Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes.

[cowden syndrome]

Cowden syndrome (CS ) is a difficult-to -recognize multiple hamartoma syndrome with high risks of breast , thyroid , and other cancers . Germline mutations in PTEN on 10 q 23 were found to cause 85 % of CS when accrued from tertiary academic centers , but prospective accrual from the community over the last 12 years has revealed a 25 % PTEN mutation frequency . PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes . PTEN antagonizes the AKT 1 /PI 3 K signaling pathway and has roles in cell cycle , migration , cell polarity , and apoptosis . We report that 8 of 91 (8 .8 %) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK 3 CA mutations (7 missense , 1 nonsense , and 2 indels ) and 2 (2 .2 %) AKT 1 mutations . These mutations result in significantly increased P-Thr 308 -AKT and increased cellular PIP 3 . Our observations suggest that PIK 3 CA and AKT 1 are CS susceptibility genes .

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