A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome
A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome
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DOI：
10.1038/modpathol.2016.211
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发表时间：
2017-03-01
期刊：
影响因子：
7.5
通讯作者：
Chung, Daniel C.
中科院分区：
文献类型：
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作者：
Adar, Tomer;Rodgers, Linda H.;Chung, Daniel C.
为了在Lynch综合征(LS)筛查程序中确定BRAF基因和MLH1启动子甲基化之间的相关性，在两个医学中心建立了LS的通用筛查程序。对MLH1染色异常的肿瘤进行BRAF V600E基因和MLH1启动子甲基化检测。两者均阳性的肿瘤被认为是散发性的，建议对所有其他肿瘤进行基因检测。共有1011例结直肠癌病例进行了Lynch综合征的筛查，其中148例(14.6%)MLH1免疫组化染色缺失。126例患者同时进行了BRAF和MLH1甲基化检测。结果符合(均阳性)86例(68.3%)，阴性16例(12.7%)，总符合率81%。在预测MLH1启动子甲基化方面，BRAF突变的阳性预测值和阴性预测值分别为98.9%和41%，而在70岁患者中，阴性预测值降至15%。将BRAF基因分型作为评估MLH1缺失病例的唯一检测方法，与单独进行MLH1甲基化检测相比，基因检测的转诊率将提高2.3倍(分别为31%和13.5%，P<；0.01)。然而，将MLH1甲基化检测仅保留用于BRAF野生型病例的混合方法将显著减少进行甲基化检测的次数，并将基因检测的转诊率降至12.7%。在预测MLH1启动子甲基化方面，BRAF突变具有很好的阳性预测价值，但阴性预测价值较差。这些测试的混合使用可能会减少接受遗传咨询的低风险患者的数量，并促进林奇综合征筛查计划的更广泛实施。
To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients >= 70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P < 0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wildtype cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.