Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

By A. Biankin, N. Waddell, K. Kassahn, M. Gingras, L. Muthuswamy, A. Johns, David K. Miller, P. J. Wilson, A. Patch, Jianmin Wu and 116 more. Nature, 2012

1,987 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/7c562279879e7a7888d4672aaf6d69f1ad36a48b

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Citations in the corpus

KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, methodology): “…data of pancreatic cancer patients shows that 93% of the rare PIK3CA mutations co-occur with aKRASmutation, suggesting activated KRAS alone is not sufficient to effectively activate PI3K (Jones et al. 2008; Biankin et al. 2012; Sausen et al. 2015; Waddell et al. 2015; Witkiewicz et al. 2015).”
KRAS: feeding pancreatic cancer proliferation (2014, positive): “Although oncogenic KRAS was first associated with PDAC decades ago, recent exome sequencing established that KRAS is the most frequently mutated gene in PDAC (95%), the predominant form of pancreatic cancer (~90%) [6,9].”
Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma (2017, positive): “Except forRREB1, these genes have been previously reported as altered in PDAC (Bailey et al., 2016; Biankin et al., 2012; Jones et al., 2008; Waddell et al., 2015; Witkiewicz et al., 2015).”