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PMID: 28708932 Published · ppublish English Journal Article

Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.

Cancer ·Vol. 123 ·No. 22 ·2017-11-15 ·Pages 4506-4514

Okazaki S, Schirripa M, Loupakis F, Cao S, Zhang W, Yang D, Ning Y, Berger MD, Miyamoto Y, Suenaga M, Iqubal S, Barzi A, Cremolini C, Falcone A, Battaglin F, Salvatore L, Borelli B, Helentjaris TG, Lenz HJ

Abstract

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.

Keywords
hypermethylated in cancer 1 (HIC1) metastatic colorectal cancer oxaliplatin predictive marker variable number of tandem repeat (VNTR) polymorphism
MeSH Terms
Adult Aged Antineoplastic Combined Chemotherapy Protocols/therapeutic use Biomarkers, Tumor/genetics Cohort Studies Colorectal Neoplasms/drug therapy,genetics,pathology Female Humans Kruppel-Like Transcription Factors/genetics Male Middle Aged Minisatellite Repeats/genetics Neoplasm Metastasis Organoplatinum Compounds/administration & dosage Oxaliplatin Polymorphism, Genetic Prognosis Promoter Regions, Genetic Treatment Outcome Young Adult
Chemicals
Biomarkers, Tumor HIC1 protein, human Kruppel-Like Transcription Factors Organoplatinum Compounds Oxaliplatin
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Okazaki Satoshi ORCID
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Schirripa Marta
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.
Loupakis Fotios
Medical Oncology 1, Veneto Institute of Oncology, Institute for Research and Health Care (IRCCS), Padova, Italy.
Cao Shu
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Zhang Wu
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Yang Dongyun
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Ning Yan
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Berger Martin D
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Miyamoto Yuji
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Suenaga Mitsukuni
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Iqubal Syma
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Barzi Afsaneh
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Cremolini Chiara
Medical Oncology Unit 2, Pisa University Hospital, Tuscan Tumor Institute, Pisa, Italy.
Falcone Alfredo
Medical Oncology Unit 2, Pisa University Hospital, Tuscan Tumor Institute, Pisa, Italy.
Battaglin Francesca
Medical Oncology 1, Veneto Institute of Oncology, Institute for Research and Health Care (IRCCS), Padova, Italy.
Salvatore Lisa
Medical Oncology Unit 2, Pisa University Hospital, Tuscan Tumor Institute, Pisa, Italy.
Borelli Beatrice
Medical Oncology Unit 2, Pisa University Hospital, Tuscan Tumor Institute, Pisa, Italy.
Helentjaris Timothy G
BIO5 Institute, University of Arizona, Tucson, Arizona. | Department of Plant Sciences, University of Arizona, Tucson, Arizona.
Lenz Heinz-Josef
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Article Info
Journal
Cancer
Abbr.
Cancer
ISSN
1097-0142
DOI
10.1002/cncr.30880
Published
2017-11-15
Epub
2017-00-14
Pages
4506-4514
Language
English
Region
United States
NLM ID
0374236
PMCID
PMC5673544
Subset
IM
Grants
NCI NIH HHS · P30 CA014089 · United States
NCI NIH HHS · R01 CA166161 · United States
NCI NIH HHS · U10 CA180830 · United States
External Links
PubMed source DOI: 10.1002/cncr.30880 PMC Full Text View journal details
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