Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.

Context: Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTENmut+) have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, less than 1% of sporadic epithelial thyroid cancer patients carry a germline PTEN mutation. Cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Objective: Our objective was to analyze the utility of patient blood phosphate and tensin homolog deleted on chromosome 10 (PTEN) protein levels in predicting germline PTEN mutations. Design, Setting, and Patients: We conducted a 5-yr, multicenter prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared blood PTEN protein levels between PTENmut+ patients and those with variants of unknown significance or wild-type PTEN (PTENwt/vus). Main Outcome Measures: We assessed the utility of PTEN protein levels in predicting germline PTEN mutations. Results: Of 2792 CS/CS-like patients, 721 patients had thyroid cancer; 582 of them (81%) had blood PTEN protein analyzed. PTEN germline pathogenic mutations were present in 27 of 582 patients (4.6%). Ninety-six percent (26 of 27) of PTENmut+ patients had blood PTEN protein levels in the lowest quartile as compared with 25% (139 of 555) of PTENwt/vus patients (P < 0.001). Low blood PTEN levels predicted for PTENmut+ cases with a 99.76% negative predictive value (95% confidence interval = 98.67-99.96) and a positive test likelihood ratio of 3.84 (95% confidence interval = 3.27-4.52). Conclusions: Our study shows that low blood PTEN protein expression could serve as a screening molecular correlate to predict for germline PTEN mutation in CS and CS-like presentations of thyroid cancer. (J Clin Endocrinol Metab 97: E2320-E2327, 2012)