Cancer Genomics, Big Data Institute, University of A number of studies are published on pancreatic ductal Oxford, Oxford, United Kingdom. 5Department of Pathology, Oslo adenocarcinomas (PDAC) using high-throughput data analysis 6 University Hospital, Oslo, Norway. Department of Hepato-Pan- (8–14). Previous studies on relatively small cohorts of PDAC creato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. 7Insti- tute of Clinical Medicine, University of Oslo, Oslo, Norway. 8Depart- have documented homozygous deletions of 1p, 3p, 6p, 9p, ment of Tumor Biology, Institute for Cancer Research, Oslo University 12q, 13q, 14q, 17p, and 18q, and amplifications of 1q, 2q, 3q, 9 Hospital, Oslo, Norway. Department of Computer Science, University 5q, 7p, 7q, 8q, 11p, 14q, 17q, and 20q (11–13). Recently, a of Oslo, Oslo, Norway. 10Department of Oncology, Oslo University Hospital, Oslo, Norway. 11Akershus University Hospital, Nordbyhagen, study of 75 PDAC and 25 cell lines derived from PDAC patients Norway. 12The Francis Crick Institute, London, United Kingdom. were analyzed using Illumina SNP arrays and whole genome 13 Department of Human Genetics, University of Leuven, Leuven, SOLID sequencing (5). The results showed that genomic altera- Belgium. tions in PDACs are dominated by structural alterations, and Note: Supplementary data for this article are available at Cancer Research were classified by the number and distribution of structural Online (http://cancerres.aacrjournals.org/). variation events. Another recent publication identified four Corresponding Author: Elin H. Kure, Institute for Cancer Research, Ullernchau- subtypes of PDAC namely squamous, pancreatic progenitor, seen 70, Oslo 0310, Norway. Phone: 472-278-1377; Fax: 472-278-1395; E-mail: immunogenic, and aberrantly differentiated endocrine exocrine [email protected] type (14), which overlapped with Collisson subtypes namely doi: 10.1158/0008-5472.CAN-16-0658 quasi-mesenchymal, exocrine, and classical subtype, except for Ó2016 American Association for Cancer Research. the immunogenic subtype (8, 14). Despite these studies, our 5092 Cancer Res; 76(17) September 1, 2016 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 3, 2016; DOI: 10.1158/0008-5472.CAN-16-0658 Copy Number Aberrations in Periampullary Adenocarcinomas knowledge about pancreatic cancer subtypes is limited, partly results, 127 PDAC samples from the TCGA cohort https://tcga- due to small samples sizes and lack of validation in different data.nci.nih.gov/tcga/ were analyzed. cohorts. Here we analyzed the copy number profile of 60 tumors from Affymetrix SNP 6.0 arrays Oslo University Hospital (OUH; Oslo, Norway) and 127 tumors The Affymetrix SNP 6.0 arrays include 1.8 million genetic from The Cancer Genome Atlas (TCGA) cohort using SNP arrays. markers, including 906,600 SNPs and 946,000 copy number Because of the low tumor purity frequently observed in pancreatic probes. DNA digestion, labeling, and hybridization were per- cancer biopsies, copy number alterations may present as subtle formed according to the manufacturer's instruction (Affymetrix). changes in copy number signals. The Battenberg analysis pipeline applied herein (ref. 15; doi: 10.5281/zenodo.16107) performs Statistical analysis phasing of both parental haplotypes to increase sensitivity. CNAs Copy number aberration profiles from the OUH (n ¼ 60) and were identified in tumors originating from the pancreatic ducts, the TCGA (n ¼ 127) cohort were generated. Segmental copy the bile duct, the ampulla and the duodenum, collectively called number information was derived for each sample using the periampullary adenocarcinomas in the OUH cohort of 60 Battenberg pipeline (https://github.com/cancerit/cgpBattenberg/) patients. Several regions of recurrent gain or loss were identified as described previously (15) to estimate tumor cell fraction, tumor in the OUH cohort and validated in TCGA cohort, providing a set ploidy, and copy numbers. The Battenberg pipeline has high of putative driver genes and deregulated pathways in periampul- sensitivity for samples with low cellularity, frequently observed lary adenocarcinomas. The frequent gain and overexpression of in pancreatic tumors. Briefly, the tool phases heterozygous SNPs genes was further associated with poor patient prognosis. with use of the 1000 genomes genotypes as a reference panel using Impute2 (17), and corrects phasing errors in regions with copy Materials and Methods number changes through segmentation (18). After segmentation of the resulting B-allele frequency (BAF) values, t tests are per- DNA extraction formed on the BAFs of each copy number segment to identify DNA was extracted from tumor tissue using the Maxwell Tissue whether they correspond to the value resulting from a fully clonal fl fi DNA kit on the Maxwell 16 Instrument (Promega). Brie y, ve 20- copy number change. If not, the copy number segment is repre- m m m sections were homogenized in 300- L lysis buffer and added sented as a mixture of two different copy number states, with fi to the cartridge. The method is based on puri cation using the fraction of cells bearing each copy number state estimated paramagnetic particles as a mobile solid phase for capturing, from the average BAF of the heterozygous SNPs in that segment. washing, and elution of genomic DNA. Elution volume was The genome instability indices (GII) were calculated for both m 200 L. DNA was extracted from 6-mL EDTA blood using the the cohorts; it is measured as the fraction of aberrant probes QiAamp DNA Blood BioRobot MDx Kit on the BioRobot MDx throughout the genome above or below the ploidy. Correlation (Qiagen). This was done at Aros Applied Biotechnology AS, and analysis was carried out to identify any association between GII
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