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.
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 RECQLA159C 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.
Authors: Kevin M Doherty; Sudha Sharma; Laura A Uzdilla; Teresa M Wilson; Sheng Cui; Alessandro Vindigni; Robert M Brosh Journal: J Biol Chem Date: 2005-05-09 Impact factor: 5.157
Authors: T Kawabe; N Tsuyama; S Kitao; K Nishikawa; A Shimamoto; M Shiratori; T Matsumoto; K Anno; T Sato; Y Mitsui; M Seki; T Enomoto; M Goto; N A Ellis; T Ide; Y Furuichi; M Sugimoto Journal: Oncogene Date: 2000-09-28 Impact factor: 9.867
Authors: Donghui Li; Hui Liu; Li Jiao; David Z Chang; Garth Beinart; Robert A Wolff; Douglas B Evans; Manal M Hassan; James L Abbruzzese Journal: Cancer Res Date: 2006-03-15 Impact factor: 12.701
Authors: Jinyun Chen; Donghui Li; Ann M Killary; Subrata Sen; Christopher I Amos; Douglas B Evans; James L Abbruzzese; Marsha L Frazier Journal: Ann Surg Oncol Date: 2008-11-20 Impact factor: 5.344
Authors: Jason A Willis; Sara H Olson; Irene Orlow; Semanti Mukherjee; Robert R McWilliams; Robert C Kurtz; Robert J Klein Journal: Clin Cancer Res Date: 2012-06-04 Impact factor: 12.531
Authors: Thomas S Frank; Xiaotian Sun; Yuqing Zhang; Jingxuan Yang; William E Fisher; Marie-Claude Gingras; Min Li Journal: Cancer Lett Date: 2015-04-15 Impact factor: 8.679
Authors: Donghui Li; Jennifer Moughan; Christopher Crane; John P Hoffman; William F Regine; Ross A Abrams; Howard Safran; Chang Liu; Ping Chang; Gary M Freedman; Kathryn A Winter; Chandan Guha; James L Abbruzzese Journal: Int J Radiat Oncol Biol Phys Date: 2015-11-05 Impact factor: 7.038