McNevin Ciara S, Keogh Anna, Mohammed Nur Mutaz, McGovern Brianán, McFadden Julie, Baird Anne-Marie, Cadoo Karen, Mc Carron Sarah, O'Brien Cathal, Barr Martin P, Gray Steven G, Sheils Orla, Sutton Lesley A, Flanagan Sinead, Mucci Lorelei A, Stopsack Konrad H, Finn Stephen P
Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
Department of Medical Oncology, St. James's Hospital, Dublin, Ireland.
Clin Cancer Res. 2025 May 1;31(9):1746-1753. doi: 10.1158/1078-0432.CCR-24-1210.
Mismatch repair (MMR) deficiency and microsatellite instability are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer.
This study included 1,016 men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study and Physicians' Health Study. The highest-grade/index lesions from radical prostatectomy (95%) or transurethral resections of the prostate were mounted on tissue microarrays. Scoring of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 required a nontumor internal positive control for designating deficiency. Validation was done on full sections and with PCR-based quantification of microsatellite repeats.
Tumor stage was predominantly pathologically localized with a full distribution of Gleason scores. MMR tumor scoring could be performed with available internal positive control tissue in 75% to 90% of cases, depending on the MMR protein. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence, 0.4%; 95% confidence interval, 0.2%-1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence, 0.4%; 95% confidence interval, 0.1%-1.2%). No tumor had loss of MLH1 or PMS2. The four MMR-deficient cases had higher Gleason scores, and three had non-zero microsatellite repeats.
In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. The low prevalence and the need for an internal positive control for this assay are feasibility concerns for unselected routine immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies.
错配修复（MMR）缺陷和微卫星不稳定性是免疫治疗反应的预测生物标志物。在前列腺癌中，识别此类肿瘤患者的最佳方法尚不清楚。
本研究纳入了1016名在健康专业人员随访研究和医生健康研究的前瞻性随访期间被诊断为原发性前列腺癌的男性。前列腺癌根治术（95%）或经尿道前列腺切除术的最高分级/索引病变被制作成组织微阵列。MMR蛋白MLH1、MSH2、MSH6和PMS2的免疫组化评分需要非肿瘤内部阳性对照来确定缺陷。通过全切片以及基于PCR的微卫星重复序列定量进行验证。
肿瘤分期主要为病理局限性，Gleason评分分布全面。根据MMR蛋白的不同，75%至90%的病例可利用可用的内部阳性对照组织进行MMR肿瘤评分。在903例可评估MSH2蛋白缺失的肿瘤中，有4例出现MSH2缺失（患病率为0.4%；95%置信区间为0.2%-1.1%），在708例可评估肿瘤中有3例同时出现MSH6缺失（患病率为0.4%；95%置信区间为0.1%-1.2%）。没有肿瘤出现MLH1或PMS2缺失。4例MMR缺陷病例的Gleason评分较高，3例有非零微卫星重复序列。
在这项全国性的前瞻性研究中，MMR缺陷在接受手术治疗的原发性前列腺癌中很少见。这种检测方法的低患病率以及对内部阳性对照的需求，对于在有限组织标本（如前列腺活检）上基于免疫组化的未选择常规MMR缺陷筛查来说，是可行性方面的问题。
