Preliminary Study On The Clinical Subtypes And Their Molecular Genetic Etiology Of Peutz-Jeghers Syndrome

BackgroundPeutz-Jeghers syndrome(PJS)is an autosomal dominant disease characterized by multiple gastrointestinal hamartoma and mucocutaneous pigmentation.PJS polyps,which are marked by being difficult in making diagnoses and giving treatments,prolonged course and various severe secondary complications,bring heavy mental stress and financial burden to PJS patients and their families.By analyzing the clinicopathological features of PJS,we found that PJS patients had strong clinical heterogeneity.Therefore,it is necessary to classify subtypes of PJS for targeted diagnosis,treatment and follow-up.At the same time,we also analyzed the internal molecular genetic mechanism of biological behavioral heterogeneity through high-throughput sequencing technology to provide the theoretical guidance in making individualized therapeutic and follow-up strategies.Method1.According to the procedure of establishing disease specimen banks at home and abroad,we arranged the clinicopathological and follow-up data of 295 patients admitted in our hospital,collected the specimens of polyp tissue,conducted statistical analysis and discussed the basis of classifying clinical subtypes.2.14 genetic mutation sites usually detected in hereditary colorectal tumors were screened by high-throughput sequencing in both subgroups of patients.The relationship between genotypes and phenotypes and the gene mutation spectrums were analyzed.Results1.295 patients with PJS belonged to 7 nationalities and came from 26 provinces and urban areas.99%of the patients had black spots on lips and buccal mucosa,and 96.6%of them had been shown before the age of 10.PJS hamartoma polyps were mostly distributed in the duodenum and small intestine.The median age of inital diagnosis and treatment was 15 years old.The median interval time between the occurrence of black spots and abdominal symptoms was about 10 years.The morbidity of gastrointestinal and other malignant tumors in patients with PJS was significantly higher than that of general population.2.Statistical results suggested that patients with black spot appearing age<3 years and/or initial treatment age<14 years were classified as the early-onset subtype;otherwise they could be assigned to the delayed-onset subtype.Patients of the delayed-onset subtype need more internal and surgical intervention.3.With high-throughput sequencing technology,80%of the patients were found carrying LKB1/STK11 mutations,and 45%of them carrying other gene mutations.13 new mutations were found.There was no significant statistical relationship between genotypes and phenotypes.Besides LKB1/STK11 variants,the most significant mutated genes in the PJS patients were that of DNA mismatch repair system(MMR).Conclusion1.PJS has prominent features,serious clinical harm,prolonged course and obvious heterogeneity of clinical manifestations.Patients need repeated diagnosis and treatment.It is very important to collect and analyze the clinicopathological data and specimens for directing the therapeutic and follow-up program.2.Black spots on the lip and buccal mucosa can be used as an early warning signal and classify the PJS patients into two clinical subtypes combined with initial treatment age.Different subgroup patients require different clinical therapies and follow-up plans.The patients of the delayed-onset subtype need more active responses.3.In addition to the mutations of LKB1/STK11 gene,there may be other genes involved in the occurrence of PJS.For example,mutated gene of the MMR may also be the genetic cause of PJS.