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Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review
Hereditary Cancer in Clinical Practice ( IF 1.7 ) Pub Date : 2021-01-09 , DOI: 10.1186/s13053-021-00165-2 Tong Xie , Qin Feng , Zhongwu Li , Ming Lu , Jian Li , Analyn Lizaso , Jianxing Xiang , Lu Zhang , Lin Shen , Zhi Peng
Hereditary Cancer in Clinical Practice ( IF 1.7 ) Pub Date : 2021-01-09 , DOI: 10.1186/s13053-021-00165-2 Tong Xie , Qin Feng , Zhongwu Li , Ming Lu , Jian Li , Analyn Lizaso , Jianxing Xiang , Lu Zhang , Lin Shen , Zhi Peng
Background 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). Case presentation 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. Conclusion 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.
中文翻译:
具有 MSH6 错义突变的异质性错配修复缺陷从帕博利珠单抗和瑞戈非尼联合治疗中获益:病例报告和文献综述
背景 生殖系 DNA 错配修复 (MMR) 基因畸变与结直肠癌 (CRC) 易感性和高肿瘤突变负荷 (TMB-H) 相关,增加了对免疫检查点抑制剂 (ICI) 有利反应的可能性。病例介绍 我们介绍了一名 32 岁男性患者,被诊断患有体质性 MMR 缺陷 (CMMRD) CRC,其 MMR 免疫组织化学 (IHC) 显示两个肿瘤块的结果不一致。MMR-IHC 和血浆来源的循环肿瘤 DNA 中使用的两个肿瘤标本的靶向测序一致揭示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。出乎意料的是,在 PCR 确认后,这两个块都是微卫星稳定 (MSS)。有趣的是,该患者未能对 ICI 单药或双药治疗显示出反应,但在临床上受益于 ICI 派姆单抗加多激酶抑制剂瑞戈非尼的联合治疗。结论 我们的病例报告了一例 MMR 结果异质性的 CMMRD 患者,该患者对 ICI 反应复杂,突出了使用多样本靶向测序准确诊断的重要性,以揭示 CMMRD 患者对 ICI 反应的可能机制。
更新日期:2021-01-09
中文翻译:
具有 MSH6 错义突变的异质性错配修复缺陷从帕博利珠单抗和瑞戈非尼联合治疗中获益:病例报告和文献综述
背景 生殖系 DNA 错配修复 (MMR) 基因畸变与结直肠癌 (CRC) 易感性和高肿瘤突变负荷 (TMB-H) 相关,增加了对免疫检查点抑制剂 (ICI) 有利反应的可能性。病例介绍 我们介绍了一名 32 岁男性患者,被诊断患有体质性 MMR 缺陷 (CMMRD) CRC,其 MMR 免疫组织化学 (IHC) 显示两个肿瘤块的结果不一致。MMR-IHC 和血浆来源的循环肿瘤 DNA 中使用的两个肿瘤标本的靶向测序一致揭示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。出乎意料的是,在 PCR 确认后,这两个块都是微卫星稳定 (MSS)。有趣的是,该患者未能对 ICI 单药或双药治疗显示出反应,但在临床上受益于 ICI 派姆单抗加多激酶抑制剂瑞戈非尼的联合治疗。结论 我们的病例报告了一例 MMR 结果异质性的 CMMRD 患者,该患者对 ICI 反应复杂,突出了使用多样本靶向测序准确诊断的重要性,以揭示 CMMRD 患者对 ICI 反应的可能机制。