Background

The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated.

Methods

Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor.

Results

Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63–79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS.

Conclusions

The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6–1.1% among unselected BC cases.

中文翻译：

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在日本医院人群中鉴定与林奇综合征相关的 DNA 错配修复缺陷膀胱癌

背景

林奇综合征 (LS) 相关的 DNA 错配修复 (MMR) 缺陷性膀胱癌 (BC) 的患病率几乎没有被调查过。

方法

四种 MMR 蛋白（MLH1、MSH2、MSH6 和 PMS2）的免疫组织化学在福尔马林固定石蜡包埋 (FFPE) 切片中进行，这些切片是从 618 个连续新诊断的 BC 病例的切除标本中制备的。对显示肿瘤中任何 MMR 蛋白丢失的患者进行遗传/表观遗传分析。

结果

在 618 名患者中，9 名 (1.5%) 通过免疫组织化学显示 MMR 蛋白表达缺失；具体而言，分别有 3、3、2 和 1 名患者表现出 MLH1/PMS2、PMS2、MSH6 和 MSH2/MSH6 的丢失。所有 9 名患者均为男性，中位年龄为 68 岁（63-79 岁）。一个人之前被诊断为患有MSH2变异的LS 。基因检测表明存在致病性PMS2变异 ( n  = 1)、MSH2 中意义不确定的变异( n  = 1)，并且没有 MMR 基因的致病性种系变异 ( n = 1)。一名 MSH6 缺陷型 BC 患者由于从 FFPE 标本中提取的 DNA 严重降解而未完成基因检测，但该患者因其结肠癌和 MSH6 缺陷型上尿路癌病史而被强烈怀疑患有 LS。其余四名拒绝基因检测的患者仍有可能患有 LS。

结论

在未选择的 BC 病例中，LS 相关 MMR 缺陷型 BC 的患病率估计为 0.6-1.1%。