Shia Jinru, Tang Laura H, Vakiani Efsevia, Guillem Jose G, Stadler Zsofia K, Soslow Robert A, Katabi Nora, Weiser Martin R, Paty Philip B, Temple Larissa K, Nash Garrett M, Wong W Douglas, Offit Kenneth, Klimstra David S
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Am J Surg Pathol. 2009 Nov;33(11):1639-45. doi: 10.1097/PAS.0b013e3181b15aa2.
The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC.
免疫组化检测DNA错配修复蛋白在筛查结直肠癌遗传性非息肉病性结直肠癌（HNPCC）中的应用正在得到广泛研究。目前，在研究和临床环境中，通常使用包含4种最常受影响蛋白（MLH1、MSH2、MSH6和PMS2）的4抗体组合。基于这些蛋白的生化特性，我们推测由MSH6和PMS2组成的2抗体组合足以检测所有4种蛋白的异常情况。我们在来自2个患者队列的232例结直肠癌样本系列上验证了这一假设：（1）根据修订的贝塞斯达指南被判定为HNPCC风险高于平均水平的前瞻性累积患者系列（n = 190）；（2）年龄在40岁及以下的回顾性患者系列（n = 42）。当肿瘤细胞中无核标记（内部对照为阳性）时，免疫组化染色被视为阴性（蛋白缺失）。总体而言，232例肿瘤中有70例显示至少一种蛋白缺失。最常见的异常是MLH1和PMS2同时缺失（在17%的病例中观察到），其次是MSH2和MSH6同时缺失（6%）。所有MLH1和MSH2异常的病例分别在PMS2和MSH6上也异常，而50例PMS2异常病例中有9例（18%）和20例MSH6异常病例中有6例（30%）仅显示PMS2或MSH6单独缺失（MLH1和MSH2染色正常）。因此，我们的研究结果提供了证据，表明2抗体组合（PMS2和MSH6）在检测DNA错配修复蛋白异常方面与当前的4抗体组合一样有效。这种具有成本效益的方法具有重要意义，因为免疫组化正被广泛用作HNPCC的一线筛查方法。
