TY - JOUR
T1 - Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer
AU - Okazaki, Satoshi
AU - Schirripa, Marta
AU - Loupakis, Fotios
AU - Cao, Shu
AU - Zhang, Wu
AU - Yang, Dongyun
AU - Ning, Yan
AU - Berger, Martin D.
AU - Miyamoto, Yuji
AU - Suenaga, Mitsukuni
AU - Iqubal, Syma
AU - Barzi, Afsaneh
AU - Cremolini, Chiara
AU - Falcone, Alfredo
AU - Battaglin, Francesca
AU - Salvatore, Lisa
AU - Borelli, Beatrice
AU - Helentjaris, Timothy G.
AU - Lenz, Heinz Josef
N1 - Attenzione: Schirripa affiliata anche a Univeristy of Southern California - Los Angeles, in quanto progetto condotto tra due enti. Richiesta correzione del documento, rifiutato dall'editore.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
KW - hypermethylated in cancer 1 (HIC1)
KW - metastatic colorectal cancer
KW - oxaliplatin
KW - predictive marker
KW - variable number of tandem repeat (VNTR) polymorphism
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U2 - 10.1002/cncr.30880
DO - 10.1002/cncr.30880
M3 - Article
C2 - 28708932
AN - SCOPUS:85023641370
VL - 123
SP - 4506
EP - 4514
JO - Cancer
JF - Cancer
SN - 0008-543X
IS - 22
ER -