title: Somatic mutations in exocrine pancreatic tumors: association with patient survival.
abstract: KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. s.rachakonda@dkfz.de
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Bauer
authors.forename: Huaping
authors.initials: H
authors.lastname: Xie
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.forename: Cosmeri
authors.initials: C
authors.lastname: Rizzato
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Stefania
authors.initials: S
authors.lastname: Beghelli
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.forename: Michaela
authors.initials: M
authors.lastname: Schanne
authors.forename: Anette
authors.initials: A
authors.lastname: Heller
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.forename: Markus
authors.initials: M
authors.lastname: Büchler
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Nathalia
authors.initials: N
authors.lastname: Giese
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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