Division of Genetics and Clinical Laboratory, Yamanashi Cental Hospital, Yamanashi, Japan.
Genome Analysis Center, Yamanashi Cental Hospital, Yamanashi, Japan.
Cancer Med. 2022 Dec;11(23):4479-4490. doi: 10.1002/cam4.4832. Epub 2022 May 21.
Evaluation of the status of mismatch repair (MMR) in tumors is crucial for determining the application of immune checkpoint inhibitors (ICIs). Conventional PCR (MSI-PCR) is the gold standard for confirming the MMR status. However, it requires visual confirmation and presents difficulties in determining MMR status. Immunohistochemistry (IHC) is a simple method and can confirming MMR protein expression in the whole tumor. We aim to investigate IHC is more suitable for evaluating MMR status in the tumor. We compared MSI-PCR and IHC by testing 319 samples from 284 patients across 14 cancer types. In discordant cases, we performed laser-capture microdissection and microsatellite instability assay by next-generation sequencing (MSI-NGS). The concordance rate between IHC and MSI-PCR testing was 98.1% (313/319). Two reasons for these discrepancies were ambiguous MSI-PCR results and heterogeneous MSI status within the tumor. Among six cases (1.9%), three were judged as MSI-H by MSI-PCR but with proficient MMR by IHC. The results of MSI-NGS revealed microsatellite stable in these three cases. The remaining three cases, two of three were MSI-H and one was MSS in whole tumor in MSI-PCR. IHC showed a "mosaic" pattern containing both proficient MMR and deficient MMR portions by IHC in all three cases. We performed microdissection and MSI-PCR and found intratumoral heterogeneity of MMR status. These results indicated the advantages of IHC and performed expanded samples (n = 1082) and two additional mosaic cases were identified. Our results clearly indicated that simple IHC is the best choice for determining MMR alterations in critical cases for ICIs treatment.
评估肿瘤错配修复（MMR）状态对于确定免疫检查点抑制剂（ICIs）的应用至关重要。传统的聚合酶链反应（MSI-PCR）是确认 MMR 状态的金标准。然而，它需要目视确认，并且在确定 MMR 状态方面存在困难。免疫组织化学（IHC）是一种简单的方法，可以确认整个肿瘤中 MMR 蛋白的表达。我们旨在研究 IHC 更适合评估肿瘤中的 MMR 状态。我们通过测试来自 14 种癌症类型的 284 名患者的 319 个样本，比较了 MSI-PCR 和 IHC。在不一致的情况下，我们通过下一代测序（MSI-NGS）进行了激光捕获显微切割和微卫星不稳定性检测。IHC 与 MSI-PCR 检测的一致性率为 98.1%（313/319）。出现这些差异有两个原因：MSI-PCR 结果不明确和肿瘤内 MMR 状态不均一。在 6 例（1.9%）中，有 3 例被 MSI-PCR 判断为 MSI-H，但 IHC 显示 MMR 功能正常。MSI-NGS 的结果显示这 3 例均为微卫星稳定。其余 3 例中，2 例 MSI-PCR 全肿瘤为 MSI-H，1 例 MSS。IHC 显示 3 例均存在“镶嵌”模式，既包含 MMR 功能正常的部分，也包含 MMR 功能缺失的部分。我们进行了微切割和 MSI-PCR，并发现 MMR 状态存在肿瘤内异质性。这些结果表明了 IHC 的优势，并进行了扩展样本（n=1082）分析，又发现了 2 例镶嵌病例。我们的结果清楚地表明，在关键的 ICIs 治疗病例中，简单的 IHC 是确定 MMR 改变的最佳选择。
