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Germline PTEN , SDHB‐D , and KLLN alterations in endometrial cancer patients with Cowden and Cowden‐like syndromes: An international, multicenter, prospective study
Author(s) -
Mahdi Haider,
Mester Jessica L.,
Nizialek Emily A.,
Ngeow Joanne,
Michener Chad,
Eng Charis
Publication year - 2015
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.29106
Subject(s) - pten , cowden syndrome , sdhb , tensin , medicine , cancer research , endometrial cancer , cancer , germline , oncology , germline mutation , pi3k/akt/mtor pathway , biology , genetics , mutation , gene , signal transduction
BACKGROUND Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog ( PTEN ; PTEN _mut+), succinate dehydrogenase B/C/D ( SDHB‐D ; SDHx _var+), and killin ( KLLN _Me+) cause CS and Cowden syndrome–like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN _mut+, SDHx _var+, and KLLN _Me+ in CS/CSL patients presenting with endometrial cancer. METHODS PTEN and SDHB‐D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005‐2011). PTEN protein was analyzed from patient‐derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression‐based risk calculator giving the a priori risk for PTEN _mut+. Demographic and clinicopathologic features were correlated with the specific gene. RESULTS Germline PTEN _mut+, SDHx _var+, and KLLN _Me+ were found in 7%, 9.8%, and 10.5% of informative samples, respectively. Predictors of PTEN _mut+ included an age ≤ 50 years (odds ratio [OR] for an age < 30 years, 6.1 [ P = .015]; OR for an age of 30‐50 years, 4.4 [ P = .001]), macrocephaly (OR, 14.4; P < .001), a higher CC score (OR for a 1‐U increment, 1.35; P < .001), a PTEN protein level within the lowest quartile (OR, 5.1; P = .039), and coexisting renal cancer (OR, 5.7; P = .002). KLLN _Me+ patients were on average 8 years younger than KLLN _Me– patients (44 vs 52 years, P = .018). Predictors of KLLN _Me+ were a younger age and a higher CC score. On the other hand, no clinical predictors of SDH _var+ were found. CONCLUSIONS Clinical predictors of PTEN and KLLN alterations, but not SDHx _var+, were identified. These predictors should alert the treating physician to potential heritable risk and the need for referral to genetic professionals. High‐risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN _Me+ patients similarly to PTEN _mut+ patients. Cancer 2015;121:688–696. © 2014 American Cancer Society .