林奇综合征患者的错配修复基因突变不仅会增加上尿路上皮癌的风险，还会增加膀胱癌的风险。
Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer.
机构信息
Department of Surgical Oncology, Urology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
出版信息
Eur Urol. 2013 Feb;63(2):379-85. doi: 10.1016/j.eururo.2012.07.047. Epub 2012 Aug 2.
BACKGROUND
Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.
OBJECTIVE
To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.
DESIGN, SETTING, AND PARTICIPANTS: Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.
RESULTS AND LIMITATIONS
Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.
CONCLUSIONS
LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.
背景
林奇综合征（LS）或遗传性非息肉病性结直肠癌，是由错配修复（MMR）基因突变引起的。在该人群中已描述了上尿路上皮癌（UTUC）的风险增加，但膀胱癌（BCa）的风险数据很少。
目的
评估 MMR 突变携带者中 BCa 的风险，并提出筛查和管理建议。
设计、设置和参与者：从多伦多家族性胃肠道癌登记处获取了 1980 年至 2007 年的癌症数据，共涉及 321 名已知 MMR 突变者：mutL 同源物 1，结肠癌，非息肉病型 2（大肠杆菌）（MLH1）；mutS 同源物 2，结肠癌，非息肉病型 1（大肠杆菌）（MSH2）；mutS 同源物 6（大肠杆菌）（MSH6）；和 PMS2 减数分裂后增加 2（酿酒酵母）（PMS2）。
结局测量和统计分析
使用安大略癌症登记处的标准化发病比，使用监测、流行病学和最终结果公共数据库，将 MMR 突变患者的癌症风险与加拿大人群进行比较。还对 MMR 蛋白进行了微卫星不稳定性分析和免疫组织化学（IHC），并将结果与匹配的散发性膀胱肿瘤进行了比较。
结果和局限性
在 177 名 MSH2 突变患者中发现 11 例（6.21%，p<0.001 与加拿大人群相比）患有 BCa，而在 129 名 MLH1 突变患者中发现 3 例（2.32%，p>0.05）。在这些肿瘤中，81.8%的肿瘤缺乏 MSH2 的 IHC 表达，而匹配的散发性病例均显示 MSH2 和 MLH1 的正常表达。MSH2 携带者的 UTUC 发生率为 3.95%（p<0.001），所有肿瘤在 IHC 上均发现 MSH2 表达缺失。MSH2 基因内含子 5 剪接位点和外显子 7 的突变增加了尿路上皮癌的风险。局限性包括由于确定偏倚导致风险估计可能过高。
结论
MSH2 突变的 LS 患者不仅患有 UTUC，而且患有 BCa 的风险增加，可提供适当的筛查。
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