Prediction of germline mutations and cancer risk in the Lynch syndrome
Prediction of germline mutations and cancer risk in the Lynch syndrome
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DOI：
10.1001/jama.296.12.1479
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发表时间：
2006-09-27
影响因子：
120.7
通讯作者：
Parmigiani, Giovanni
中科院分区：
文献类型：
--
作者：
Chen, Sining;Wang, Wenyi;Parmigiani, Giovanni
确定Lynch综合征（即遗传性非息肉病性结直肠癌）的高风险家庭对于遗传咨询和癌症预防至关重要。目前的临床指南是有效的，但受到适用性和成本的限制。目的开发和验证一种遗传咨询和风险预测工具，估计错配修复基因MLH 1，MSH 2或MSH 6中携带有害突变的概率和发生结直肠癌或子宫内膜癌的概率。MMRpro模型的外部验证是在来自美国，加拿大，和澳大利亚（1993-2005年）通过比较模型预测与高度敏感的生殖系突变检测技术的结果。MMRpro对错配修复突变的常染色体显性遗传进行建模，参数基于突变发生率和患病率以及肿瘤特征预测值的荟萃分析。该模型的预测是根据每个人有关结直肠癌和子宫内膜癌的详细家族史信息以及包括微卫星不稳定性在内的肿瘤特征量身定制的。主要结果衡量MMRpro正确预测突变携带者状态的能力，通过操作特征、校准和总体来衡量准确性。结果在独立验证中，MMRpro提供的一致性指数为0.83（95%置信区间，0.78-0.88），观察病例与预测病例的比值为0.94（95%置信区间，0.84-1.05）。这导致更高的准确性比现有的替代品和当前的临床guidelines.Conclusions MMRpro是一个广泛适用的，准确的预测模型，可以有助于目前的筛查和遗传咨询的做法在高危人群。它比现有的临床指南更敏感，更具体，以确定谁可能受益于MMR生殖细胞检测的个人。它适用于无法获得肿瘤样本的个体和生殖细胞检测未发现突变的个体。
Context Identifying families at high risk for the Lynch syndrome (ie, hereditary non-polyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.Objective To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.Design, Setting, and Patients External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Main Outcome Measure Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.Results In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.Conclusions MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.