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

Abstract

Background Endometrial cancer (EC) has only been recently recognized as a major component in Cowden syndrome (CS). Germline PTEN (PTEN_mut+), SDHB-D (SDHx_var+) and KLLN (KLLN_Me+) alterations cause CS and CS-like (CSL) phenotypes. This study aims to identify prevalence and clinico-pathologic predictors of germline PTEN_mut+, SDHx_var+ or KLLN_Me+ in CS/CSL patients presenting with EC. Methods PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed on 371 prospectively enrolled (2005–2011) patients. PTEN protein was analyzed from patient-derived lymphoblast lines. PTEN Cleveland Clinic score (CC score) is a weighted regression-based risk calculator that gives a priori risk of PTEN_mut+. Demographic and clinicopathologic features were correlated with 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 age≤50 (OR6.1, p=0.015 for age<30, OR4.4, p=0.001 for age 30–50), macrocephaly (OR14.4, p<0.001), higher CC score (OR1.35 for 1 unit increment, p<0.001), PTEN protein level at the lowest quartile (OR5.1, p=0.039) and coexisting renal cancer (OR5.7, p=0.002). KLLN_Me+ patients were a mean 8 years younger than KLLN_Me− ones (44 vs. 52, p=0.018). Predictors of KLLN_Me+ were younger age and higher CC score. On the other hand, no clinical predictors of SDH_var+ were found. Conclusions We identified clinical predictors of PTEN and KLLN alterations, but not SDHx_var+. Having these predictors should alert the treating physician to potential heritable risk for referral to genetic professionals. High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN_Me+ similar to PTEN_mut+ patients.

Exome sequencing reveals germline gain-of-function EGFR mutation in an adult with Lhermitte–Duclos disease

“…Deletion analysis was performed for PTEN and SDHx using the multiplex ligation-dependent probe amplification (MLPA) assay, according to the manufacturer's protocol (Schouten et al 2002). KLLN promoter methylation analysis was performed using the Sequenom MassArray assay, as previously reported (Mahdi et al 2015). For all selected individuals, we reviewed the Cleveland Clinic (CC) score (Tan et al 2011), a semiquantitative score that is based on weighting clinical features and that estimates the pretest probability of finding a germline PTEN mutation ().…”

Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes

“…The prevalence of LS in unselected EC patients was reported to be 2–6%, mainly from Caucasian populations and based on an MSI phenotype‐based preselection approach . Less commonly, EC occurs as a component of Cowden syndrome caused by germline mutations in the PTEN gene . However, the prevalence in unselected EC patients seems to be very low, as revealed by a study showing that no germline PTEN mutation was detected among 240 unselected EC patients .…”

“…6,7,[13][14][15] Less commonly, EC occurs as a component of Cowden syndrome caused by germline mutations in the PTEN gene. 16,17 However, the prevalence in unselected EC patients seems to be very low, as revealed by a study showing that no germline PTEN mutation was detected among 240 unselected EC patients. 18 Moreover, the association between EC and hereditary breast and ovary cancer syndrome (HBOC) has also been suggested, seemingly involving a subtype known as uterine serous carcinoma (USC) that accounts for less than 10% of EC.…”

Das Lynch-Syndrom als bedeutendes erbliches Tumorsyndrom

“…Die Mehrzahl der sporadischen Endometriumkarzinome mit Ausnahme des Copy-number-high-Typs (Typ 2 EC) hat somatische PTEN-Mutationen, die nicht mit einem Cowden-Syndrom verwechselt werden dürfen [32,33].…”