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Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF , chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development ( FOXA2/3 , PDX1 and MNX1 ). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine ( NR5A2 and RBPJL ), and endocrine differentiation ( NEUROD1 and NKX2-2 ). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development. An integrated genomic analysis of 456 human pancreatic ductal adenocarcinomas identifies four subtypes defined by transcriptional expression profiles and show that these are associated with distinct histopathological characteristics and differential prognosis. Pancreatic cancer genomics Sean Grimmond and colleagues report integrated genomic analysis of 456 pancreatic ductal adenocarcinomas. They identify four subtypes defined by expression profiles, characterize their transcriptional networks, and show that these are associated with distinct histopathological characteristics and differential survival.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH , which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH , CHEK2 and BRCA2 . Together with mutations in MEN1 and VHL , these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling. The genomes of 102 primary pancreatic neuroendocrine tumours have been sequenced, revealing mutations in genes with functions such as chromatin remodelling, DNA damage repair, mTOR activation and telomere maintenance, and a greater-than-expected contribution from germ line mutations. The genomics of pancreatic neuroendocrine tumours Pancreatic neuroendocrine tumours (PanNETs) are the second most common epithelial neoplasm of the pancreas. Aldo Scarpa, Sean Grimmond and colleagues report whole-genome sequencing of 102 primary PanNETs and present analysis of their mutational signatures as part of the International Cancer Genome Consortium. They find frequent mutations in genes with functions that include chromatin remodelling, DNA damage repair, activation of mTOR signalling, and telomere maintenance. They also identify mutational signatures, including one resulting from inactivation of the DNA repair gene MUTYH , and report a larger than expected germline contribution to PanNET development.

This corrects the article DOI: 10.1038/nature21063.

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 mutations ( KRAS , TP53 , CDKN2A, SMAD4 , MLL3 , TGFBR2, ARID1A and SF3B1 ), and uncover novel mutated genes including additional genes involved in chromatin modification ( EPC1 and ARID2 ), DNA damage repair ( ATM ) and other mechanisms ( ZIM2 , MAP2K4 , NALCN , SLC16A4 and MAGEA6 ). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance. New mutations identified in pancreatic cancer This large-scale study presents exome sequencing and copy number variant analysis from 142 patients with pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer. Among the findings are mutations in genes involved in chromatin modification and DNA damage repair, not previously implicated in this disease. Importantly, the data show that abnormal expression of genes involved in slit and semaphorin signalling is associated with poor patient survival, and in animal models was associated with disease development and progression.

Nature 543, 65–71 (2017); doi:10.1038/nature21063 It has been brought to our attention that in Fig. 2d of this Article, an incorrect Sanger trace was used to represent the breakpoint of the EWSR1 and FLI1 type 2 fusion. This was due to an error during manuscript preparation, when we inadvertently inserted the electrophoretic trace referring to EWSR1 splicing variants.