Exploratory Study On Clinical Phenotyping And Genotype Of Peutz-jeghers Syndrome

BackgroundPeutz-Jeghers syndrome(PJS)is a rare clinical autosomal dominant genetic disease,which belongs to the category of hereditary colorectal cancer.The main clinical manifestations of the disease are mucocutaneous melanotic spots,multiple gastrointestinal hamartoma polyps,and tumor susceptibility.Hamartomatous polyps throughout the gastrointestinal tract are prone to serious complications such as intestinal obstruction,intussusception,polyp ulceration and bleeding,and malignant transformation.There is currently no effective prevention and cure for the disease.The course of the disease is prolonged repeatedly and patients often need lifelong follow-up treatment,which brings a heavy burden to patients and families.In previous studies we found that the clinical heterogeneity of PJS patients was more obvious,and there were large differences in polyp growth rate,polyp size,and distribution within the gastrointestinal tract.Therefore,we try to classify the clinical phenotypes of PJS patients,so as to provide a reference for developing personalized treatment and follow-up plans for PJS patients with different types.At the same time,we found that the disease has obvious genetic heterogeneity.At present,there are no other pathogenic genes except STK11 gene,and the relationship between genotype and phenotype is not clear.Therefore,this study intends to use high-throughput gene sequencing technology to explore the genotypes of PJS patients with different clinical phenotypes,and to explore whether there is some correlation and try to provide a basis for further elucidating the pathogenesis of the disease.Method1.The clinical and follow-up data of a total of 420 PJS patients admitted to the hospital were arranged,and retrospective statistical analysis was conducted to explore the relationship between different clinical phenotypes and preliminary clinical phenotyping.2.A total of 24 patients were randomly selected from the two types of patients according to the criteria of phenotype classification.Pathogenic germline mutation screening and analysis of 139 common hereditary colorectal tumor-associated gene loci including STK11 were performed by high-throughput sequencing and to explore the correlation between PJS genotype and clinical phenotype.Results1.Based on the time of appearance of black spots as the classification basis,the age of appearance of black spots < 3 years is called early-onset subtype,and those ? 3 years are called delayed-onset subtype.There were significant differences between the two types of patients in phenotypes such as small bowel polyp burden and number of treatments received.Patients of delayed-onset subtype have a larger polyp burden and more severe clinical hazards.2.This group of studies found that black spots tended to appear earlier in patients of PJS with family history,and the later the black spot appeared,the larger the gastrointestinal polyp load.3.83.3% of the PJS patients in this group of studies carried mutations in the STK11 gene and 90% of these mutations were associated with pathogenicity.The mutation of STK11 gene in exon 7 is significantly less pathogenic than other exons,and the truncated mutation is significantly more pathogenic than the missense mutation.4.The SLX4 gene mutation was detected intensively in patients with this disease for the first time,which may have important significance for the pathogenesis of PJS.Conclusion1.PJS has obvious clinical heterogeneity,the course of the patient is prolonged repeatedly,which is seriously harmful.Typing the phenotype of the disease based on a large sample of clinical data is of great significance in guiding clinical diagnosis and treatment and developing a follow-up plan.2.The appearance time of black spot and whether there is a family history can be used as the basis of clinical phenotype classification.Patients with delayed-onset and nonfamily history have a larger gastrointestinal polyp load,and they may need more active follow-up and treatment.3.STK11 gene mutations play an important role in the pathogenicity of the disease,but genetic heterogeneity may still exist.4.SLX4 gene is considered to be an important regulator of DNA repair,and DNA replication errors have been shown to be directly related to the occurrence of some genetic colorectal cancers.The mutations found in this gene in PJS patients may explain the genetic heterogeneity of PJS to some extent.