Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Michael T. Barrett, Valsamo Anagnostou, Sonya Parpart-Li, Derek Murphy, Qing Kay Li, Carolyn A. Hruban, Rob Scharpf, James R. White, Peter J. O'Dwyer, Peter J. Allen, James R. Eshleman, Craig B. Thompson, David S. Klimstra, David C. Linehan, Anirban Maitra & 6 others Ralph H. Hruban, Luis A. Diaz, Daniel D. Von Hoff, Julia S. Johansen, Jeffrey A. Drebin, Victor E. Velculescu

Research output: Research - peer-reviewArticle

Abstract

Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

LanguageEnglish (US)
Article number7686
JournalNature Communications
Volume6
DOIs
StatePublished - Jul 7 2015

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Pancreatic Neoplasms
Neoplasms
tumors
cancer
Tumors
deoxyribonucleic acid
DNA
mutations
genes
Genes
Recurrence
Mutation
Therapeutics
chromatin
mortality
liquids
predictions
Biopsy
Chromatin
Imaging techniques

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. / Sausen, Mark; Phallen, Jillian; Adleff, Vilmos; Jones, Siân; Leary, Rebecca J.; Barrett, Michael T.; Anagnostou, Valsamo; Parpart-Li, Sonya; Murphy, Derek; Li, Qing Kay; Hruban, Carolyn A.; Scharpf, Rob; White, James R.; O'Dwyer, Peter J.; Allen, Peter J.; Eshleman, James R.; Thompson, Craig B.; Klimstra, David S.; Linehan, David C.; Maitra, Anirban; Hruban, Ralph H.; Diaz, Luis A.; Von Hoff, Daniel D.; Johansen, Julia S.; Drebin, Jeffrey A.; Velculescu, Victor E.

In: Nature Communications, Vol. 6, 7686, 07.07.2015.

Research output: Research - peer-reviewArticle

Sausen, M, Phallen, J, Adleff, V, Jones, S, Leary, RJ, Barrett, MT, Anagnostou, V, Parpart-Li, S, Murphy, D, Li, QK, Hruban, CA, Scharpf, R, White, JR, O'Dwyer, PJ, Allen, PJ, Eshleman, JR, Thompson, CB, Klimstra, DS, Linehan, DC, Maitra, A, Hruban, RH, Diaz, LA, Von Hoff, DD, Johansen, JS, Drebin, JA & Velculescu, VE 2015, 'Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients' Nature Communications, vol 6, 7686. DOI: 10.1038/ncomms8686
Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nature Communications. 2015 Jul 7;6. 7686. Available from, DOI: 10.1038/ncomms8686
Sausen, Mark ; Phallen, Jillian ; Adleff, Vilmos ; Jones, Siân ; Leary, Rebecca J. ; Barrett, Michael T. ; Anagnostou, Valsamo ; Parpart-Li, Sonya ; Murphy, Derek ; Li, Qing Kay ; Hruban, Carolyn A. ; Scharpf, Rob ; White, James R. ; O'Dwyer, Peter J. ; Allen, Peter J. ; Eshleman, James R. ; Thompson, Craig B. ; Klimstra, David S. ; Linehan, David C. ; Maitra, Anirban ; Hruban, Ralph H. ; Diaz, Luis A. ; Von Hoff, Daniel D. ; Johansen, Julia S. ; Drebin, Jeffrey A. ; Velculescu, Victor E./ Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. In: Nature Communications. 2015 ; Vol. 6.
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abstract = "Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.",
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