Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation.
Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation.
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DOI：
10.1002/cjp2.120
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Chetty R
中科院分区：
文献类型：
--
作者：
McCarthy AJ;Capo-Chichi JM;Spence T;Grenier S;Stockley T;Kamel-Reid S;Serra S;Sabatini P;Chetty R
错配修复 (MMR) 蛋白的免疫组织化学 (IHC) 用于识别 MMR 状态：呈弥漫性阳性（完整/保留核染色）或显示核肿瘤染色缺失（MMR 蛋白缺陷）。通过下一代测序 (NGS) 表征了四种结肠腺癌和一种伴有相关不典型增生的胃腺癌，这些腺癌在四种 MMR 蛋白中的至少一种中表现出异质 IHC 染色模式。为了检查这些染色模式的潜在分子机制，对各个区域进行了宏观解剖，分析了微卫星不稳定性 (MSI)，并通过 NGS 和 MLH1、MSH2、MSH6 和 PMS2 基因的多重连接依赖性探针扩增 (MLPA) 分析（包括 MLH1 甲基化分析）进行了研究。一种结肠腺癌显示出异质性 MSH6 IHC 染色，分子分析表明，与保留 MSH6 的区域相比，MSH6 蛋白缺失区域中两种 MSH6 移码变体（c.3261delC 和 c.3261dupC）的等位基因负荷增加。两种具有异源 MLH1 染色的结肠腺癌显示序列变异没有差异。然而，在其中一个案例中，MLH1 在 MLH1 缺失区域过度甲基化。另一种具有异质 PMS2 染色（但保留了 MSH6）的结肠癌显示 MSH6 c.3261dupC 和 3260_3261dupCC 均丢失，其中 PMS2 蛋白丢失，仅 c.3261dupC 保留 PMS2。胃癌显示发育异常病灶中 MSH6 完全缺失，而潜在的浸润性癌则显示 MSH6 保留。然而，这两个区域的 MSI 均较高，并显示出相同的 MSH6 变体：c.3261delC。胃发育不良还显示MSH6 c.3261dupC。在 MMR 蛋白丢失的 5 例中，有 4 例的这些区域的 MSI 较高。异质 MMR IHC（同一肿瘤内或侵袭性和发育不良性侵袭前区域之间的局灶性和/或带状性）并不总是由人为造成，并且总是与丢失区域的 MSI 高状态相关。这项研究的一个有趣的方面是 MSH6 体细胞突变的存在，无论 MSH6 IHC 染色是否完整或丢失。
Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is used to identify MMR status: being diffusely positive (intact/retained nuclear staining) or showing loss of nuclear tumour staining (MMR protein deficient). Four colonic adenocarcinomas and a gastric adenocarcinoma with associated dysplasia that displayed heterogenous IHC staining patterns in at least one of the four MMR proteins were characterised by next‐generation sequencing (NGS). In order to examine a potential molecular mechanism for these staining patterns, the respective areas were macrodissected, analysed for microsatellite instability (MSI) and investigated by NGS and multiplex ligation‐dependent probe amplification (MLPA) analysis of MLH1, MSH2, MSH6 and PMS2 genes, including MLH1 methylation analysis. One colonic adenocarcinoma showed heterogenous MSH6 IHC staining and molecular analysis demonstrated increasing allelic burden of two MSH6 frameshift variants (c.3261delC and c.3261dupC) in areas with MSH6 protein loss compared to areas where MSH6 was retained. Two colonic adenocarcinomas with heterogenous MLH1 staining showed no differences in sequence variants. In one of these cases, however, MLH1 was hypermethylated in the area of MLH1 loss. Another colon carcinoma with heterogenous PMS2 staining (but with retained MSH6) showed both MSH6 c.3261dupC and 3260_3261dupCC where PMS2 protein was lost and only c.3261dupC where PMS2 was retained. The gastric carcinoma showed complete loss of MSH6 in dysplastic foci, while the underlying invasive carcinoma showed retention of MSH6. Both these areas, however, were MSI‐high and showed the same MSH6 variant: c.3261delC. The gastric dysplasia additionally showed MSH6 c.3261dupC. In four of the five cases where MMR protein was lost, these areas were MSI‐high. Heterogenous MMR IHC (focal and/or zonal within the same tumour or between invasive and dysplastic preinvasive areas) is not always due to artefact and is invariably related to MSI‐high status in the areas of loss. An interesting aspect to this study is the presence of MSH6 somatic mutations irrespective of whether MSH6 IHC staining was intact or lost.
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