Frequency of germline PTEN mutations in differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancer (DTC) is seen in 3%-10% of individuals carrying a germline PTEN mutation. Patients with PTEN mutations are at risk for additional neoplasms as are their affected offspring. However, the frequency of PTEN mutations among DTC cases has not been systematically analyzed. The objective of this study was to determine the frequency of PTEN mutations in an unselected group of patients with DTC and to identify whether additional clinical features might indicate the need for referral for genetic counseling and possible testing. METHODS: We collected personal medical and family history information, head circumference data, and blood from 259 consecutively identified clinic-based patients with DTC, unselected for personal or family history. Individuals were categorized for diagnostic criteria for Cowden syndrome (CS) using the 2009 National Comprehensive Cancer Network (NCCN) guidelines and underwent germline PTEN mutation analysis. RESULTS: Two of the 259 patients (0.8%), with both follicular thyroid carcinoma and macrocephaly, were found to carry a germline mutation in the PTEN gene. The PTEN mutation frequency in unselected cases of follicular thyroid carcinoma was 4.8%. CONCLUSION: The frequency of germline pathogenic PTEN mutations in an unselected series of patients with DTC is relatively low, but it is enriched by considering follicular histology and macrocephaly. These results suggest that by adding head circumference to the clinical assessment, thyroid cancer specialists can more effectively identify patients needing referral for cancer genetic services.

A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands.

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.