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 | |
| State | Published - Jul 7 2015 |
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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; 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
}
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
AU - Anagnostou, Valsamo
AU - Parpart-Li, Sonya
AU - Murphy, Derek
AU - Li, Qing Kay
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.
UR - http://www.scopus.com/inward/record.url?scp=84987784586&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987784586&partnerID=8YFLogxK
U2 - 10.1038/ncomms8686
DO - 10.1038/ncomms8686
M3 - Article
C2 - 26154128
AN - SCOPUS:84987784586
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 7686
ER -