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.

Background-Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. Aims-To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. Methods-Thirty one at risk or aVected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. Results-Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. Conclusions-Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in aVected members. (Gut 1998;43:548-552)

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the general population, and regular NSAID use is associated with improved survival among colorectal cancer (CRC) patients. We examined the association of NSAID use prior to, and after, diagnosis in relation to CRC-specific and overall survival. Methods: Study subjects were incident, invasive CRC cases from the population-based Seattle Colon Cancer Family Registry. Eligible cases were 20-74 years of age, diagnosed from 1997 to 2008, and identified from the Puget Sound Surveillance, Epidemiology and End Results (SEER) Registry. NSAID use two years prior to the interview date ("pre-diagnosis period") was collected by telephone interview at study enrollment an average of eight months after diagnosis. A follow-up questionnaire was administered approximately five years after the cases' CRC diagnosis ("post-diagnosis period"). Regular NSAID use was defined as having taken aspirin or ibuprofen at least twice per week for more than a month. Follow-up for survival and cause of death was completed through linkage to the National Death Index. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of pre-and post-diagnostic NSAID use, and initiation, continuation and discontinuation of NSAIDs between pre-and post-diagnostic periods with survival after CRC diagnosis. Results: Compared to never users, regular NSAID use after diagnosis was associated with better overall survival (HR ¼ 0.69, 95% CI, 0.54-0.89) and CRC-specific survival (HR ¼ 0.48, 95% CI, 0.29-0.80). Among people who survived five years after diagnosis, both overall and CRC-specific survival were better for patients who initiated NSAID use postdiagnosis compared to never users, with HRs (95% CI) of 0.70 (0.51-0.95) and 0.43 (0.23-0.82), respectively. HR estimates were stronger for CRC-specific survival among those with non-advanced (local and regional) CRC (HR ¼ 0.38, 95% CI, 0.18-0.77). Conclusion: Our results suggest that among longterm CRC survivors, regular use of NSAID after CRC diagnosis, including when initiated after diagnosis, is significantly associated with longer CRC-specific survival. This association is more pronounced for patients with non-advanced CRC. Studies of dietary patterns and cancer outcomes also suggest that diet might influence an individual's risk of PanC through modulation of inflammation. We, therefore, examined independent and joint associations between inflammatory potential of diet, cigarette smoking and long-standing type II diabetes (greater than 5 years) in relation to risk of PanC. Methods: Data were from a clinic-based, case-control study of rapidly ascertained patients with incident adenocarcinoma of the exocrine pancreas (n ¼ 819) evaluated at Mayo Clinic and non-cancer control patients (n ¼ 1,769) recruited from Mayo Clinic primary care facilities. Controls were frequency-matched to cases on age, race, and sex. Inflammatory potential of diet was measured using the dietary inflamm...

150 Word count -Abstract: 148 151 Word count -Text: 4,119 152 Word count Methods: 1,963 153 Number of References: 75 154 Number of Figures: 6 155 Number of supplementary tables: 8 156 ABSTRACT 158 Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors 159 interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of 160 European descent, explaining 4.1% of the phenotypic variance. Here, we complemented 161 PanC4, have been described elsewhere 6-9 . Genotyping for PanScan studies was performed

Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression. Through global transcriptomic analysis, we uncover a basal preinflammatory state in the pancreas of Nr5a2 heterozygous mice that is reminiscent of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2 +/-mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from tissue-specific to inflammatory loci thereby promoting AP-1-dependent gene transcription. Importantly, deletion of c-Jun in the pancreas of these mice rescues the pre-inflammatory phenotype and the defective regenerative response to damage. These findings provide compelling evidence that the same transcriptional networks supporting homeostasis in normal tissue can be subverted to foster inflammation upon genetic or environmental constraints.