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 .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated