Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy.
Molecular and Pharmaco-Epidemiology Unit, Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy.
Dig Liver Dis. 2020 Dec;52(12):1503-1511. doi: 10.1016/j.dld.2020.06.002. Epub 2020 Jun 30.
Tumor testing utility in Lynch syndrome (LS) diagnosis is established.
Analyze the differences between tumor testing efficiency in rectal (RC) and colon cancer (CC).
We performed immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins (IHC-MMR) and MicroSatellite Instability analysis (MSI) on 482 unselected primary tumors: 320 CCs and 162 RCs. Samples had proficient-IHC, deficient-IHC or borderline-IHC ("patchy" expression). MSI-H borderline-IHC tumors were considered as likely MMR-deficient. Germline testing was offered to MMR-deficient patients without BRAF mutation or MLH1 promoter hypermetilation (MLH1-Hy).
We identified 51/482 (10.6%) MMR-defective tumors. Multivariable analysis demonstrated a significant correlation between tumor testing results with histotype, lymph-node involvement and tumor location. In particular, RC showed a lower MMR-deficiency rate than CC (p<0.0001). Interestingly, MLH1 loss was detected in 0% RCs and 76.1% CCs, with 80% of them showing BRAF mutation/MLH1-Hy. A germline variant was detected in 12 out of 18 patients (mutation detection rate of 66.7%).
Tumor testing results showed molecular differences between CCs and RCs, in terms of MMR proteins expression, and presence of BRAF mutation/MLH1-Hy. MSH6 variants were the most frequent ones (50%). Although young age at diagnosis was associated with mutation detection (p = 0.045), 33.3% of LS patients were >50 years.
在林奇综合征（LS）诊断中，肿瘤检测的效用已得到确立。
分析直肠（RC）和结肠癌（CC）肿瘤检测效率的差异。
我们对 482 例未经选择的原发性肿瘤进行了免疫组织化学（IHC）错配修复（MMR）蛋白检测（IHC-MMR）和微卫星不稳定性分析（MSI）：320 例 CC 和 162 例 RC。样本具有充分的 IHC、不足的 IHC 或边界 IHC（“斑驳”表达）。MSI-H 边界 IHC 肿瘤被认为可能存在 MMR 缺陷。对于没有 BRAF 突变或 MLH1 启动子超甲基化（MLH1-Hy）的 MMR 缺陷患者，提供种系检测。
我们发现了 51/482（10.6%）个 MMR 缺陷肿瘤。多变量分析表明，肿瘤检测结果与组织类型、淋巴结受累和肿瘤位置之间存在显著相关性。特别是，RC 的 MMR 缺陷率低于 CC（p<0.0001）。有趣的是，0%的 RC 和 76.1%的 CC 检测到 MLH1 缺失，其中 80%的病例存在 BRAF 突变/MLH1-Hy。在 18 名患者中的 12 名（突变检测率为 66.7%）中检测到种系变异。
在 MMR 蛋白表达和 BRAF 突变/MLH1-Hy 方面，CC 和 RC 的肿瘤检测结果显示出分子差异。MSH6 变异最为常见（50%）。尽管诊断时的年龄较小与突变检测相关（p=0.045），但 33.3%的 LS 患者年龄大于 50 岁。
