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

Institut for Klinisk Medicin

237 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	7686
Tidsskrift	Nature Communications
Vol/bind	6
Antal sider	6
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms8686
Status	Udgivet - 7 jul. 2015

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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., Kay Li, Q., 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, Artikel 7686. https://doi.org/10.1038/ncomms8686

Sausen, M, Phallen, J, Adleff, V, Jones, S, Leary, RJ, Barrett, MT, Anagnostou, V, Parpart-Li, S, Murphy, D, Kay Li, Q, 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, bind 6, 7686. https://doi.org/10.1038/ncomms8686

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title = "Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients",

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.",

keywords = "Biomarkers, Tumor, DNA, Gene Expression Regulation, Neoplastic, Genomics, Humans, Pancreatic Neoplasms, Predictive Value of Tests, Recurrence, Treatment Outcome",

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AU - Sausen, Mark

AU - Phallen, Jillian

AU - Adleff, Vilmos

AU - Jones, Siân

AU - Leary, Rebecca J

AU - Barrett, Michael T

AU - Anagnostou, Valsamo

AU - Parpart-Li, Sonya

AU - Murphy, Derek

AU - Kay Li, Qing

AU - Hruban, Carolyn A

AU - Scharpf, Rob

AU - White, James R

AU - O'Dwyer, Peter J

AU - Allen, Peter J

AU - Eshleman, James R

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

PY - 2015/7/7

Y1 - 2015/7/7

N2 - 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.

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.

KW - Biomarkers, Tumor

KW - DNA

KW - Gene Expression Regulation, Neoplastic

KW - Genomics

KW - Humans

KW - Pancreatic Neoplasms

KW - Predictive Value of Tests

KW - Recurrence

KW - Treatment Outcome

U2 - 10.1038/ncomms8686

DO - 10.1038/ncomms8686

M3 - Journal article

C2 - 26154128

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7686

ER -

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

Abstract

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