HAMARTOMATOUS POLYPOSIS SYNDROMES:MOLECULAR MECHANISMS AND GENETIC TESTING.
Creators: name: Galatola, Martina
Publisher: name: Università degli Studi di Napoli Federico II
Year: 2010

description: Hamartomatous polyposis syndromes are a rare group of hereditary autosomal dominant disorders that comprise less than 1% of all hereditary colorectal cancers. However, these hamartomatous polyposis syndromes have a malignant potential for the development of colorectal cancer as well as extracolonic cancers. The hamartomatous polyposis syndromes include juvenile polyposis syndrome (JPS); PTEN hamartoma tumor syndrome, which includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), and Peutz-Jeghers syndrome (PJS). Due to the rarity of these conditions, a thorough understanding of their clinical presentation, including extraintestinal manifestations, and genetics is important. For pediatric gastroenterologists, understanding how to recognize and establish the appropriate diagnosis and cancer risk and following appropriate screening and surveillance guidelines is crucial for early detection to minimize the risk of carcinoma as children reach adulthood. 
Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited syndrome characterized by mucocutanoeus pigmentation, multiple hamartomatous polyps in the gastrointestinal tract and an increased risk of cancer at a young age. Inactivating germ-line mutations in the tumor suppressor gene STK11/LKB1 have been detected in approximately 80% of patients.  
The aim of this work is to clarify the molecular basis of the disease in Italian PJS patients.  
We investigate the STK11/LKB1 gene mutations in a well-characterized series of 9 unrelated Italian PJS patients, by using a combination of PCR, RT-PCR, DNA sequencing, Southern blot analysis and real-time polymerase chain reaction techniques.  
We have characterized the specific STK11 mutation in 6 probands, and identified 2 truncating mutations (1 novel and 1 known mutation), one missense known mutation in the exon four, and two novel small in-frame deletions in the exon six. Finally, we have found an intra-exonic in-frame deletion encompassing exons 2 and 4: the possible mechanism leading to this genomic rearrangement is most likely an Alu-Alu homologous recombination.  
In our study point mutations, small scale deletions/insertions and exonic STK11 deletions account for about 67% of PJS; mutations in other STK11 related genes examined have not be found. Other gene inactivating methods, such as chromosomal rearrangements mediated by Alu-Alu homologous recombination, which cannot be detected by routinely molecular biology screening methods, might be responsible for PJS in mutations negative population subset. However, the existence of genetic heterogeneity cannot be excluded. 
The “PTEN hamartomatous tumor sindrome” (PHTS), include a group af syndromes that are caused by germline mutations of the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome ten). They belong to hamartomatous polyposis syndromes family, a rare and  heterogeneous group of hereditary autosomal dominant disorders characterized by multiple polyps in the gastrointestinal tract and greatly increased risk of developing malignant tumours in multiple tissues. 
The PTEN tumor suppressor gene affects multiple cellular processes including cell growth, proliferation, and cell migration by antagonizing phosphatidylinositol 3-kinase (PI3K)/Akt phatway.  
we have first screened the PTEN coding region in three italian patients with clinical diagnosis of PHTS by using a combination of RT-PCR, direct sequencing of the amplified fragments and real-time polymerase chain reaction techniques. Afterwards, in periferal blood cells of these patients, we have defined the expression profile of other genes directly related to PI3K/Akt phatway, as cMYC, COX2, CCND1 and TNFa, or involved in colorectal cancer onset, as APC, DKC1 and hTERT. 
We have characterized the specific PTEN mutation in 1 subject, the c406C-&gt;T (C136R) mutation, a missence mutation of the catalytic domain just described in literature before. The others two patients showed a low level of PTEN mRNA expression, respectively of 0,3 and 0,4 fold change, related to a healthy controls. All three patients were characterized by an high level of COX2, TNFa and CCND1 genes expression and decrease expression of APC gene. 
Our data represent the first evidence of a PI3K/Akt phatway dysregulation in periferal blood cells of PHTS patients that probably determine a pro inflammation attivation. Knowledge of specific molecular phatways costitutively dysregulated in this syndrome could be helpful in optimizing molecular targeted therapy and preventative care.