Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
HPB (Oxford). 2009 Aug;11(5):435-44. doi: 10.1111/j.1477-2574.2009.00089.x.
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.
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.
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.
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.
RECQL 是一种参与 DNA 错配修复的 DNA 解旋酶。RECQL 多态性，3'非翻译区（UTR）A159C，先前与接受新辅助放化疗的可切除胰腺腺癌患者的总生存期相关。在本研究中，我们检查了 RECQL 的体细胞突变和其他多态性，并将这些发现与接受辅助或新辅助放化疗的患者的结果进行了比较。我们假设 (i) RECQL 在癌症中会发生突变，(ii) 会有与 3'UTR A159C 相关的多态性，并且这些事件中的一个或两个都会影响功能。我们还假设 (iii) 这些变化将与两个队列的患者的生存相关。
我们对 39 名患者的配对血液和肿瘤 DNA 中的 RECQL 的 15 个外显子和周围序列进行了测序。从 176 名接受辅助（53 名）或新辅助（123 名）放化疗的可切除胰腺腺癌患者的血液 DNA 样本中确定了 3'UTR A159C 基因型。使用 Kaplan-Meier 方法计算生存时间，并通过对数秩检验比较组间差异。使用 Cox 比例风险模型评估基因型对总生存时间的相对影响。
在 RECQL 基因的 UTR 和内含子区域发现了体细胞突变，但在外显子编码区域没有发现。位于内含子 2 和 11 中的两个单核苷酸多态性（SNP）被发现是与 RECQL A159C SNP 相同的单倍型块的一部分，并且与总生存期具有相似的关联。两种治疗策略之间没有发现短期生存差异。我们确定了一个对新辅助治疗有反应的患者亚组，其中 159A 等位基因赋予了惊人的长期生存改善。
RECQL 3'UTR A159C SNP 与 RECQL 内的其他功能 SNP 不相关，但可能作为调节分子的作用位点。作用机制需要进一步澄清。
