Résumé
BACKGROUND & AIMS: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP) 110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T-17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T-17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. METHODS: We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T-17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T-17. RESULTS: HSP110 and HSP110DE9 interacted in a 1: 1 ratio. Tumor cells with large deletions in T-17 had increased ratios of HSP110DE9: HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T-17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T-17 deletions (>= 5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (<4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P = .03). We found a significant interaction between chemotherapy and T-17 deletion (P = .009). CONCLUSIONS: About 25% of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T-17 intron repeat of HSP110 in tumor DNA.