Xie Tong, Feng Qin, Li Zhongwu, Lu Ming, Li Jian, Lizaso Analyn, Xiang Jianxing, Zhang Lu, Shen Lin, Peng Zhi
Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China.
Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Hered Cancer Clin Pract. 2021 Jan 9;19(1):7. doi: 10.1186/s13053-021-00165-2.
Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).
We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
种系DNA错配修复（MMR）基因畸变与结直肠癌（CRC）易感性及高肿瘤突变负荷（TMB-H）相关，对免疫检查点抑制剂（ICI）产生良好反应的可能性增加。
我们报告一名32岁男性患者，诊断为遗传性MMR缺陷（CMMRD）的CRC，其MMR免疫组化（IHC）显示两个肿瘤组织块的结果不一致。对用于MMR-IHC的两个肿瘤标本和血浆来源的循环肿瘤DNA进行靶向测序，一致检测到双等位基因种系MSH6 c.3226C>T（p.R1076C）突变、TMB-H以及肿瘤样本的基因异质性。出乎意料的是，经PCR确认后，两个组织块均为微卫星稳定（MSS）。有趣的是，该患者对ICI单药治疗或联合治疗均无反应，但在临床上从ICI帕博利珠单抗加多重激酶抑制剂瑞戈非尼的联合治疗中获益。
我们的病例报告了一名MMR结果异质性的CMMRD患者，其对ICI表现出复杂的反应，强调了使用多个标本进行靶向测序以准确诊断的重要性，从而揭示CMMRD患者对ICI反应的可能机制。
