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

Cancer. 2015 Mar 1;121(5):688-96. doi: 10.1002/cncr.29106. Epub 2014 Nov 5.

Abstract

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.

Keywords: Cowden syndrome; Cowden-like syndrome; endometrial cancer; killin (KLLN); phosphatase and tensin homolog (PTEN); succinate dehydrogenase B/D (SDHB-D).

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Cells, Cultured
  • DNA Methylation
  • Endometrial Neoplasms / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Hamartoma Syndrome, Multiple / genetics*
  • Humans
  • Middle Aged
  • Mitochondrial Diseases / genetics*
  • Mutation
  • PTEN Phosphohydrolase / genetics*
  • Promoter Regions, Genetic
  • Prospective Studies
  • Succinate Dehydrogenase / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Young Adult

Substances

  • Tumor Suppressor Proteins
  • killin protein, human
  • SDHB protein, human
  • Succinate Dehydrogenase
  • PTEN Phosphohydrolase
  • PTEN protein, human

Supplementary concepts

  • Cowden-Like Syndrome