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


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.


CONCLUSIONS
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.
Cotton
Ronald T
RT
Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
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