Okazaki Satoshi, Schirripa Marta, Loupakis Fotios, Cao Shu, Zhang Wu, Yang Dongyun, Ning Yan, Berger Martin D, Miyamoto Yuji, Suenaga Mitsukuni, Iqubal Syma, Barzi Afsaneh, Cremolini Chiara, Falcone Alfredo, Battaglin Francesca, Salvatore Lisa, Borelli Beatrice, Helentjaris Timothy G, Lenz Heinz-Josef
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Medical Oncology 1, Veneto Institute of Oncology, Institute for Research and Health Care (IRCCS), Padova, Italy.
Cancer. 2017 Nov 15;123(22):4506-4514. doi: 10.1002/cncr.30880. Epub 2017 Jul 14.
The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy.
Four independent cohorts were tested. Patients who received oxaliplatin-based chemotherapy served as the training cohort (n = 218), and those who received treatment without oxaliplatin served as the control cohort (n = 215). Two cohorts of patients who received oxaliplatin-based chemotherapy were used for validation studies (n = 176 and n = 73). The VNTR sequence near HIC1 was analyzed by polymerase chain reaction analysis and gel electrophoresis and was tested for associations with the response rate, progression-free survival, and overall survival.
In the training cohort, patients who harbored at least 5 tandem repeats (TRs) in both alleles had a significantly shorter PFS compared with those who had fewer than 4 TRs in at least 1 allele (9.5 vs 11.6 months; hazard ratio, 1.93; P = .012), and these findings remained statistically significant after multivariate analysis (hazard ratio, 2.00; 95% confidence interval, 1.13-3.54; P = .018). This preliminary association was confirmed in the validation cohort, and patients who had at least 5 TRs in both alleles had a worse PFS compared with the other cohort (7.9 vs 9.8 months; hazard ratio, 1.85; P = .044).
The current findings suggest that the VNTR sequence near HIC1 could be a predictive marker for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 2017;123:4506-14. © 2017 American Cancer Society.
癌症高甲基化 1/沉默调节蛋白 1（HIC1/SIRT1）轴在调节核苷酸切除修复途径中起重要作用，该途径是奥沙利铂诱导损伤的主要修复系统。基于先前的证据，即位于 HIC1 启动子损伤附近的可变数目串联重复序列（VNTR）与 HIC1 基因表达相关，作者检验了这样一个假设：该 VNTR 与接受奥沙利铂为基础化疗的转移性结直肠癌患者的临床结局相关。
对四个独立队列进行了检测。接受奥沙利铂为基础化疗的患者作为训练队列（n = 218），未接受奥沙利铂治疗的患者作为对照队列（n = 215）。两个接受奥沙利铂为基础化疗的患者队列用于验证研究（n = 176 和 n = 73）。通过聚合酶链反应分析和凝胶电泳分析 HIC1 附近的 VNTR 序列，并检测其与缓解率、无进展生存期和总生存期的相关性。
在训练队列中，两个等位基因中均含有至少 5 个串联重复序列（TRs）的患者与至少 1 个等位基因中 TRs 少于 4 个的患者相比，无进展生存期显著缩短（9.5 个月对 11.6 个月；风险比，1.93；P = 0.012），多因素分析后这些结果仍具有统计学意义（风险比，2.00；95%置信区间，1.13 - 3.54；P = 0.018）。在验证队列中证实了这种初步关联，两个等位基因中均含有至少 5 个 TRs 的患者与另一队列相比无进展生存期更差（7.9 个月对 9.8 个月；风险比，1.85；P = 0.044）。
目前的研究结果表明，HIC1 附近的 VNTR 序列可能是转移性结直肠癌患者接受奥沙利铂为基础化疗的预测标志物。《癌症》2017 年；123:4506 - 14。©2017 美国癌症协会。
