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 LaheruAlison P. Klein, Bert Vogelstein, Kenneth W. Kinzler, Victor E. Velculescu, Ralph H. Hruban

Research output: Contribution to journalArticle

243 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Blackford, A., Serrano, O. K., Wolfgang, C. L., Parmigiani, G., Jones, S., Zhang, X., Parsons, D. W., Lin, J. C. H., Leary, R. J., Eshleman, J. R., Goggins, M., Jaffee, E. M., Iacobuzio-Donahue, C. A., Maitra, A., Cameron, J. L., Olino, K., Schulick, R., Winter, J., Herman, J. M., ... 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