SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer

Amanda Blackford, Oscar K. Serrano, Christopher L. Wolfgang, Giovanni Parmigiani, Siân Jones, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng Ho Lin, Rebecca J. Leary, James R. Eshleman, Michael Goggins, Elizabeth M. Jaffee, Christine A. Iacobuzio-Donahue, Anirban Maitra, John L. Cameron, Kelly Olino, Richard Schulick, Jordan Winter, Joseph M. Herman, Daniel Laheru & 5 others Alison P. Klein, Bert Vogelstein, Kenneth W. Kinzler, Victor E. Velculescu, Ralph H. Hruban

Research output: Contribution to journalArticle

228 Citations (Scopus)

Abstract

Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. Results: When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). P atients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (≥4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. Conclusions: SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.

Original languageEnglish (US)
Pages (from-to)4674-4679
Number of pages6
JournalClinical Cancer Research
Volume15
Issue number14
DOIs
StatePublished - Jul 15 2009
Externally publishedYes

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Pancreatic Neoplasms
Pancreas
Adenocarcinoma
Gene Silencing
Mutation
Genes
Neoplasms
Pancreaticoduodenectomy
Survival
Genetic Markers
Base Pairing
Research Design
Lymph Nodes
Confidence Intervals
DNA
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blackford, A., Serrano, O. K., Wolfgang, C. L., Parmigiani, G., Jones, S., Zhang, X., ... Hruban, R. H. (2009). SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clinical Cancer Research, 15(14), 4674-4679. https://doi.org/10.1158/1078-0432.CCR-09-0227

SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. / Blackford, Amanda; Serrano, Oscar K.; Wolfgang, Christopher L.; Parmigiani, Giovanni; Jones, Siân; Zhang, Xiaosong; Parsons, D. Williams; Lin, Jimmy Cheng Ho; Leary, Rebecca J.; Eshleman, James R.; Goggins, Michael; Jaffee, Elizabeth M.; Iacobuzio-Donahue, Christine A.; Maitra, Anirban; Cameron, John L.; Olino, Kelly; Schulick, Richard; Winter, Jordan; Herman, Joseph M.; Laheru, Daniel; Klein, Alison P.; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.; Hruban, Ralph H.

In: Clinical Cancer Research, Vol. 15, No. 14, 15.07.2009, p. 4674-4679.

Research output: Contribution to journalArticle

Blackford, A, Serrano, OK, Wolfgang, CL, Parmigiani, G, Jones, S, Zhang, X, Parsons, DW, Lin, JCH, Leary, RJ, Eshleman, JR, Goggins, M, Jaffee, EM, Iacobuzio-Donahue, CA, Maitra, A, Cameron, JL, Olino, K, Schulick, R, Winter, J, Herman, JM, Laheru, D, Klein, AP, Vogelstein, B, Kinzler, KW, Velculescu, VE & Hruban, RH 2009, 'SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer', Clinical Cancer Research, vol. 15, no. 14, pp. 4674-4679. https://doi.org/10.1158/1078-0432.CCR-09-0227
Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clinical Cancer Research. 2009 Jul 15;15(14):4674-4679. https://doi.org/10.1158/1078-0432.CCR-09-0227
Blackford, Amanda ; Serrano, Oscar K. ; Wolfgang, Christopher L. ; Parmigiani, Giovanni ; Jones, Siân ; Zhang, Xiaosong ; Parsons, D. Williams ; Lin, Jimmy Cheng Ho ; Leary, Rebecca J. ; Eshleman, James R. ; Goggins, Michael ; Jaffee, Elizabeth M. ; Iacobuzio-Donahue, Christine A. ; Maitra, Anirban ; Cameron, John L. ; Olino, Kelly ; Schulick, Richard ; Winter, Jordan ; Herman, Joseph M. ; Laheru, Daniel ; Klein, Alison P. ; Vogelstein, Bert ; Kinzler, Kenneth W. ; Velculescu, Victor E. ; Hruban, Ralph H. / SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 14. pp. 4674-4679.
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abstract = "Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. Results: When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95{\%} confidence interval, 1.20-3.05; P = 0.006). P atients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (≥4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. Conclusions: SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.",
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T1 - SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer

AU - Blackford, Amanda

AU - Serrano, Oscar K.

AU - Wolfgang, Christopher L.

AU - Parmigiani, Giovanni

AU - Jones, Siân

AU - Zhang, Xiaosong

AU - Parsons, D. Williams

AU - Lin, Jimmy Cheng Ho

AU - Leary, Rebecca J.

AU - Eshleman, James R.

AU - Goggins, Michael

AU - Jaffee, Elizabeth M.

AU - Iacobuzio-Donahue, Christine A.

AU - Maitra, Anirban

AU - Cameron, John L.

AU - Olino, Kelly

AU - Schulick, Richard

AU - Winter, Jordan

AU - Herman, Joseph M.

AU - Laheru, Daniel

AU - Klein, Alison P.

AU - Vogelstein, Bert

AU - Kinzler, Kenneth W.

AU - Velculescu, Victor E.

AU - Hruban, Ralph H.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. Results: When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). P atients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (≥4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. Conclusions: SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.

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