SMAD4 Gene Mutations Are Associated with Poor Prognosis in Pancreatic Cancer
Open accessAbstract
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). Patients 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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SMAD4 loss has a profound deleterious effect on prognosis.
“SMAD4 loss has a profound deleterious effect on prognosis54”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [54]
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- Authors
- 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., Laheru, D., Klein, A. P., Vogelstein, B., Kinzler, K. W., Velculescu, V. E., & Hruban, R. H.
- Affiliations
- 1Oncology, Departments of
- 2Surgery,
- Johns Hopkins University (US)
- ORCID
- Blackford, Amanda
- Serrano, Oscar K.
- Wolfgang, Christopher L.
- Parmigiani, Giovanni
- Zhang, Xiaosong
- Parsons, D. Williams
- Lin, Jimmy Cheng-Ho
- Leary, Rebecca J.
- Eshleman, James R.
- Goggins, Michael
- Jaffee, Elizabeth M.
- Maitra, Anirban
- 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.
- Venue
- Clinical Cancer Research
- Published
- 2009-07-15
- Volume
- 15
- Issue
- 14
- Pages
- 4674-4679
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2819274
- OpenAlex
- W2005021386
- Cited by
- 371
- References
- 52
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 18 · 2023: 19 · 2022: 15 · 2021: 18 · 2020: 29 · 2019: 26 · 2018: 15 · 2017: 33 · 2016: 25 · 2015: 37 · 2014: 29 · 2013: 21 · 2012: 26
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lustgarten Foundation
- Rolfe Pancreatic Cancer Foundation
- National Institutes of Health (5r01ca121113-15, CA121113, CA62924)
- National Cancer Institute (R01-CA121113, CA-121113, P50CA062924, CA 62924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- SMAD4, pancreatic ductal adenocarcinoma, somatic mutations, prognosis, overall survival, gene inactivation, CDKN2A, TP53, multiple mutations, homozygous deletion, pancreaticoduodenectomy, genetic markers
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Pancreatic Neoplasms, Prognosis, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Gene Deletion, Receptors, Transforming Growth Factor beta, Smad4 Protein, Kaplan-Meier Estimate
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