Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets

By A. Witkiewicz, E. McMillan, U. Balaji, GuemHee Baek, Wan-chi Lin, J. Mansour, M. Mollaee, K. Wagner, P. Koduru, A. Yopp and 5 more. Nature Communications, 2015

990 citations recorded by the source corpus.

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets. Diagnosis of pancreatic ductal adenocarcinoma (PDA) has poor long-term survival rates with limited therapy options. Here Witkiewicz et al.use microdissection and whole-exome sequencing to identify novel recurrent PDA mutations, highlighting the genetic diversity of this aggressive cancer.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/1c0f25f89f4d30e0b9094bd3854e36e216a8c778

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Oncology

Citations in the corpus

KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, methodology): “Although there are cancer-type differences in the sensitivity to BRAFselective inhibitors, the infrequent BRAF mutant PDACswere responsive in vitro (Witkiewicz et al. 2015).”
RAS isoforms and mutations in cancer at a glance (2016, background): “Recent analyses observed that patients with KRAS Q61 mutations showed significantly improved survival (Witkiewicz et al., 2015) and, interestingly, Q61-mutant tumors showed decreased ERK activation in these samples.”
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma (2017, positive): “Eight LZTR1 mutations were inactivating splice-site mutations at codon 217, a mutation observed in adrenocortical and pancreatic cancers (Witkiewicz et al., 2015).”
Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma (2016, background): “Mutations in RBM10 were described in lung and pancreatic adenocarcinomas and shown to be associated with male sex and an improved prognosis, respectively (Cancer Genome Atlas Research Network, 2014; Witkiewicz et al., 2015).”
Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade (2016, background): “G12D mutation of KRAS, which is shared across a large fraction of PAAD patients (Witkiewicz et al., 2015).”
Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma (2017, positive): “, 2015), or have employed techniques that purify tumor samples, either by generating cell lines or patient-derived xenografts, or by using mechanical enrichment techniques such as macrodissection or laser capture microdissection (Jones et al., 2008; Witkiewicz et al., 2015).”