Evaristo Gertruda, Harmath Carla, Segal Jeremy P, Shergill Ardaman, Setia Namrata
Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
Department of Radiology, The University of Chicago, Chicago, Illinois, USA.
Cancer Rep (Hoboken). 2024 Dec;7(12):e70037. doi: 10.1002/cnr2.70037.
Rapid and accurate identification of mismatch repair (MMR) deficiency and Lynch syndrome is critical in the prognostication and clinical management of patients with colorectal carcinoma.
We describe here a young woman who developed a locally aggressive rectal adenocarcinoma with intact MMR protein expression by immunohistochemistry and absence of histologic evidence of MMR deficiency-associated increased tumoral immune response. Germline DNA-targeted sequencing identified MSH2 variant p.R711P, initially classified as a variant of undetermined significance. Somatic tumoral DNA analysis revealed the identical MSH2 variant, high tumor mutational burden, and microsatellite instability, in addition to superimposed alterations in β2-microglobulin gene, possibly explaining the altered intratumoral immunity. Consequently, the patient was started on immunotherapy, leading to successful disease control (33 month follow-up).
The findings emphasize the utility of an integrative approach in the assessment of MMR status for determining candidacy for immunotherapy, especially in the setting of missense variants in MMR genes.
快速准确地识别错配修复（MMR）缺陷和林奇综合征对于结直肠癌患者的预后评估和临床管理至关重要。
我们在此描述一名年轻女性，她患有一种局部侵袭性直肠腺癌，免疫组化显示MMR蛋白表达完整，且缺乏MMR缺陷相关肿瘤免疫反应增强的组织学证据。种系DNA靶向测序鉴定出MSH2基因变异p.R711P，最初被归类为意义未明的变异。体细胞肿瘤DNA分析显示存在相同的MSH2基因变异、高肿瘤突变负荷和微卫星不稳定性，此外β2-微球蛋白基因也有叠加改变，这可能解释了肿瘤内免疫的改变。因此，该患者开始接受免疫治疗，疾病得到成功控制（随访33个月）。
这些发现强调了综合方法在评估MMR状态以确定免疫治疗候选资格方面的实用性，尤其是在MMR基因错义变异的情况下。
