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


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.


METHODS
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)).


METHODS
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 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).


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.
Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Joanne
J
Ngeow
Xin
X
He
Jessica L
JL
Mester
Junying
J
Lei
Todd
T
Romigh
Mohammed S
MS
Orloff
Mira
M
Milas
Charis
C
Eng
D000236:Adenoma / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D018095:Germ-Line Mutation / Q000502:physiology; D006223:Hamartoma Syndrome, Multiple / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011237:Predictive Value of Tests; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D011506:Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human