Clinical study of genomic drivers in pancreatic ductal adenocarcinoma

Michael T. Barrett, Ray Deiotte, Elizabeth Lenkiewicz, Smriti Malasi, Tara Holley, Lisa Evers, Richard G Posner, Timothy Jones, Haiyong Han, Mark Sausen, Victor E. Velculescu, Jeffrey Drebin, Peter O'Dwyer, Gayle Jameson, Ramesh K. Ramanathan, Daniel D. Von Hoff

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.Methods: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.Results: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its' 3′ region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (≥ 40 months) and short-term (≤ 12 months) survival after surgical resection.Conclusions: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.

Original languageEnglish (US)
Pages (from-to)572-582
Number of pages11
JournalBritish Journal of Cancer
Volume117
Issue number4
DOIs
StatePublished - Aug 8 2017

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Keywords

  • CNVs
  • flow sorting
  • focal amplicons
  • homozygous deletions
  • KRAS mutations
  • pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Barrett, M. T., Deiotte, R., Lenkiewicz, E., Malasi, S., Holley, T., Evers, L., Posner, R. G., Jones, T., Han, H., Sausen, M., Velculescu, V. E., Drebin, J., O'Dwyer, P., Jameson, G., Ramanathan, R. K., & Von Hoff, D. D. (2017). Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. British Journal of Cancer, 117(4), 572-582. https://doi.org/10.1038/bjc.2017.209