Screening Of Stk11 Gene Mutation And Its Correlation With Intussusception And Malignant Tumors In Peutz-jeghers Syndrome

Peutz-Jeghers Syndrome(PJS)is a rare hereditary hamartomatous polyposis disease.PJS is characterized by mucocutaneous pigmentation,multiple hamartoma polyps in the gastrointestinal tract and an increased predisposition towards developing malignancy.Serine-Threonine Kinase 11(STK11)is the only identified PJS pathogenic gene.In order to screening of STK11 gene mutation and its correlation with intussusception and malignant tumors in PJS,the study was performed.A total of 239 cases were clinically diagnosed with PJS who obtained informed consent for Next-generation Sequencing from December 2017 to September 2019,in a tertiary care center(Air Force Medical Center,PLA,Beijing,China),were included.The detection rate of STK11 gene mutation was 92.9%(222/239).Among then,41 cases were large fragment deletions,37 cases were splicing mutations,44 cases were frameshift mutations,41 cases were missense mutations,50 cases were nonsense mutations and 12 cases of other mutations.A total of 49 novel STK11 gene mutations were reported in this study,further enriching the STK11 gene mutation spectrum.It is worth noting that the 180th base,the 250th base,the 290th base,the 580th base,the 863th base,and the 921th base ofSTK11 gene may be high-frequency mutation sites in Chinese PJS cases.Among the 239 patients,there were 140 patients with complete clinical data had a history of intussusception.Taking this as the research object,they were divided into groups according to the status of STK11 gene mutation to analyze the relationship between the mutation status of STK11gene and the occurrence of intussusception in PJS.The median age of first intussusception of STK11 gene mutation group was younger than that of STK11 gene non-mutation group(15years vs 31 years).The Kaplan-Meier method was used to analyze the cumulative risk of intussusception in the two groups,and the difference between the two groups was statistically significant(χ~2=5.899,P=0.015).Subgroup analysis found that the cumulative risk of intussusception in the splicing mutation group,missense mutation group,and large fragment deletions were significantly higher than that of the STK11 gene non-mutation group,and the difference was statistically significant(χ~2=9.527、5.999、7.042,all P>0.05).Among the 239 patients,there were 15 patients with complete clinical data developed malignant tumors,including 13 cases of digestive system tumors and 2 cases of reproductive system tumors.All PJS patients complicated with malignant tumor carried STK11 gene mutation.26.7%of the mutation sites are exon1(4/15).According to variant mutation sites,all cases in this cohort were divided into exon1 mutation group and other sites mutation group.The median onset age of cancer in exon1 mutation of STK11 gene group and other sites mutation of STK11 gene group was 27years and 36 years,respectively.Patients in exon1 mutation of STK11 gene group tended to have a younger median age at the first diagnosis of cancers than those in other sites mutation of STK11 gene group,the difference was statistically significant(z=-2.027,P=0.043).Based on the results of STK11 detection and their impact on clinical phenotypes in large cohort study,we concluded that:patients and their impact on clinical phenotypes,we believe that:(1)The incidence of STK11mutations in PJS patients is high,and a total of 49 novel STK11 gene mutations enlarge the spectrum of STK11 gene mutations.Six high-frequency mutation sites may be population-specific,providing a factual basis for further research of STK11 mutations in Chinese PJS patients;(2)Splicing mutation,missesen mutation and large deletions of STK11 gene may related to the early occurrence of intussusception (especially in the age group of 10-30 years).Therefore,after the target mutation is found through genetic testing,PJS polyp screening time can be considered in clinical work to advance,so as to reduce the occurrence of intussusception;(3)Patients with exon1 mutation of STK11 gene tended to have a younger median age at the first diagnosis of cancers.Further investigations are required to identify these links and understand the molecular basis for this genotype-phenotype relationship.