Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Am J Hum Genet. 2011 Jan 7;88(1):42-56. doi: 10.1016/j.ajhg.2010.11.013. Epub 2010 Dec 30.
Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score-the Cleveland Clinic (CC) score-resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.
考登综合征(CS)和班纳扬-赖利-鲁瓦尔卡巴综合征是等位基因疾病,由种系 PTEN 突变定义,统称为 PTEN 错构瘤肿瘤综合征。迄今为止,尚无基于大型前瞻性患者队列的现有标准来选择进行 PTEN 突变检测的患者。为了解决这些问题,我们进行了一项多中心前瞻性研究,共纳入了 3042 名符合放宽 CS 临床标准的先证者。对所有受试者进行了 PTEN 突变扫描,包括启动子和大片段缺失分析。在 290 名个体(9.5%)中发现了致病性突变。为了评估临床表型和 PTEN 基因型与蛋白表达的关系,我们对患者亚组(n = 423)进行了免疫印迹(PTEN、P-AKT1、P-MAPK1/2)。为了获得种系 PTEN 突变的个体预测概率的个体化估计,我们开发了一种优化的临床实践模型来识别成人和儿科患者。对于成年人,半定量评分-克利夫兰诊所(CC)评分-导致对 PTEN 状态的个体预测概率的校准良好的估计。总体而言,PTEN 蛋白表达降低与 PTEN 突变状态相关;PTEN 蛋白表达降低与 CC 评分增加相关(p < 0.001),但与国家综合癌症网络(NCCN)标准无关(p = 0.11)。对于儿科患者,我们确定了高度敏感的标准来指导 PTEN 突变检测,其表型特征与成人不同。与 NCCN 2010 标准相比,我们的模型在两个队列中均提高了种系 PTEN 突变的敏感性和阳性预测值。我们提出了第一个基于循证的临床实践模型,以选择患者进行遗传学咨询和 PTEN 突变检测,进一步得到了蛋白相关性的生物学支持。