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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

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Abstract

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.

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Figure 1: Mutations and copy number variation in axon guidance genes.
Figure 2: SLIT/ROBO signalling in pancreatic ductal adenocarcinoma.
Figure 3: Axon guidance genes in human and murine pancreatic ductal adenocarcinoma.

Accession codes

Data deposits

BAM files and associated metadata in XML format have been uploaded to the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega) under accession numbers GAS00001000154 and EGAS00001000343. Additional sequence data is located at dbGAP accession number phs000516.v1.p1.

Change history

  • 14 November 2012

    The spelling of author ‘Qinying Xu’ was corrected; minor formatting changes were made to the Acknowledgements and Affiliations.

References

  1. Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010)

    Article  Google Scholar 

  2. Butturini, G. et al. Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch. Surg. 143, 75–83 (2008)

    Article  Google Scholar 

  3. Neoptolemos, J. P. et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. J. Am. Med. Assoc. 304, 1073–1081 (2010)

    Article  CAS  Google Scholar 

  4. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)

    Article  ADS  CAS  Google Scholar 

  5. International Cancer Genome Consortium International network of cancer genome projects. Nature 464, 993–998 (2010)

    Article  ADS  Google Scholar 

  6. Biankin, A. V. et al. Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer. Gastroenterology 137, 558–568 (2009)

    Article  Google Scholar 

  7. Chang, D. K. et al. Margin clearance and outcome in resected pancreatic cancer. J. Clin. Oncol. 27, 2855–2862 (2009)

    Article  Google Scholar 

  8. Jamieson, N. B. et al. A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. Ann. Surg. Oncol. 18, 2318–2328 (2011)

    Article  Google Scholar 

  9. Wang, L. et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res. 22, 208–219 (2012)

    Article  CAS  Google Scholar 

  10. Song, S. et al. qpure: A tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles. PLoS ONE 7, e45835 (2012)

    Article  ADS  CAS  Google Scholar 

  11. Samuel, N. & Hudson, T. J. The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nature Rev. Gastroenterol. Hepatol. 9, 77–87 (2012)

    Article  CAS  Google Scholar 

  12. Dees, N. D. et al. MuSiC: Identifying mutational significance in cancer genomes. Genome Res. 22, 1589–1598 (2012)

    Article  CAS  Google Scholar 

  13. Roberts, N. J. et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2, 41–46 (2011)

    Article  Google Scholar 

  14. Mermel, C. H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011)

    Article  Google Scholar 

  15. Sun, W. et al. Integrated study of copy number states and genotype calls using high-density SNP arrays. Nucleic Acids Res. 37, 5365–5377 (2009)

    Article  CAS  Google Scholar 

  16. Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010)

    Article  ADS  CAS  Google Scholar 

  17. Mann, K. M. et al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 5934–5941 (2012)

    Article  ADS  CAS  Google Scholar 

  18. Pérez-Mancera, P. A. et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 486, 266–270 (2012)

    Article  Google Scholar 

  19. Cheung, H. W. et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc. Natl Acad. Sci. USA 108, 12372–12377 (2011)

    Article  ADS  CAS  Google Scholar 

  20. Mehlen, P., Delloye-Bourgeois, C. & Chedotal, A. Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nature Rev. Cancer 11, 188–197 (2011)

    Article  CAS  Google Scholar 

  21. Sabatier, C. et al. The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117, 157–169 (2004)

    Article  CAS  Google Scholar 

  22. Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev. Cancer 2, 289–300 (2002)

    Article  CAS  Google Scholar 

  23. Birnbaum, D. J. et al. Genome profiling of pancreatic adenocarcinoma. Genes Chromosom. Cancer 50, 456–465 (2011)

    Article  CAS  Google Scholar 

  24. Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004)

    Article  CAS  Google Scholar 

  25. Jones, S. et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum. Mutat. 33, 100–103 (2012)

    Article  CAS  Google Scholar 

  26. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011)

    Article  ADS  CAS  Google Scholar 

  27. Comoglio, P. M. & Trusolino, L. Invasive growth: from development to metastasis. J. Clin. Invest. 109, 857–862 (2002)

    Article  CAS  Google Scholar 

  28. Chédotal, A., Kerjan, G. & Moreau-Fauvarque, C. The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ. 12, 1044–1056 (2005)

    Article  Google Scholar 

  29. Ong, C. K. et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nature Genet. 44, 690–693 (2012)

    Article  CAS  Google Scholar 

  30. Capparuccia, L. & Tamagnone, L. Semaphorin signaling in cancer cells and in cells of the tumor microenvironment–two sides of a coin. J. Cell Sci. 122, 1723–1736 (2009)

    Article  CAS  Google Scholar 

  31. Müller, M. W. et al. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int. J. Cancer 121, 2421–2433 (2007)

    Article  Google Scholar 

  32. Ellis, L. M. The role of neuropilins in cancer. Mol. Cancer Ther. 5, 1099–1107 (2006)

    Article  CAS  Google Scholar 

  33. Kikuchi, K. et al. In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin. J. Biol. Chem. 278, 42985–42991 (2003)

    Article  CAS  Google Scholar 

  34. Cao, Y., DePinho, R. A., Ernst, M. & Vousden, K. Cancer research: past, present and future. Nature Rev. Cancer 11, 749–754 (2011)

    Article  CAS  Google Scholar 

  35. Pajic, M., Scarlett, C. J., Chang, D. K., Sutherland, R. L. & Biankin, A. V. Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes. Hum. Genet. 130, 93–101 (2011)

    Article  CAS  Google Scholar 

  36. Biankin, A. V. & Hudson, T. J. Somatic variation and cancer: therapies lost in the mix. Hum. Genet. 130, 79–91 (2011)

    Article  Google Scholar 

  37. Kris M. G., Meropol N. J., Winer E. P., eds. Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research (Am. Soc. Clin. Oncol., 2011)

  38. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

This paper is dedicated to Robert L. Sutherland who died on 10 October 2012 of pancreatic cancer. We would like to thank C. Axford, D. Gwynne, M.-A. Brancato, S. Rowe, M. Thomas, S. Simpson and G. Hammond for central coordination of the Australian Pancreatic Cancer Genome Initiative, data management and quality control; M. Martyn-Smith, L. Braatvedt, H. Tang, V. Papangelis and M. Beilin for biospecimen acquisition; and W. Waterson, J. Shepperd, E. Campbell and E. Glasov for their efforts at the Queensland Centre for Medical Genomics. We also thank M. B. Hodgin, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University, and J. Lau, M. Karaus, K. Rabe, L. Zhang and T. Smyrk at the Mayo Clinic. We acknowledge the following funding support: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601, 535914); Australian Government: Department of Innovation, Industry, Science, Research and Tertiary Education (DIISRTE); Australian Cancer Research Foundation (ACRF); Queensland Government (NIRAP); University of Queensland; Cancer Council NSW (SRP06-01; ICGC09-01; SRP11-01); Cancer Institute NSW (06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; R.T. Hall Trust; Petre Foundation; Jane Hemstritch in memory of Philip Hemstritch; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation – INNOVATOR Award; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); HGSC-BCM: NHGRI U54 HG003273; CPRIT grant RP101353-P7 (Tumor Banking for Genomic Research and Clinical Translation Site 1); The Ontario Institute for Cancer Research; The Ontario Ministry of Economic Development and Innovation; Canada Foundation for Innovation; Pancreatic Cancer Genetic Epidemiology Consortium, NIH grant R01 CA97075; The Agency for Science, Technology, and Research (Singapore); University of Verona and Italian Ministry of University (FIRB RBAP10AHJB), Rome, Italy; Cancer Research UK; Wellcome Trust; CPRIT (Cancer Prevention Research Institute of Texas); NIH P50CA062924 (SPORE) and P01CA134292 (PPG); The Sol Goldman Pancreatic Cancer Research Center; NCI grant P50 CA102701 (Mayo Clinic SPORE in Pancreatic Cancer) and NCI grant R01 CA97075 (Pancreatic Cancer Genetic Epidemiology Consortium); NIH SPORE grant 2P50CA101955 (UMN/UAB), and AIRC (Associazione Italiana Ricerca sul Cancro) 5xmille grant 12182, Italy.

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Contributions

The research network comprising the Australian Pancreatic Cancer Genome Initiative, the Baylor College of Medicine Cancer Genome Project and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study (ABO collaboration) contributed collectively to this study as part of the International Cancer Genome Consortium. Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. Investigator contributions are as follows: S.M.G., A.V.B., J.V.P., R.L.S., R.A.G., D.A.W., M.-C.G., J.D.M., L.D.S and T.J.H. (project leaders); A.V.B., S.M.G. and R.L.S. (writing team); A.L.J., J.V.P., P.J.W., J.L.F., C.L., M.A., O.H., J.G.R., D.T., C.X., S.Wo., F.N., S.So., G.K. and W.K. (bioinformatics/databases); D.K.M., I.H., S.I., C.N., S.M., A.Chr., T.Br., S.Wa., E.N., B.B.G., D.M.M., Y.Q.W., Y.H., L.R.L., H.D., R. E. D., R.S.M. and M.W. (sequencing); N.W., K.S.K., J.V.P., A.-M.P., K.N., N.C., M.G., P.J.W., M.J.C., M.P., J.W., N.K., F.Z., J.D., K.C., C.J.B., L.B.M., D.P., R.E.D., R.D.B., T.Be. and C.K.Y. (mutation, copy number and gene expression analysis); A.L.J., D.K.C., M.D.J., M.P., C.J.S., E.K.C., C.T., A.M.N., E.S.H., V.T.C., L.A.C., E.N., J.S.S., J.L.H., C.T., N.B. and M.Sc. (sample processing and quality control); A.J.G., J.G.K., R.H.H., C.A.I.-D., A.Cho., A.Mai., J.R.E., P.C. and A.S. (pathology assessment); J.W., M.J.C., M.P., C.K.Y. and mutation analysis team (network/pathway analysis and functional data integration); K.M.M., N.A.J., N.G.C., P.A.P.-M., D.J.A., D.A.L., L.F.A.W., A.G.R., D.A.T., R.J.D., I.R., A.V.P., E.A.M., R.L.S., R.H.H. and A.Maw. (functional screens); E.N., A.L.J., J.S.S., A.J.G., J.G.K., N.D.M., A.B., K.E., N.Q.N., N.Z., W.E.F., F.C.B., S.E.H., G.E.A., L.M., L.T., M.Sam., K.B., A.B., D.P., A.P., N.B., R.D.B., R.E.D., C.Y., S.Se., N.O., D.M., M-S.T., P.A.S., G.M.P., S.G., L.D.S., C.A.I.-D., R.D.S., C.L.W., R.A.M., R.T.L., S.B., V.C., M.Sca., C.B., M.A.T., G.T., A.S. and J.R.E. (sample collection and clinical annotation); D.K.C., M.P., C.J.S., E.S.H., J.A.L., R.J.D., A.V.P. and I.R. (preclinical models).

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Correspondence to Sean M. Grimmond.

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Biankin, A., Waddell, N., Kassahn, K. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012). https://doi.org/10.1038/nature11547

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