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

Department of Clinical Medicine

237 Citations (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.

Original language	English
Article number	7686
Journal	Nature Communications
Volume	6
Number of pages	6
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms8686
Publication status	Published - 7 Jul 2015

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms8686Licence: CC BY

Cite this

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, Article 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, vol. 6, 7686. https://doi.org/10.1038/ncomms8686

@article{f710f5046aac4d65b2b9057daf92019d,

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",

author = "Mark Sausen and Jillian Phallen and Vilmos Adleff and Si{\^a}n Jones and Leary, {Rebecca J} and Barrett, {Michael T} and Valsamo Anagnostou and Sonya Parpart-Li and Derek Murphy and {Kay Li}, Qing and Hruban, {Carolyn A} and Rob Scharpf and White, {James R} and O'Dwyer, {Peter J} and Allen, {Peter J} and Eshleman, {James R} and Thompson, {Craig B} and Klimstra, {David S} and Linehan, {David C} and Anirban Maitra and Hruban, {Ralph H} and Diaz, {Luis A} and {Von Hoff}, {Daniel D} and Johansen, {Julia S} and Drebin, {Jeffrey A} and Velculescu, {Victor E}",

year = "2015",

month = jul,

day = "7",

doi = "10.1038/ncomms8686",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

TY - JOUR

T1 - Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

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

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this