Germline PTEN, SDHB‐D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden‐like syndromes: An international, multicenter, prospective study

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