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SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

ABSTRACT: Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

SUBMITTER: Mohelnikova-Duchonova B

PROVIDER: S-EPMC5341046 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

Mohelnikova-Duchonova Beatrice B Strouhal Ondrej O Hughes David J DJ Holcatova Ivana I Oliverius Martin M Kala Zdenek Z Campa Daniele D Rizzato Cosmeri C Canzian Federico F Pezzilli Raffaele R Talar-Wojnarowska Renata R Malecka-Panas Ewa E Sperti Cosimo C Federico Zambon Carlo C Pedrazzoli Sergio S Fogar Paola P Milanetto Anna Caterina AC Capurso Gabriele G Delle Fave Gianfranco G Valente Roberto R Gazouli Maria M Malleo Giuseppe G Teresa Lawlor Rita R Strobel Oliver O Hackert Thilo T Giese Nathalia N Vodicka Pavel P Vodickova Ludmila L Landi Stefano S Tavano Francesca F Gioffreda Domenica D Piepoli Ada A Pazienza Valerio V Mambrini Andrea A Pedata Mariangela M Cantore Maurizio M Bambi Franco F Ermini Stefano S Funel Niccola N Lemstrova Radmila R Soucek Pavel P

Scientific reports 20170308

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the ...[more]

PMID: 28272475

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Project description:BackgroundPancreatic carcinoma is one of the most lethal human cancers. In patients with resectable tumors, surgery followed by adjuvant chemotherapy is the only curative treatment. However, the 5-year survival is 20%. Because of a strong metastatic propensity, neoadjuvant chemotherapy is being tested in randomized clinical trials. In this context, improving the selection of patients for immediate surgery or neoadjuvant chemotherapy is crucial, and high-throughput molecular analyses may help; the present study aims to address this.MethodsClinicopathological and gene expression data of 695 pancreatic carcinoma samples were collected from nine datasets and supervised analysis was applied to search for a gene expression signature predictive for overall survival (OS) in the 601 informative operated patients. The signature was identified in a learning set of patients and tested for its robustness in a large independent validation set.ResultsSupervised analysis identified 1400 genes differentially expressed between two selected patient groups in the learning set, namely 17 long-term survivors (LTS; ≥ 36 months after surgery) and 22 short-term survivors (STS; dead of disease between 2 and 6 months after surgery). From these, a 25-gene prognostic classifier was developed, which identified two classes ("STS-like" and "LTS-like") in the independent validation set (n = 562), with a 25% (95% CI 18-33) and 48% (95% CI 42-54) 2-year OS (P = 4.33 × 10-9), respectively. Importantly, the prognostic value of this classifier was independent from both clinicopathological prognostic features and molecular subtypes in multivariate analysis, and existed in each of the nine datasets separately. The generation of 100,000 random gene signatures by a resampling scheme showed the non-random nature of our prognostic classifier.ConclusionThis study, the largest prognostic study of gene expression profiles in pancreatic carcinoma, reports a 25-gene signature associated with post-operative OS independently of classical factors and molecular subtypes. This classifier may help select patients with resectable disease for either immediate surgery (the LTS-like class) or neoadjuvant chemotherapy (the STS-like class). Its assessment in the current prospective trials of adjuvant and neoadjuvant chemotherapy trials is warranted, as well as the functional analysis of the classifier genes, which may provide new therapeutic targets.

Dataset Information

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

Publications

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

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