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PTEN  is a well-described predisposition gene for Cowden syndrome (CS), a familial cancer syndrome characterized by a high risk of breast and other cancers.  KLLN , which shares a bidirectional promoter with  PTEN , causes cell cycle arrest and apoptosis. We previously identified germline hypermethylation of the  KLLN  promoter in 37% of  PTEN  mutation-negative CS/CS-like (CSL) patients. Patients with germline  KLLN  hypermethylation have an increased prevalence of breast and renal cancers when compared with  PTEN  mutation carriers. We have consequently sought to identify and characterize germline  KLLN  variants/mutations in CS/CSL and in apparently sporadic breast cancer patients.  KLLN  variants in CS/CSL patients are rare (1 of 136, 0.007%). Interestingly, among 438 breast cancer patients, 13 (3%) have germline  KLLN  variants when compared with none in 128 controls ( P  = 0.049). Patients with  KLLN  variants have a family history of breast cancer when compared with those without ( P  = 0.02). We demonstrate that germline  KLLN  variants dysregulate the cell cycle at G2 .  Of 24 breast carcinomas analyzed, 3 (13%) have somatic  KLLN  hemizygous deletions, with somatic loss of the wild-type allele in a patient with germline  KLLN  p.Leu119Leu. Of 452 breast carcinomas in The Cancer Genome Atlas project, 93 (21%) have  KLLN  hemizygous or homozygous deletions. This is the first study to associate germline  KLLN  variants with sporadic breast cancer and to recognize somatic  KLLN  deletions in breast carcinomas. Our observations suggest that  KLLN  may be a low penetrance susceptibility factor for apparently sporadic breast cancer.

Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest