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.

The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

TP53 mutation occurs in 50-75% of human pancreatic ductal adenocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in expression of a stable protein, p53 R175H , rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53 R172H ), compared to knockout p53 (Trp53 fl ), in a mouse model of PDAC. First we find that although Kras G12D is one of the major oncogenic drivers of PDAC, most Kras G12D-expressing pancreatic cells are selectively lost from the tissue, and those that remain form premalignant lesions. Loss, or mutation, of Trp53 allows retention of the Kras G12D -expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progression is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53 R172P, which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we find that despite similar kinetics of primary tumor formation, mutant p53 R172H , as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53 R172H -expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation significantly correlates with lymph node metastasis. In summary, by using 'knock-in' mutations of Trp53 we have identified two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; first, an escape from Kras G12D -induced senescence/ growth arrest and second, the promotion of metastasis.Kras | metastasis | p53 | pancreatic cancer | senescence P ancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer deaths in Europe and the United States, with an estimated 5-year overall survival of less than 5% (1, 2). Poor prognosis results from the aggressive nature of the disease, with as many as 90% of patients at the time of diagnosis harboring unresectable cancer that is extremely resistant to chemotherapy. PDAC arises from precursor lesions called pancreatic intraepithelial neoplasms (PanINs), which are characterized by the sequential accumulation of alterations in the KRAS oncogene and loss of the CDKN2A, TP53, and/or SMAD4 tumor suppressors in many cases (3). Although we know the frequencies of such mutations in PDAC, their specific functions during the development of pancreatic cancer remain unclear. Here we have used a genetically engineered mouse model of pancreatic cancer (4) to aid in understanding of the respective roles of gain-of-function Kras and Trp53 mutations.KRAS is mutated in almost all human PDACs (5), and this is one of the earliest genetic events driving development of human PanINs. Studies in murine models have further shown that activating KRAS mutation represents an initiating step in PDAC (6-9). The TP53 tumor suppressor gene is also frequently mutated in human pancreatic cancer (50-75%), predominantly through missense mutations (10). These often result in accumulati...

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Relatives of patients with gastric cancer have an increased prevalence of precancerous gastric abnormalities, but this increase is confined to those with H. pylori infection. Consequently, prophylactic eradication of the infection should be offered to such subjects.

N-WASP is critical for cancer cell invasion through its promotion of the trafficking and capture of MT1-MMP in invasive pseudopods.

Purpose: Patients with metastatic adenocarcinoma of unknown origin are a common clinical problem. Knowledge of the primary site is important for their management, but histologically, such tumors appear similar. Better diagnostic markers are needed to enable the assignment of metastases to likely sites of origin on pathologic samples. Experimental Design: Expression profiling of 27 candidate markers was done using tissue microarrays and immunohistochemistry. In the first (training) round, we studied 352 primary adenocarcinomas, from seven main sites (breast, colon, lung, ovary, pancreas, prostate and stomach) and their differential diagnoses. Data were analyzed in Microsoft Access and the Rosetta system, and used to develop a classification scheme. In the second (validation) round, we studied 100 primary adenocarcinomas and 30 paired metastases. Results: In the first round, we generated expression profiles for all 27 candidate markers in each of the seven main primary sites. Data analysis led to a simplified diagnostic panel and decision tree containing 10 markers only: CA125, CDX2, cytokeratins 7 and 20, estrogen receptor, gross cystic disease fluid protein 15, lysozyme, mesothelin, prostate-specific antigen, and thyroid transcription factor1. Applying the panel and tree to the original data provided correct classification in 88%.The 10 markers and diagnostic algorithm were then tested in a second, independent, set of primary and metastatic tumors and again 88% were correctly classified.Conclusions:This classification scheme should enable better prediction on biopsy material of the primary site in patients with metastatic adenocarcinoma of unknown origin, leading to improved management and therapy.