Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracilbased chemotherapy.
Gastroenterology
; 146(2): 401-11.e1, 2014 Feb.
Article
en En
| MEDLINE
| ID: mdl-24512910
ABSTRACT
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-fluorouracilbased 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 IIIII colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17).RESULTS:
HSP110 and HSP110DE9 interacted in a11 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9HSP110, 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 IIIII 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, 0.0120.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009).CONCLUSIONS:
About 25% of patients with stages IIIII 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.
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Bases de datos:
MEDLINE
Asunto principal:
Secuencia de Bases
/
Neoplasias Colorrectales
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Biomarcadores de Tumor
/
Eliminación de Secuencia
/
Proteínas del Choque Térmico HSP110
/
Inestabilidad de Microsatélites
Tipo de estudio:
Evaluation_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Aged
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Gastroenterology
Año:
2014
Tipo del documento:
Article