Dataset Information

Genome Sequencing of Pancreatic Ductal Adenocarcinoma at The Human Genome Sequencing Center of Baylor College of Medicine (HGSC-BCM)

ABSTRACT:

Pancreatic ductal adenocarcinomas (PDAC) is the 11th most common cancer in the USA but the 4th in fatalities. The onset and progression of cancer is driven by extensive rearrangement and mutation of the genome. We combined our capability to capture and enrich exome DNA with the next generation sequencing capacity to allow us to detect and characterize the somatic mutation profile of 24 patients with PDAC. Patient samples were collected by the Elkins Pancreatic Center in the Baylor College of Medicine Department of Surgery. Sequencing of the pancreatic ductal adenocarcinoma is one of the NHGRI Center Initiated Projects in progress in the Human Genome Sequencing Center at Baylor College of Medicine. These data are also contributed to an ICGC study and will be published with the ICGC collaborators.

PROVIDER: phs000516.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Biankin Andrew V AV Waddell Nicola N Kassahn Karin S KS Gingras Marie-Claude MC Muthuswamy Lakshmi B LB Johns Amber L AL Miller David K DK Wilson Peter J PJ Patch Ann-Marie AM Wu Jianmin J Chang David K DK Cowley Mark J MJ Gardiner Brooke B BB Song Sarah S Harliwong Ivon I Idrisoglu Senel S Nourse Craig C Nourbakhsh Ehsan E Manning Suzanne S Wani Shivangi S Gongora Milena M Pajic Marina M Scarlett Christopher J CJ Gill Anthony J AJ Pinho Andreia V AV Rooman Ilse I Anderson Matthew M Holmes Oliver O Leonard Conrad C Taylor Darrin D Wood Scott S Xu Qinying Q Nones Katia K Fink J Lynn JL Christ Angelika A Bruxner Tim T Cloonan Nicole N Kolle Gabriel G Newell Felicity F Pinese Mark M Mead R Scott RS Humphris Jeremy L JL Kaplan Warren W Jones Marc D MD Colvin Emily K EK Nagrial Adnan M AM Humphrey Emily S ES Chou Angela A Chin Venessa T VT Chantrill Lorraine A LA Mawson Amanda A Samra Jaswinder S JS Kench James G JG Lovell Jessica A JA Daly Roger J RJ Merrett Neil D ND Toon Christopher C Epari Krishna K Nguyen Nam Q NQ Barbour Andrew A Zeps Nikolajs N Kakkar Nipun N Zhao Fengmei F Wu Yuan Qing YQ Wang Min M Muzny Donna M DM Fisher William E WE Brunicardi F Charles FC Hodges Sally E SE Reid Jeffrey G JG Drummond Jennifer J Chang Kyle K Han Yi Y Lewis Lora R LR Dinh Huyen H Buhay Christian J CJ Beck Timothy T Timms Lee L Sam Michelle M Begley Kimberly K Brown Andrew A Pai Deepa D Panchal Ami A Buchner Nicholas N De Borja Richard R Denroche Robert E RE Yung Christina K CK Serra Stefano S Onetto Nicole N Mukhopadhyay Debabrata D Tsao Ming-Sound MS Shaw Patricia A PA Petersen Gloria M GM Gallinger Steven S Hruban Ralph H RH Maitra Anirban A Iacobuzio-Donahue Christine A CA Schulick Richard D RD Wolfgang Christopher L CL Morgan Richard A RA Lawlor Rita T RT Capelli Paola P Corbo Vincenzo V Scardoni Maria M Tortora Giampaolo G Tempero Margaret A MA Mann Karen M KM Jenkins Nancy A NA Perez-Mancera Pedro A PA Adams David J DJ Largaespada David A DA Wessels Lodewyk F A LF Rust Alistair G AG Stein Lincoln D LD Tuveson David A DA Copeland Neal G NG Musgrove Elizabeth A EA Scarpa Aldo A Eshleman James R JR Hudson Thomas J TJ Sutherland Robert L RL Wheeler David A DA Pearson John V JV McPherson John D JD Gibbs Richard A RA Grimmond Sean M SM

Nature 20121024 7424

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutation ...[more]

PMID: 23103869

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Project description:Epigenetic modifications, particularly DNA methylation have been increasingly implicated in cancer. Although some genes display aberrant methylation in pancreatic cancer, a comprehensive global analysis is yet to be performed. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), the methylation profile of 156 PDAC and 23 non-malignant pancreas was captured using high-density arrays. More than 90,000 CpG sites were significantly differentially methylated (DM) in PDAC relative to non-malignant pancreas, with pronounced alterations in a sub-set of 13,517 CpG sites. This sub-set of differentially methylated CpG sites segregated PDAC from non-malignant pancreas, regardless of tumour cellularity. As expected, PDAC hyper-methylation was most prevalent in the 5’ region of genes (including the proximal promoter, 5’UTR and CpG islands). From 3981 genes aberrantly methylated, approximately 36% showed significant correlation between methylation and mRNA expression levels. Pathway analysis revealed an enrichment of aberrant methylation in genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, Integrin signaling, Cell adhesion, Stellate cell activation and Axon guidance. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, SRGAP1, and MET suggested epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET expression. Hypo-methylation of MET and ITGA2 correlated with high gene expression, which correlated with poor survival of PDAC patients. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting known core signaling pathways with important implications for disease pathophysiology and therapy. This dataset includes gene expression data from 103 primary tumour samples. 86 samples from this dataset have already been deposited into GEO (GSE36924), and has been duplicated here since the data has been processed differently. This data is also available through the International Cancer Genome Consortium (ICGC) Data Portal (http://dcc/icgc.org), under the project code: Pancreatic Cancer (QCMG, AU). Access to the restricted clinical data must be made through the ICGC Data Access Compliance Office (http://www.icgc.org/daco). This dataset contains gene expression array data from 103 primary pancreatic ductal adenocarcinoma samples. All samples have 1 biological replicate. These data have corresponding methylation 450K array data (GSE49149).

Dataset Information

Genome Sequencing of Pancreatic Ductal Adenocarcinoma at The Human Genome Sequencing Center of Baylor College of Medicine (HGSC-BCM)

Publications

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

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