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Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma.

ABSTRACT: BACKGROUND: RECQL is a DNA helicase involved in DNA mismatch repair. The RECQL polymorphism, 3' untranslated region (UTR) A159C, was previously associated with overall survival of patients with resectable pancreatic adenocarcinoma treated with neoadjuvant chemoradiation. In the present study, we examined RECQL for somatic mutations and other polymorphisms and compared these findings with the outcome in patients who received adjuvant or neoadjuvant chemoradiation. We hypothesized that RECQL (i) would be mutated in cancer, (ii) would have polymorphisms linked to the 3'UTR A159C and that either or both events would affect function. We also hypothesized that (iii) these changes would be associated with survival in both cohorts of patients. MATERIAL AND METHODS: We sequenced RECQL's 15 exons and surrounding sequences in paired blood and tumour DNA of 39 patients. The 3'UTR A159C genotype was determined in blood DNA samples from 176 patients with resectable pancreatic adenocarcinoma treated with adjuvant (53) or neoadjuvant (123) chemoradiation. Survival was calculated using the Kaplan-Meier method, with log rank comparisons between groups. The relative impact of genotype on time to overall survival was performed using the Cox proportional hazards model. RESULTS: Somatic mutations were found in UTRs and intronic regions but not in exonic coding regions of the RECQL gene. Two single nucleotide polymorphisms (SNPs), located in introns 2 and 11, were found to be part of the same haplotype block as the RECQL A159C SNP and showed a similar association with overall survival. No short-term difference in survival between treatment strategies was found. We identified a subgroup of patients responsive to neoadjuvant therapy in which the 159 A allele conferred strikingly improved long-term survival. DISCUSSION: The RECQL 3'UTR A159C SNP is not linked with other functional SNPs within RECQL but may function as a site for regulatory molecules. The mechanism of action needs to be clarified further.

SUBMITTER: Cotton RT

PROVIDER: S-EPMC2742614 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma.

Cotton Ronald T RT Li Donghui D Scherer Steven E SE Muzny Donna M DM Hodges Sally E SE Catania Robbi L RL Witkiewicz Agnieszka K AK Brody Jonathan R JR Kennedy Eugene P EP Yeo Charles J CJ Brunicardi F Charles FC Gibbs Richard A RA Gingras Marie-Claude MC Fisher William E WE

HPB : the official journal of the International Hepato Pancreato Biliary Association 20090801 5

<h4>Background</h4>RECQL is a DNA helicase involved in DNA mismatch repair. The RECQL polymorphism, 3' untranslated region (UTR) A159C, was previously associated with overall survival of patients with resectable pancreatic adenocarcinoma treated with neoadjuvant chemoradiation. In the present study, we examined RECQL for somatic mutations and other polymorphisms and compared these findings with the outcome in patients who received adjuvant or neoadjuvant chemoradiation. We hypothesized that RECQ ...[more]

PMID: 19768149

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ?10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGF?-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

Project description:Background Pancreatic ductal adenocarcinoma (PDAC) displays a typical mucin expression pattern which is characterized by MUC1 positive, MUC2 negative, and MUC5AC positive. More and more evidences show that mucins are involved in the development of pancreatic diseases. However, the relationship between mucin expression and prognosis of PDAC patients has been controversial in the past decades; therefore, we aim to figure out the association of mucin expression with survival in PDAC patients who underwent radical resection. Methods We performed immunohistochemistry (IHC) to detect the expression of MUC1, MUC2, and MUC5AC in resected PDAC specimens from Shanghai Cancer Center, Fudan University (FUSCC, n = 427) and obtained the corresponding clinical statistical data for retrospective study. Kaplan-Meier methods and Mantel-Cox tests were used to compare the survival curves, and the Cox regression model was employed for multivariate analyses to determine the independent risk factors. Survival analysis was also performed in the Queensland Centre for Medical Genomics (QCMG, n = 70) PDAC cohort to verify the conclusion. Results Both the FUSCC cohort and the QCMG cohort demonstrated that MUC1 absence was significantly correlated with worse overall survival (OS). The presence of MUC2 showed marginal significance in predicting shorter OS of PDAC patients, while MUC5AC had no prognostic value. In the FUSCC cohort, MUC1 absence was associated with increased proportion of stage III PDAC (p = 0.011), and MUC1 absence and MUC2 presence were associated with tumour perineural aggression (p = 0.011 and p = 0.030, respectively). Multivariable adjusted hazard ratios (HRs) for mortality of MUC1 and MUC2 were 0.492 (95% CI: 0.274-0.883, p = 0.017) and 1.596 (95% CI: 1.061-2.401, p = 0.025), respectively. Conclusions MUC1 absence or MUC2 presence is independently associated with poor OS among patients with resectable PDAC. MUC5AC absence tended to be associated with short-term death.

Dataset Information

Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma.

Publications

Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma.

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