TY - JOUR
T1 - A clinical scoring system for selection of patients for pten mutation testing is proposed on the basis of a prospective study of 3042 probands
AU - Tan, Min Han
AU - Mester, Jessica
AU - Peterson, Charissa
AU - Yang, Yiran
AU - Chen, Jin Lian
AU - Rybicki, Lisa A.
AU - Milas, Kresimira
AU - Pederson, Holly
AU - Remzi, Berna
AU - Orloff, Mohammed S.
AU - Eng, Charis
N1 - Funding Information:
We would like to thank the Genomic Medicine Biorepository of the Cleveland Clinic Genomic Medicine Institute, as well as the Eng laboratory personnel over the last 14 years who have contributed technical assistance, technical advice, and helpful discussions. We would also like to express our gratitude to all the patients and clinical collaborators from all the centers around the world who have contributed their time and specimens over the last 10 years. This study is funded, in part, by the National Cancer Institute (P01CA124570 and R01CA118989), American Cancer Society (RPG-02-151-01-CCE), William Randolph Hearst Foundations, and Doris Duke Distinguished Clinical Scientist Award (all to C.E.). M.-H.T. is the Lee Foundation (Singapore) Fellow and an Ambrose Monell Foundation Cancer Genomic Medicine Clinical Fellow at the Cleveland Clinic Genomic Medicine Institute. C.E. is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic. C.E. is the recipient of an American Cancer Society Clinical Research Professorship, generously funded, in part, by the F.M. Kirby Foundation.
PY - 2011/1/7
Y1 - 2011/1/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.11.013
DO - 10.1016/j.ajhg.2010.11.013
M3 - Article
C2 - 21194675
AN - SCOPUS:78650908302
SN - 0002-9297
VL - 88
SP - 42
EP - 56
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -