Tandem repeat variation in HIC1 gene predicts outcome for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

Background

HIC1 (Hypermethylated in Cancer 1) is a transcription repressor, which cooperates with several partners to suppress the expression of multiple target genes. Among HIC1 targets, SIRT1 (Sirtuin1) plays a critical role in promoting the nucleotide excision repair (NER) pathway, which is the main oxaliplatin-induced damage repair system. HIC1 expression might be influenced by the number of variations in a tandemly-repeated sequence, situated close to the promoter region. We tested the hypothesis that variable number of tandem repeat (TR) in HIC1 will be associated with outcome in metastatic colorectal cancer patients (mCRC pts) receiving 1st-line chemotherapy with oxaliplatin.

Methods

This study enrolled 3 independent cohorts. Pts treated with FOLFOXIRI + bevacizumab in the phase III TRIBE study served as a training set (TRIBE-B cohort, n = 218). Pts receiving FOLFOXIRI + bevacizumab in the phase II MOMA study served as a validation set (MOMA cohort, n = 176). Pts treated without oxaliplatin (FOLFIRI + bevacizumab) in the TRIBE study served as a control set (TRIBE-A cohort, n = 215). Genomic DNA was isolated from blood samples. Variations in the number of TR were analyzed by PCR and Gel electrophoresis, and tested for the association with PFS and OS.

Results

Main patients characteristics' were the following: TRIBE-A; M/F 60/40%, median age 60, TRIBE-B; M/F 60/40%, median age 60, MOMA; M/F 57/43%, median age 61. Median follow-up times were 49.9, 48.0, and 25.3 months, respectively. Pts with number of TR ≤4 or ≥5 were 90/10% (TRIBE-A), 91/9% (TRIBE-B), and 95/5% (MOMA), respectively. In the training cohort, pts with TRs ≥5 showed a significantly shorter PFS compared to those with TRs ≤4 (9.5 vs. 11.6 mo, HR 1.93, P = 0.012), which retained statistical significance in multivariate analysis (HR 2.00, 95%CI: 1.13-3.54, P = 0.018). This preliminary association was confirmed in the validation cohort, and pts with TRs ≥5 showed a worse PFS compared to others (7.9 vs. 9.8 mo, HR 1.85, P = 0.044). This correlation was not observed in the control cohort.

Conclusions

Our findings suggest that variable number of TRs in HIC1 could be a predictive marker for oxaliplatin-containing chemotherapy in mCRC pts.

Clinical trial identification

Legal entity responsible for the study

University of Southern California

Funding

National Institute of Health

Disclosure

All authors have declared no conflicts of interest.