Beta2-microglobulin mutations in microsatellite unstable colorectal tumors
Beta2-microglobulin mutations in microsatellite unstable colorectal tumors
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DOI：
10.1002/ijc.22691
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发表时间：
2007-07-15
影响因子：
6.4
通讯作者：
Doeberitz, Magnus von Kriebel
中科院分区：
文献类型：
--
作者：
Kloor, Matthias;Michel, Sara;Doeberitz, Magnus von Kriebel
DNA 错配修复 (MMR) 缺陷会导致高水平的微卫星不稳定性 (MSI-H) 表型。 MSI-H 癌症可能是散发性的，也可能是在由 MMR 基因种系突变引起的遗传性非息肉病性结直肠癌 (HNPCC) 综合征的背景下发生的。在结直肠癌 (CRC) 中，MSI-H 的特点是密集的淋巴细胞浸润，反映了这些癌症的高免疫原性。作为免疫选择的结果，MSI-H CRC 经常表现出由 β 2-微球蛋白 (β 2m) 基因突变引起的人类白细胞抗原 (HLA) I 类抗原呈递的缺失。为了研究 MSI-H 结直肠肿瘤发展过程中 β 2m 突变的影响，我们分析了不同阶段的 MSI-H 结直肠腺瘤 (n = 38) 和癌 (n = 104) 中 β 2m 突变的患病率。在 6/38 (15.8%) MSI-H 腺瘤和 29/104 (27.9%) MSI-H CRC 中观察到突变。与没有种系突变的患者 (15.4%) 相比，MMR 基因 MLH1 或 MSH2 种系突变 (36.4%) 的 MSI-H CRC 患者中观察到 β2m 突变的频率更高。 HNPCC 相关 MSI-H CRC 中 β 2m 突变的高频率与免疫选择在具有发展 MSI-H 癌症遗传倾向的 HNPCC 患者中尤其明显的假设相符。 beta 2m 突变与无远处转移的肿瘤分期 (UICC I-III) 呈正相关，表明 beta 2m 表达缺失可能促进结直肠 MSI-H 肿瘤的局部进展。然而，在转移性 CRC 中未观察到 β2m 突变（UICC IV 期，p = 0.04）。这些结果表明，功能性 β2m 可能是 CRC 患者远处转移形成所必需的。 (C) 2007 Wiley-Liss, Inc.
Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the beta 2-microglobulin (beta 2m) gene. To examine the implications of beta 2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of beta 2m mutations in MSI-H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of beta 2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of beta 2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. beta 2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of beta 2m expression may promote local progression of colorectal MSI-H tumors. However, no beta 2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional beta 2m may be necessary for distant metastasis formation in CRC patients. (C) 2007 Wiley-Liss, Inc.