Whole-exome Sequencing of Pancreatic Cancer Defines Genetic Diversity and Therapeutic Targets

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Apr 10

PMID 25855536

Citations 601

Authors

Agnieszka K Witkiewicz

Elizabeth A McMillan

Uthra Balaji

GuemHee Baek

Wan-Chi Lin

John Mansour

Mehri Mollaee

Kay-Uwe Wagner

Prasad Koduru

Adam Yopp

Michael A Choti

Charles J Yeo

Peter McCue

Michael A White

Erik S Knudsen

Affiliations

Soon will be listed here.

Abstract

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.

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References

Goode D, Hunter S, Doyle M, Ma T, Rowley S, Choong D . A simple consensus approach improves somatic mutation prediction accuracy. Genome Med. 2013; 5(9):90. PMC: 3978449. DOI: 10.1186/gm494. View

Klein A, Hruban R, Brune K, Petersen G, Goggins M . Familial pancreatic cancer. Cancer J. 2001; 7(4):266-73. View

Imielinski M, Berger A, Hammerman P, Hernandez B, Pugh T, Hodis E . Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012; 150(6):1107-20. PMC: 3557932. DOI: 10.1016/j.cell.2012.08.029. View

Collisson E, Trejo C, Silva J, Gu S, Korkola J, Heiser L . A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012; 2(8):685-93. PMC: 3425446. DOI: 10.1158/2159-8290.CD-11-0347. View

Yadav D, Lowenfels A . The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013; 144(6):1252-61. PMC: 3662544. DOI: 10.1053/j.gastro.2013.01.068. View

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View

Koboldt D, Zhang Q, Larson D, Shen D, McLellan M, Lin L . VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012; 22(3):568-76. PMC: 3290792. DOI: 10.1101/gr.129684.111. View

Lin W, Rajbhandari N, Liu C, Sakamoto K, Zhang Q, Triplett A . Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Res. 2013; 73(6):1821-30. PMC: 3602120. DOI: 10.1158/0008-5472.CAN-12-2067. View

Lawrence M, Stojanov P, Mermel C, Robinson J, Garraway L, Golub T . Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014; 505(7484):495-501. PMC: 4048962. DOI: 10.1038/nature12912. View

10.

Frey B, Dueck D . Clustering by passing messages between data points. Science. 2007; 315(5814):972-6. DOI: 10.1126/science.1136800. View

11.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

12.

Ihle N, Byers L, Kim E, Saintigny P, Lee J, Blumenschein G . Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012; 104(3):228-39. PMC: 3274509. DOI: 10.1093/jnci/djr523. View

13.

Biankin A, Waddell N, Kassahn K, Gingras M, Muthuswamy L, Johns A . Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012; 491(7424):399-405. PMC: 3530898. DOI: 10.1038/nature11547. View

14.

Shi T, Seligson D, Belldegrun A, Palotie A, Horvath S . Tumor classification by tissue microarray profiling: random forest clustering applied to renal cell carcinoma. Mod Pathol. 2004; 18(4):547-57. DOI: 10.1038/modpathol.3800322. View

15.

Holzmann K, Kohlhammer H, Schwaenen C, Wessendorf S, Kestler H, Schwoerer A . Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res. 2004; 64(13):4428-33. DOI: 10.1158/0008-5472.CAN-04-0431. View

16.

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

17.

Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton T . APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 2014; 7(6):1833-41. DOI: 10.1016/j.celrep.2014.05.012. View

18.

Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G . The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat Med. 2014; 20(6):596-8. PMC: 4048332. DOI: 10.1038/nm.3548. View

19.

Vincent A, Herman J, Schulick R, Hruban R, Goggins M . Pancreatic cancer. Lancet. 2011; 378(9791):607-20. PMC: 3062508. DOI: 10.1016/S0140-6736(10)62307-0. View

20.

Helming K, Wang X, Wilson B, Vazquez F, Haswell J, Manchester H . ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med. 2014; 20(3):251-4. PMC: 3954704. DOI: 10.1038/nm.3480. View