Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"

The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration.We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques.Our data provide the first evidence of β-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1β) was found to be overexpressed.In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as β-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers.PTEN hamartoma tumor syndrome is the term that has recently been used to describe Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. These disorders are all caused by mutations in the PTEN gene and are all characterized by extraintestinal manifestations in addition to intestinal polyposis. PHTS is inherited in an autosomal dominant manner, and is likely to be underdiagnosed because of its phenotypic variability, its incomplete penetrance, and the fact that many of its component features are subtle and occur in the general population [1].CS is a rare multiple hamartoma syndrome with a reported incidence of 1 in 200,000 individuals. This syndrome is characterized by macrocephaly, mucocutaneous lesions (such as facial trichilemmoma), acral keratosis, and glycogenic acanthosis of the esophagus and papillomatous papules. It is also associated with thyroid, breast, and endometrial