期刊
CLINICAL CANCER RESEARCH
卷 18, 期 22, 页码 6339-6347出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-1215
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资金
- National Institutes of Health [CA140599, CA101955, CA62924, CA121113]
- The Uehara Memorial Foundation
- The Alfredo Scatena Memorial
- The George Rubis Endowment for Pancreatic Cancer Research
- The Michael Rolfe Pancreatic Cancer Foundation
- Sigma Beta Sorority
- The Joseph C. Monastra Foundation
- The Gloria Swan Pancreatic Cancer Foundation
- The Skip Viragh Pancreatic Cancer Center
- The Patty Boshell Pancreas Cancer Foundation
- Stand Up To Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-CT0109]
- Grants-in-Aid for Scientific Research [24659612, 23390326] Funding Source: KAKEN
Purpose: Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome. Experimental Design: Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. Results: The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53). Conclusions: Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status. Clin Cancer Res; 18(22); 6339-47. (C) 2012 AACR.
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