A Clinical Scoring System for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 Probands
Min-Han Tan,Jessica Mester,Jessica Mester,Charissa Peterson,Charissa Peterson,Yi-Ran Yang,Yi-Ran Yang,Jin Lian Chen,Jin Lian Chen,Lisa Rybicki,Lisa Rybicki,Kresimira Milas,Holly J. Pederson,Berna K. Remzi,Mohammed S. Orloff,Mohammed S. Orloff,Charis Eng +16 more
TLDR
The first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing is presented, further supported biologically by protein correlation.Abstract:
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.read more
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Lifetime Cancer Risks in Individuals with Germline PTEN Mutations
TL;DR: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations, and a comprehensive approach is proposed to surveillance of patients withPTEN mutations.
Journal ArticleDOI
Genetic/familial high-risk assessment: breast and ovarian.
Mary B. Daly,Jennifer E. Axilbund,Saundra S. Buys,Beth Crawford,Carolyn Farrell,Susan Friedman,Judy Garber,Salil Goorha,Stephen B. Gruber,Heather Hampel,Virginia Kaklamani,Wendy Kohlmann,Allison W. Kurian,Jennifer K. Litton,P. Kelly Marcom,Robert L. Nussbaum,Kenneth Offit,Tuya Pal,Boris Pasche,Robert Pilarski,Gwen Reiser,Kristen M. Shannon,Jeffrey R. Smith,Elizabeth M. Swisher,Jeffrey N. Weitzel +24 more
TL;DR: Overview All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair, but not all of these mutations are inherited from a parent.
Journal ArticleDOI
Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: Systematic Review and Revised Diagnostic Criteria
Robert Pilarski,Randall W. Burt,Wendy K. Kohlman,Lana Pho,Kristen M. Shannon,Elizabeth M. Swisher +5 more
TL;DR: It is found that there is no sufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria, and revised, evidence-based diagnostic criteria are proposed covering the spectrum of PTEN-related clinical disorders.
Journal ArticleDOI
The functions and regulation of the PTEN tumour suppressor: new modes and prospects
TL;DR: New insights are provided into its anti-oncogenic functions and offer novel opportunities for cancer treatment through restoration of PTEN tumour suppressor activity.
Journal ArticleDOI
Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome
Kyle C. Kurek,Valerie L. Luks,Ugur M. Ayturk,Ugur M. Ayturk,Ahmad I. Alomari,Steven J. Fishman,Samantha A. Spencer,John B. Mulliken,Margot E. Bowen,Margot E. Bowen,Guilherme L. Yamamoto,Harry P.W. Kozakewich,Matthew L. Warman +12 more
TL;DR: It is concluded that CLOVES is caused by postzygotic activating mutations in PIK3CA, which have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity.
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