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.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

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.

C ancer cells may acquire the capacity for autonomous and dysregulated proliferation through the uncontrolled production of specific molecules that promote cell growth (growth factors) or through abnormal, enhanced expression of specific proteins (growth factor receptors) on the cell membranes to which growth factors selectively bind. Both processes trigger a series of intracellular signals that ultimately lead to the proliferation of cancer cells, induction of angiogenesis, and metastasis. 1 The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family. Given this phenomenon, EGFR was the first growth factor receptor to be proposed as a target for cancer therapy. After 20 years of drug development, four EGFR antagonists are currently available for the treatment of four metastatic epithelial cancers: non-small-cell lung cancer, squamous-cell carcinoma of the head and neck, colorectal cancer, and pancreatic cancer. Less information is available about the use of EGFR antagonists in the treatment of earlier stages of cancer. This article summarizes the mechanisms of action of EGFR inhibitors, presents the clinical evidence of their anticancer activity, and considers the current, and controversial, clinical issues with respect to their optimal use in the treatment of patients with cancer.EGFR in Hum a n C a rcinogenesis EGFR is a transmembrane receptor belonging to a family of four related proteins (Fig. 1). 2 Ten different ligands can selectively bind to each receptor. After a ligand binds to a single-chain EGFR, the receptor forms a dimer 3 that signals within the cell by activating receptor autophosphorylation through tyrosine kinase activity. 3 Autophosphorylation triggers a series of intracellular pathways that may result in cancer-cell proliferation, blocking apoptosis, activating invasion and metastasis, and stimulating tumor-induced neovascularization. 3,4 Dev el opment of EGFR A ntag onis t s for A ntic a ncer Ther a pyThe first anti-EGFR drugs were developed in the 1980s. 18 Two classes of EGFR antagonists have been successfully tested in phase 3 trials and are now in clinical use: anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors (Tables 1 and 2). 4,5,[10][11][12]18 Anti-EGFR monoclonal antibodies, such as cetuximab, bind to the extracellular domain of EGFR when it is in the inactive configuration, compete for receptor binding by occluding the ligand-binding region, and thereby block ligand-induced EGFR tyrosine kinase activation. 4,5,19 Small-molecule EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, compete reversibly with ATP to bind to the intracellular catalytic domain of EGFR tyrosine kinase and, thus, inhibit EGFR autophosphorylation and downstream signaling. Anti-EGFR monoclonal antibodies recognize EGFR The New England Journal of Medicine Downloaded from nejm.org at DUKE MEDICAL CENTER LIBRARY on September 28, 2012. For personal use only. No ot...

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