Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer
Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer
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DOI：
10.1002/ijc.24808
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发表时间：
2010-02-15
影响因子：
6.4
通讯作者：
Gill, Sharlene
中科院分区：
文献类型：
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作者：
Monzon, Jose G.;Cremin, Carol;Gill, Sharlene
Lynch综合征的定义是错配修复(MMR)基因中存在胚系突变。最近设计了几种预测突变携带者状态的模型(Myriad Genetics、Wijnen、Barnetson、PREMM和MMRPro模型)。BC癌症机构(BCCA)遗传性癌症计划(HCP)提到的携带Lynch相关突变的中高风险家庭接受了突变分析、免疫组织化学和/或微卫星测试。其中包括72个测试案例。突变阳性25例(34.7%)，突变阴性47例(65.3%)。免疫组织化学检测MLH1和MSH2基因的43例患者中，19例微卫星检测结果稳定且正常，19例MMR基因突变均为阴性。计算模型得出的先证者携带MMR基因突变的概率，并与观察结果进行比较。Myriad、Barnetson、Wijnen、MMRPro和PREMM模型的ROC曲线下面积分别为0.75(95%CI；0.63~0.87)、0.86(0.7~0.96)、0.89(0.82~0.97)、0.89(0.81~0.98)和0.93(0.86~0.99)。阿姆斯特丹II标准在该队列中的敏感性和特异性分别为0.76和0.74。PREMM模型在基于概率阈值为10%、20%和30%的正似然比预测载波状态方面表现出最佳性能。在该参考队列中，PREMM模型对基于正LR的载波状态具有最有利的一致性指数和预测性能。这些预测模型(PREMM、MMRPro和Wijnen)可能很快取代阿姆斯特丹II和修订的Bethesda标准，成为Lynch突变的预筛查工具。
Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.