Year: 2014
Type: article
Study design: Observational Study
Abstract: EMILY ALISON NIZIALEKKLLN and PTEN, on 10q23, share a bidirectional promoter and are transcribed in opposite directions.Cowden syndrome (CS) is an autosomal dominant disorder with a high risk of cancers.While PTEN is believed to be the major CS gene, our recent study of 3042 probands with classic CS or CS-like (CSL) phenotypes revealed 25% of CS and 5% of CSL probands have germline PTEN mutations.In our pilot study, we found KLLN germline DNA hypermethylation in 37% of 123 PTEN mutation-negative CS/CSL patients revealing KLLN as a novel predisposition gene for cancer.We sought to prove and further characterize this association between KLLN and CS/CSL.Significantly increased KLLN promoter DNA methylation was found in 1012 PTEN mutation-negative CS/CSL patients compared to 111 controls (p<0.001).We further analyzed CS patients for KLLN mutations and found only 1 patient out of 136 (0.7%) with a KLLN mutation, indicating CS is likely not causally associated to KLLN mutations.Interestingly, 13 of 438 (3%) patients with apparently sporadic breast cancer have KLLN mutations not found in 128 controls.These mutations were all observed to significantly impact KLLN's function.Patients with breast cancer and KLLN mutations had a significant family history of breast cancer, which suggests that KLLN is a low/moderate penetrant breast cancer susceptibility gene.We wanted to further understand the mechanism by which KLLN is acting as a tumor suppressor.Through genome-wide studies, we discovered a novel mechanism for KLLN in genome stability.Germline KLLN alterations may be an important mechanism for CS/CSL and sporadic breast cancer.
Author: Emily Nizialek
Institution: Case Western Reserve University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2783982065