LS CancerDiag Ltd., Helsinki, Finland.
Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Cancer Res Commun. 2023 Mar 2;3(3):361-370. doi: 10.1158/2767-9764.CRC-22-0384. eCollection 2023 Mar.
Lynch syndrome (LS) is the most common hereditary cancer syndrome. Early diagnosis improves prognosis and reduces health care costs, through existing cancer surveillance methods. The problem is finding and diagnosing the cancer predisposing genetic condition. The current workup involves a complex array of tests that combines family cancer history and clinical phenotypes with tumor characteristics and sequencing data, followed by a challenging task to interpret the found variant(s). On the basis of the knowledge that an inherited mismatch repair (MMR) deficiency is a hallmark of LS, we have developed and validated a functional MMR test, DiagMMR, that detects inherited MMR deficiency directly from healthy tissue without need of tumor and variant information. The validation included 119 skin biopsies collected from clinically pathogenic MMR variant carriers (, ) and controls, and was followed by a small clinical pilot study. The repair reaction was performed on proteins extracted from primary fibroblasts and the interpretation was based on the MMR capability of the sample in relation to cutoff, which distinguishes MMR proficient (non-LS) from MMR deficient (LS) function. The results were compared with the reference standard (germline NGS). The test was shown to have exceptional specificity (100%) with high sensitivity (89%) and accuracy (97%). The ability to efficiently distinguish LS carriers from controls was further shown with a high area under the receiving operating characteristic (AUROC) value (0.97). This test offers an excellent tool for detecting inherited MMR deficiency linked to or and can be used alone or with conventional tests to recognize genetically predisposed individuals.
Clinical validation of DiagMMR shows high accuracy in distinguishing individuals with hereditary MSH2 or MSH6 MMR deficiency (i.e., LS). The method presented overcomes challenges faced by the complexity of current methods and can be used alone or with conventional tests to improve the ability to recognize genetically predisposed individuals.
林奇综合征（LS）是最常见的遗传性癌症综合征。通过现有的癌症监测方法，早期诊断可改善预后并降低医疗保健成本。问题在于发现和诊断易患癌症的遗传状况。目前的检查包括一系列复杂的测试，这些测试将家族癌症史和临床表型与肿瘤特征和测序数据相结合，然后是一项具有挑战性的任务，即解释发现的变异。基于遗传性错配修复（MMR）缺陷是 LS 的标志这一知识，我们已经开发并验证了一种功能性 MMR 测试 DiagMMR，该测试可直接从健康组织中检测到遗传性 MMR 缺陷，而无需肿瘤和变异信息。验证包括从临床致病性 MMR 变体携带者（、）和对照中收集的 119 个皮肤活检，并随后进行了小型临床试点研究。修复反应在从原代成纤维细胞中提取的蛋白质上进行，解释基于样本相对于截止值的 MMR 能力，该截止值区分 MMR 功能正常（非 LS）与 MMR 功能缺陷（LS）。结果与参考标准（种系 NGS）进行了比较。该测试显示出极高的特异性（100%），具有较高的灵敏度（89%）和准确性（97%）。通过高接收者操作特征（AUROC）值（0.97）进一步显示出区分 LS 携带者和对照组的能力。该测试提供了一种用于检测与或相关的遗传性 MMR 缺陷的极好工具，可单独使用或与常规测试一起用于识别遗传易感个体。
DiagMMR 的临床验证显示，在区分具有遗传性 MSH2 或 MSH6 MMR 缺陷（即 LS）的个体方面具有很高的准确性。该方法克服了当前方法复杂性所面临的挑战，可单独使用或与常规测试一起使用，以提高识别遗传易感个体的能力。
