Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome

Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals. These observations need to be replicated.

To determine whether germline methylation is found in Cowden syndrome or Cowden-like syndrome in individuals lacking germline PTEN mutations. Design, setting, and participants: Nucleic acids from prospective nested series of 123 patients with Cowden syndrome or Cowden-like syndrome and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN at the Cleveland Clinic, August 2008-June 2010. Prevalence of component cancers between groups was compared using the Fisher exact test. Main outcome measures: Frequency of germline methylation in PTEN mutation-negative Cowden syndrome and Cowden syndrome-like individuals. Prevalence of component cancers in methylation-positive and PTEN mutation-positive individuals.

Of 123 patients with Cowden syndrome or Cowden-like syndrome, 45 (37%; 95% confidence interval [CI], 29%-45%) showed hypermethylation upstream of PTEN but no transcriptional repression. The germline methylation was found to transcriptionally down-regulate KILLIN by 250-fold (95% CI, 45-14 286; P = .007) and exclusively disrupted TP53 activation of KILLIN by 30% (95% CI, 7%-45%; P = .008). Demethylation treatment increased only KILLIN expression 4.88-fold (95% CI, 1.4-18.1; P = .05). Individuals with KILLIN -promoter methylation had a 3-fold increased prevalence of breast cancer (35/42 vs 24/64; P < .0001) and a greater than 2-fold increase of kidney cancer (4/45 vs 6/155; P = .004) over individuals with germline PTEN mutations. Conclusions: Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals. These observations need to be replicated.