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; Ralph H. Hruban; Luis A. Diaz; Daniel D. Von Hoff; Julia S. Johansen; Jeffrey A. Drebin; Victor E. Velculescu

doi:10.1038/ncomms8686

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 MaitraRalph H. Hruban, Luis A. Diaz, Daniel D. Von Hoff, Julia S. Johansen, Jeffrey A. Drebin, Victor E. Velculescu

Health Sciences Research

Research output: Contribution to journal › Article

205 Scopus citations

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.

Original language	English (US)
Article number	7686
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8686
State	Published - Jul 7 2015

ASJC Scopus subject areas

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

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Sausen, M., Phallen, J., Adleff, V., Jones, S., Leary, R. J., Barrett, M. T., Anagnostou, V., Parpart-Li, S., Murphy, D., Li, Q. K., Hruban, C. A., Scharpf, R., White, J. R., O'Dwyer, P. J., Allen, P. J., Eshleman, J. R., Thompson, C. B., Klimstra, D. S., Linehan, D. C., ... Velculescu, V. E. (2015). Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nature communications, 6, [7686]. https://doi.org/10.1038/ncomms8686

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: Contribution to journal › Article

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. https://doi.org/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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AU - Anagnostou, Valsamo

AU - Parpart-Li, Sonya

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AU - Hruban, Carolyn A.

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AU - Thompson, Craig B.

AU - Klimstra, David S.

AU - Linehan, David C.

AU - Maitra, Anirban

AU - Hruban, Ralph H.

AU - Diaz, Luis A.

AU - Von Hoff, Daniel D.

AU - Johansen, Julia S.

AU - Drebin, Jeffrey A.

AU - Velculescu, Victor E.

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AB - 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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