Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTEN^mut+) 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.

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.

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 PTEN^mut+ patients and those with variants of unknown significance or wild-type PTEN (PTEN^wt/vus).

We assessed the utility of PTEN protein levels in predicting germline PTEN mutations.

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 PTEN^mut+ patients had blood PTEN protein levels in the lowest quartile as compared with 25% (139 of 555) of PTEN^wt/vus patients (P < 0.001). Low blood PTEN levels predicted for PTEN^mut+ 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).

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.