Gastroenterology. 2014 Feb;146(2):401-11.e1. doi: 10.1053/j.gastro.2013.10.054.
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.
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).
HSP110 and HSP110DE9 interacted in a1:1 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 T17 deletion (P =.009).
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.
与无微卫星不稳定性（MSI）的结直肠肿瘤患者相比，具有 MSI 的结直肠肿瘤患者预后更好，但对基于 5-氟尿嘧啶的化疗反应较差。通过体细胞 T(17)内含子重复缺失导致的外显子跳跃，在具有 MSI 的癌细胞中表达的热休克蛋白（HSP）110 的一种显性负形式（HSP110DE9），使细胞对 5-氟尿嘧啶和奥沙利铂敏感。我们研究了 HSP110T(17)是否可用于鉴定接受 5-氟尿嘧啶和奥沙利铂辅助化疗的结直肠癌患者是否受益。
我们使用表面等离子体共振技术来描述 HSP110 和 HSP110DE9 之间的相互作用。通过聚合酶链反应和片段分析，我们检查了 HSP110T(17)中体细胞等位基因缺失的大小如何影响肿瘤细胞中表达的 HSP110 蛋白。我们筛选了在三级医疗中心接受手术切除的 329 例连续的 II 期至 III 期 MSI 结直肠肿瘤患者的 HSP110T(17)。
HSP110 和 HSP110DE9 以 1:1 的比例相互作用。由于全长 HSP110 的表达丢失，T(17)中有较大缺失的肿瘤细胞具有更高的 HSP110DE9:HSP110 比值。在具有 MSI 的原发性肿瘤样本中，HSP110T(17)的缺失主要是双等位基因的。在多变量分析中，接受化疗且 HSP110T(17)缺失较大（≥5 bp；77 例患者中的 18 例，23.4%）的 II 期至 III 期癌症患者的无复发生存时间长于缺失较小或无缺失（≤4 bp；77 例患者中的 59 例，76.6%）（危险比，0.16；95%置信区间，0.012-0.8；P =.03）。我们发现化疗和 T17 缺失之间存在显著的相互作用（P =.009）。
约 25%的具有 MSI 的 II 期至 III 期结直肠肿瘤患者对化疗有良好的反应，这是由于肿瘤 DNA 中 HSP110T(17)内含子重复的大、双等位基因缺失所致。
