Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by hamartomatous polyps in the small bowel and mucocutaneous pigmentation. Patients with Peutz-Jeghers syndrome often present as surgical emergencies with complications of the polyps, such as intussusception, bowel obstruction and bleeding. Furthermore, repeated operations may be needed in some patients, which may result in short bowel syndrome. Although early reports did not demonstrate a predisposition to cancer in patients with this syndrome, more recent studies have described an increased risk for both gastrointestinal and extra-gastrointestinal cancers. Women with the Peutz-Jeghers syndrome have the extremely high risk for breast and gynecologic cancer. Recently, Peutz-Jeghers syndrome susceptibility gene, encoding the serine threonine kinase STK11 (also called LKB1), was identified in families with Peutz-Jeghers syndrome. The identifications of germline mutations in families with Peutz-Jeghers syndrome could be a turning point in the management of Peutz-Jeghers syndrome.
Female ; Human ; Neoplasms/etiology ; Peutz-Jeghers Syndrome*/pathology ; Peutz-Jeghers Syndrome*/genetics ; Peutz-Jeghers Syndrome*/complications ; Phenotype ; Risk Factors

BACKGROUNDPeutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease. STK11/LKB1 gene germline mutations have been identified as responsible for PJS. In our study, we investigated the molecular basis of PJS and evaluated correlation between the STK11 mutations and the Chinese population.

METHODSWe collected three pedigrees of PJS and screened the 9 exons and their flanking intronic sequences of STK11/LKB1 gene in the probands and normal individuals in the families using polymerase chain reaction (PCR) and direct sequencing.

RESULTSSequencing of the STK11 gene in the probands of 3 families revealed two novel mutations (c180C-->G and c998-1002delGCAGC) in exon 1 and exon 8, respectively. The mutation of c180C-->G resulted in a premature termination codon. The other mutation, a deletion of five nucleotides (998-1002delGCAGC) in exon 8, predicted to generate a translational frameshift and a termination at codon 1070.

CONCLUSIONSThe growing number of mutations in PJS pedigrees suggests the molecular basis of PJS. STK11 gene mutation can be detected in most patients with PJS.

Child ; Female ; Humans ; Male ; Mutation ; Pedigree ; Peutz-Jeghers Syndrome ; genetics ; Protein-Serine-Threonine Kinases ; genetics

OBJECTIVETo investigate the diagnostic methods and reasonable treatment of Peutz-Jeghers syndrome (PJS).

METHODSClinical data of six patients with PJS were reviewed.

RESULTSRepeated abdominal pain, intussusception and intestinal polyp with bleeding were main manifestations. Four patients father,three patients grandfather and one patients mother were diagnosed with PJS. Three patients had family history of cancer. Case 4 and case 5 underwent laparotomy for many times because of intussusceptions caused by polyps or recurrent abdominal pain. Case 1 and case 4 had polyps synchronous with adenoma, and case 2 had polyp with gastric cancer. Main treatment included polyp resection and partial small intestinal and colon resection.

CONCLUSIONSPatients with PJS have family history of cancer and a high incidence of polyp recurrence of small intestine. Surgical intervention is the first choice regimen. Surveillance should be emphasized on gastrointestinal tract and other potential malignant organs in PJS patients.

Adolescent ; Adult ; Female ; Humans ; Intestine, Small ; surgery ; Male ; Pedigree ; Peutz-Jeghers Syndrome ; diagnosis ; genetics ; surgery

OBJECTIVETo investigate common chromosomal changes and the LOH frequency of microsatellite loci in primary gastric cancer samples in order to locate the deleted regions in which human gastric cancer related genes might exist.

METHODSComparative genomic hybridization (CGH) was used to define global chromosomal aberrations in 43 primary gastric tumors. Based on the results of CGH, analysis of loss of heterozygosity (LOH) was performed in chromosome 19 in which the loss was first discovered in the gastric cancers. The PCR-based approach was used to investigate 22 loci, which are spaced at 1.1 - 10.9 cM intervals throughout chromosome 19. The amplified PCR fragments were subjected to electrophoresis in PAGE gel and analyzed with Genescan trade mark and Genotyper trade mark.

RESULTSCGH analysis revealed gains in chromosome 3p (8/43), 8q (8/43), 20 [20 (9/43), 20p (7/43), 20q (4/43)], 12q (16/43), 13q (12/43) and losses in 19 [19 (15/43)], 7 [17 (8/43), 17p (10/43)], 16 (10/43) and 1p (11/43). Among the 43 evaluated samples, the most frequent LOH was detected at locus D19S571 (27.81%).

CONCLUSIONSThe tumorigenesis of gastric cancer includes several chromosomal changes. The aberration of chromosome 19 was the first common change founded in gastric cancer. The region near the D19S571 might harbor potential genes related to the tumorigenesis of gastric cancer.

Chromosomes, Human, Pair 19 ; Humans ; Loss of Heterozygosity ; Nucleic Acid Hybridization ; Peutz-Jeghers Syndrome ; genetics ; Stomach Neoplasms ; genetics

OBJECTIVE: To screen for pathogenic variants in the coding regions of STK11 gene among Chinese patients with Peutz-Jeghers syndrome (PJS). METHODS: Peripheral blood samples were collected from 64 patients. The coding regions of the STK11 gene were detected by PCR and Sanger sequencing. RESULTS: Fourty-eight patients were found to harbor STK11 gene variants, which included 39 types of variants consisting of missense, nonsense, insertional, deletional and splice site variants. Among 64 PJS patients, the detection rate of point variants was 75.00% (48/64), of which missense variants accounted for 29.17% (14/48), nonsense variants accounted for 29.17%(14/48), insertion variants accounted for 2.08% (1/48), deletional variants accounted for 10.42% (5/48), and splice site variants accounted for 29.17% (14/48). The detection rates of sporadic cases and those with a family history were 71.8% (28/39) and 80.0% (20/25), respectively. Two variants (c.250A>T, c.580G>A) occurred in 3 PJS probands. Thirteen variants were unreported previously and were considered to be pathogenic. CONCLUSION The detection rate of variants among Chinese PJS patients is similar to that of other countries. A number of novel common variant sites were discovered, which enriched the spectrum of PJS-related variants.
Asian Continental Ancestry Group ; China ; DNA Mutational Analysis ; Humans ; Peutz-Jeghers Syndrome ; genetics ; Protein-Serine-Threonine Kinases ; genetics

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).
Adenomatous Polyposis Coli/*genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis/*genetics ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Intestinal Polyposis/diagnosis/*genetics ; Peutz-Jeghers Syndrome/diagnosis/*genetics

OBJECTIVETo detect the expression of important proteins associated with transforming growth factor-beta (TGF-beta)/Smad signaling pathway in Peutz-Jeghers syndrome (PJS) and investigate the correlation of these proteins to LKB1 gene expression.

METHODSThe expression and localization of LKB1, TGFbeta1 and pSmad2 proteins in 20 PJS polyp samples and normal intestinal mucosal tissues were detected with immunohistochemical staining.

RESULTSThe expressions of LKB1, TGFbeta1 and pSmad2 were lower in PJS polyps than in normal mucosa, and the differences in LKB1 and TGFbeta1 proteins were significantly different between them (P<0.05). In PJS polyps, positive correlations were found between LKB1 and TGFbeta1 and between TGFbeta1 and pSmad2 expressions.

CONCLUSIONTGFbeta/Smad pathway is probably subjected to the regulation by LKB1 and may play a role in the occurrence of PJS.

Humans ; Immunohistochemistry ; Peutz-Jeghers Syndrome ; metabolism ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Signal Transduction ; Smad2 Protein ; genetics ; metabolism ; Transforming Growth Factor beta ; genetics ; metabolism

OBJECTIVETo analyze the sequence of STK11 gene coding region in 20 patients with Peutz-Jeghers syndrome and identify the point mutations in STK11 gene associated with the occurrence of the disease.

METHODSBlood samples were collected from 20 inpatients with Peutz-Jeghers syndrome treated in our center between January 2009 and October 2010. The sequence of STK11 gene coding region was analyzed using PCR and DNA sequencing and compared with the normal sequence of STK11 gene.

RESULTSOf the 20 patients with Peutz-Jeghers syndrome, 14 showed STK11 gene mutations in the coding region, including 1 patient having two mutations and 13 patients with a single mutation site. In one case, sequence analysis of the STK11 gene identified a novel type of STK11 germline mutation, in which the cytosine (C)460 was substituted by guanine (G) in exon 3 to result in a new amino acid at codon 154. Four patients from 2 families were found to have a common mutation. The remaining 6 patients were not found to have mutations in STK11 gene coding region.

CONCLUSIONMutations of STK11 gene is a major cause of Peutz-Jeghers syndrome. The missense mutation of 460 C→G in exon 3 of STK11 gene is a novel mutation associated with Peutz-Jeghers syndrome.

Adult ; Asian Continental Ancestry Group ; genetics ; Codon ; DNA Mutational Analysis ; Exons ; Female ; Humans ; Male ; Mutation ; Pedigree ; Peutz-Jeghers Syndrome ; genetics ; Protein-Serine-Threonine Kinases ; genetics

OBJECTIVE: To explore the relationship between the sequence variation of the promoter region (-1543 approximately -1160) of STK11 gene and the risk of developing Peutz-Jeghers syndrome (PJS). METHODS: The sequences of the promoter region of 14 PJS patients (7 patients are inherited and the other 7 patients are sporadic) and 42 normal individuals were PCR amplified and then sequenced. RESULTS: A new single nucleotide polymorphism (SNP) G/T (-1275) in STK11 promoter region was identified. The frequency of genotype GG, GT, and TT was 53.3%, 26.7%, and 20%, respectively among PJS patients and 33.3%, 64.3%, and 2.4%, respectively among the normal individuals. The frequency of genotype GG and TT among patients was significantly higher than that among the normal individuals, and the frequency of genotype GT among patients was significantly lower than that among the normal individuals (chi(2)=8.521, P<0.05). CONCLUSION G/T(-1275) in STK11 promoter region is a new SNP. The genotype of this new SNP may relate to the risk of developing Peutz-Jeghers syndrome (PJS) deserve further research.
Base Sequence ; Gene Frequency ; Genotype ; Humans ; Molecular Sequence Data ; Peutz-Jeghers Syndrome ; genetics ; Polymorphism, Genetic ; Promoter Regions, Genetic ; genetics ; Protein-Serine-Threonine Kinases ; genetics

Peutz-Jeghers syndrome (PJS) is a very rare genetic disorder. PJS carries a high risk of developing gastrointestinal (GI) cancer or non-GI cancer with advancing years. However, major symptoms of PJS in childhood are obstruction, intussusception, and bleeding from hamartomatous intestinal polyps which in majority of cases are not related to cancer. Generally, first GI symptom develops by 20 years in one half of children diagnosed with PJS. Children under two years of age who had PJS polyp-related intestinal symptoms are rare, and there have been no published report on intestinal carcinoma development, adenomatous change or dysplasia of polyps in Korean children with PJS. Recently, the authors have experienced a case PJS with adenomatous polyp change in a 15-month-old boy who had STK11 gene mutation. Therefore, early evaluation could be necessary and considered in children with PJS.
Adenoma/*diagnosis/pathology ; Base Sequence ; Colonoscopy ; Heterozygote ; Humans ; Infant ; Male ; Peutz-Jeghers Syndrome/*diagnosis/genetics/pathology ; Polymorphism, Single Nucleotide ; Polyps/pathology ; Protein-Serine-Threonine Kinases/chemistry/genetics