HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression.
HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression.
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DOI：
10.1186/1471-2407-7-33
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发表时间：
2007-02-22
期刊：
影响因子：
3.8
通讯作者：
Morreau H
中科院分区：
文献类型：
--
作者：
Dierssen JW;de Miranda NF;Ferrone S;van Puijenbroek M;Cornelisse CJ;Fleuren GJ;van Wezel T;Morreau H
人类白细胞抗原(HLAI)类分子表达异常在结直肠癌中十分常见。由于肿瘤抗原特异性细胞毒性T淋巴细胞(CTL)的激活需要人类白细胞抗原的表达，因此人类白细胞抗原I类异常是肿瘤逃避免疫监视的一种机制。具有高微卫星不稳定性(MSI-H)的肿瘤由于产生大量的免疫原肽而被认为面临着逃避CTL活性的强大选择压力。以前的研究证实了MSI-H肿瘤中存在人类白细胞抗原I类改变的发生率。然而，这些报告没有比较遗传性和散发性MSI-H肿瘤之间的改变频率，也没有比较导致每个亚组中HLAI类改变的机制。为探讨HLAI类分子在散发性微卫星H和微卫星稳定型HNPCC肿瘤中的表达特征，采用免疫组织化学方法比较了81例右侧散发性肿瘤和75例HNPCC肿瘤中HLAI类分子、β2微球蛋白(β2M)和抗原处理机成分的表达。此外，我们还研究了这些变化的遗传基础。人类白细胞抗原I类缺失在微卫星细胞瘤中比在多发性硬化症肿瘤中更常见(p<；0.0001)。不同的机制导致HNPCC和散发性MSI-H肿瘤的HLAI类丢失。在HNPCC肿瘤中，HLAI类表达缺失与APM2M缺失有关，而在散发性β-H肿瘤中，HLAI类表达缺失与APM2M缺失相关(p<；0.0001)。在大约一半的病例中，HLAI类基因的表达缺失与检测到β2M和APM组分基因的一个或多个突变是一致的。在不同类型的结直肠肿瘤中，发现不同频率的人类白细胞抗原I类基因异常，并由不同的遗传机制引起。主要是，散发性和遗传性MSI-H肿瘤沿着不同的途径导致HLAI类基因表达缺失，支持这一观点，即这些肿瘤在肿瘤发生中遵循不同的进化途径。由此产生的免疫逃逸机制的变化可能会对肿瘤的进展和行为产生影响。
Abnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer. Since HLA expression is required to activate tumor antigen-specific cytotoxic T-lymphocytes (CTL), HLA class I abnormalities represent a mechanism by which tumors circumvent immune surveillance. Tumors with high microsatellite instability (MSI-H) are believed to face strong selective pressure to evade CTL activity since they produce large amounts of immunogenic peptides. Previous studies identified the prevalence of HLA class I alterations in MSI-H tumors. However, those reports did not compare the frequency of alterations between hereditary and sporadic MSI-H tumors neither the mechanisms that led to HLA class I alterations in each subgroup. To characterize the HLA class I expression among sporadic MSI-H and microsatellite-stable (MSS) tumors, and HNPCC tumors we compared immunohistochemically the expression of HLA class I, β2-microglobulin (β2m), and Antigen Processing Machinery (APM) components in 81 right-sided sporadic and 75 HNPCC tumors. Moreover, we investigated the genetic basis for these changes. HLA class I loss was seen more frequently in MSI-H tumors than in MSS tumors (p < 0.0001). Distinct mechanisms were responsible for HLA class I loss in HNPCC and sporadic MSI-H tumors. Loss of HLA class I expression was associated with β2m loss in HNPCC tumors, but was correlated with APM component defects in sporadic MSI-H tumors (p < 0.0001). In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the β2m and APM components genes. HLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms. Chiefly, sporadic and hereditary MSI-H tumors follow different routes toward HLA class I loss of expression supporting the idea that these tumors follow different evolutionary pathways in tumorigenesis. The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.
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影响因子：
3.2
作者：
Maleno, I;Cabrera, CM;Garrido, F
通讯作者：
Garrido, F
影响因子：
4.4
作者：
Perosa, F;Luccarelli, G;Dammacco, F
通讯作者：
Dammacco, F
影响因子：
--
作者：
Cabrera, CM;Jiménez, P;Garrido, F
通讯作者：
Garrido, F
影响因子：
8
作者：
de Leeuw, WJF;van Puijenbroek, M;Morreau, H
通讯作者：
Morreau, H
影响因子：
7.3
作者：
Corver, WE;ter Haar, NT;Fleuren, GJ
通讯作者：
Fleuren, GJ