Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

[cowden syndrome]

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 G 2 . 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 .Leu 119 L eu . 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 .