Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Colorectal tumors with microsatellite instability (MSI) generally have a better prognosis but respond poorly to 5-fluorouracil-based chemotherapy.
• A dominant-negative form of heat shock protein 110 (HSP110DE9), arising from exon skipping due to somatic deletions in the HSP110 T(17) intron repeat, sensitizes MSI cancer cells to 5-fluorouracil and oxaliplatin.

Purpose of the Study:

• To investigate if the HSP110 T(17) deletion status can identify patients with colorectal cancer who will benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin.

Main Methods:

• Surface plasmon resonance was used to characterize the interaction between HSP110 and HSP110DE9.
• Polymerase chain reaction and fragment analysis were employed to assess the impact of somatic allelic deletion size in HSP110 T(17) on HSP110 protein expression.
• HSP110 T(17) was screened in 329 consecutive patients with stage II–III MSI colorectal tumors.

Main Results:

• HSP110 and HSP110DE9 exhibited a 1:1 interaction ratio.
• Tumor cells with large T(17) deletions showed increased HSP110DE9:HSP110 ratios, linked to loss of full-length HSP110 expression.
• Patients with stage II–III cancer receiving chemotherapy and exhibiting large HSP110 T(17) deletions (≥5 bp) demonstrated significantly longer relapse-free survival compared to those with smaller or no deletions (≤4 bp) (HR, 0.16; P = .03).
• A significant interaction was observed between chemotherapy and T17 deletion status (P = .009).

Conclusions:

• Approximately 25% of patients with stage II–III MSI colorectal tumors possess large, biallelic deletions in the HSP110 T(17) intron repeat.
• These deletions in tumor DNA are associated with an excellent response to adjuvant chemotherapy, specifically 5-fluorouracil and oxaliplatin.