The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults.
To establish whether germline mutations of STK11/LKB1 account for familial breast cancer, 22 patients from 14 breast cancer families with LOH on 19p and one PJS family were selected for screening for germline mutations of LKB1/STK11.
This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.
Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li-Fraumeni and Peutz-Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer.
Although a tentative molecular classification of PJS patients was recently made according to their LKB1 mutation status, it is difficult to clarify the genotype-phenotype relationship because of the rarity and genetic heterogeneity of this disease.
Germline LKB1 mutations cause Peutz-Jeghers syndrome, a hereditary disorder that predisposes to gastrointestinal hamartomatous polyposis and several types of malignant tumors.
Germline mutations of the STK11/LKB1 tumour suppressor gene (19p13.3) are responsible for Peutz-Jeghers syndrome (PJS), a rare genetic disorder, which is dominantly inherited.
To understand the molecular pathogenesis of PJS phenotypes, we used microarrays to analyze gene expression profiles in proliferating HeLa cells transduced with lentiviral vectors expressing wild type or mutant LKB1 proteins.
LKB1 was discovered as a tumour suppressor mutated in Peutz-Jeghers syndrome, and is a gene involved in cell polarity as well as an upstream protein kinase for members of the AMP-activated protein kinase family.
As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS (Bannayan-Riley-Ruvalcaba syndrome and Cowden disease), our study suggests a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasizes the central role played by LKB1 as a tumor suppressor in the small intestine.
The results presented herein enlarge the spectrum of mutations of the STK11 gene by identifying a novel de novo mutation in a PJS patient and further support the hypothesis that STK11 mutations are disease-causing mutations for PJS with or without a positive family history.
This is the first report of clinical overlap in individuals with PCOS and PJS, even though some individuals with PCOS show a polymorphism in STK11, which is the gene mutated in PJS.
Germline mutations of the STK11 gene lead to emergence of hamartomas in the gastrointestinal tract of patients with Peutz-Jeghers syndrome, who bear an increased risk of malignancies of the gastrointestinal tract, genital tract, and other organs.
The substitutions of single amino acids in highly conserved regions of the STK11 protein are associated with Peutz-Jeghers syndrome (PJS), which is an autosomal dominant inherited disorder.
STK 11 testing can confirm those at risk of PJS, who require lifelong surveillance, and possibly release those with a simple dermatosis, such as LHS, from invasive and thus potentially harmful surveillance.
Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection.