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< 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; 121:688-96.