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KLLN – Cowden Disease

Germline inactivation of KLLN has been investigated as a genetic etiology in PTEN‐negative Cowden syndrome (CS) patients. In a cohort of 136 CS/CS‐like individuals, a single patient harbored a germline [NM_001126049.2]c.357C>T (p.Leu119=) variant in KLLN, corresponding to a frequency of <1% (PMID:23446638). No additional segregation data were reported, limiting case‐level evidence for sequence variants in CS.

Functional and epigenetic analyses provide concordant evidence that KLLN acts as a tumor suppressor in CS. Germline hypermethylation of the KLLN promoter occurs in ~37% of PTEN mutation-negative CS patients and associates with elevated risks of breast and renal cancers (PMID:23446638; PMID:25669429). In vitro studies demonstrate that KLLN loss impairs p53-mediated G2 arrest and G1 checkpoint via downregulation of p21, confirming a loss-of-function mechanism (PMID:23446638; PMID:34878965).

References

  • Human molecular genetics • 2013 • Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest. PMID:23446638
  • European journal of human genetics • 2015 • KLLN epigenotype-phenotype associations in Cowden syndrome. PMID:25669429
  • Cell cycle (Georgetown, Tex.) • 2022 • p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells. PMID:34878965

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single CS/CSL proband with germline KLLN variant; no segregation; supportive epigenetic and functional data

Genetic Evidence

Limited

One proband with c.357C>T (p.Leu119=) in 136 CS/CSL patients (PMID:23446638)

Functional Evidence

Moderate

KLLN promoter hypermethylation in CS cohorts and in vitro studies show loss-of-function disrupts G2/M and G1 checkpoints (PMID:23446638; PMID:25669429; PMID:34878965)