MLH1/PMS2 loss due toMLH1promoter hypermethylation (MLH1-PHM) is the most common cause of mismatch repair (MMR) deficiency in endometrial cancer (EC). This study aimed to determine the proportion ofMLH1-deficient EC with PHM, assess the impact of the reflexMLH1-PHM testing strategy, and evaluate the associated costs within the publicly funded Canadian healthcare system. In a cohort of 2504 EC samples, 534 (21.4%) exhibited dual MLH1/PMS2 loss, promptingMLH1-PHM testing. Among 418 cases with available testing results, 404 (96.7%) wereMLH1-hypermethylated, while 14 (3.3%) were non-methylated. The incidence ofMLH1non-methylated cases in our cohort was 14/2504 (0.56%) of all ECs, underscoring the prevalence of hypermethylation-driven MLH1/PMS2 loss in ECs universally screened for MMR deficiency. ReflexMLH1-PHM testing incurs substantial costs and resource utilization. Assay cost is CAD 231.90 per case, amounting to CAD 123,834.60 for 534 cases, with 30 tests needed per additional candidate forMLH1germline analysis (CAD 6957.00 per candidate). This raises a provocative question: can we assume that the majority of the MLH1-deficient ECs are due to PHM and forgo further testing in healthcare systems with finite resources? It is imperative to assess resource utilization efficiency and explore optimized approaches that encompass clinical correlation, family history and judicious utilization of methylation testing to ensure it is provided only to those who stand to benefit from it.
MLH1启动子高甲基化（MLH1-PHM）导致的MLH1/PMS2缺失是子宫内膜癌（EC）中错配修复（MMR）缺陷最常见的原因。本研究旨在确定MLH1缺陷型EC中PHM的比例，评估反射性MLH1-PHM检测策略的影响，并评估其在加拿大公共资助医疗体系中的相关成本。在2504例EC样本队列中，534例（21.4%）表现出MLH1/PMS2双重缺失，从而进行了MLH1-PHM检测。在获得检测结果的418例中，404例（96.7%）存在MLH1高甲基化，而14例（3.3%）为非甲基化。本队列中MLH1非甲基化病例的发生率为14/2504（0.56%），这突显了在普遍进行MMR缺陷筛查的EC中，高甲基化驱动的MLH1/PMS2缺失具有普遍性。反射性MLH1-PHM检测产生了显著的成本和资源消耗。每例检测成本为231.90加元，534例总计123,834.60加元，且每增加一名MLH1种系分析候选者需进行30次检测（每位候选者成本6957.00加元）。这引发了一个值得深思的问题：在资源有限的医疗体系中，我们是否可以假设大多数MLH1缺陷型EC是由PHM引起的，从而放弃进一步检测？必须评估资源利用效率，并探索优化方法，包括结合临床相关性、家族史以及审慎使用甲基化检测，以确保检测仅提供给那些可能从中受益的患者。
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