| Multiple endocrine neoplasia type 1(MEN1)is an autosomal dominant tumor syndrome caused by MEN1 gene germ-line alteration with a prevalence of1-10/100000.Clinical manifestations of MEN1 patients are of high heterogeneity,which increased the rate of misdiagnosis and seriously affected the prognosis of the disease.Although currently we had a preliminary understanding of the pathogenicity of MEN1,we still can not elaborate its precise mechanism of tumorigenesis.Objective This research aimed to investigate the clinical features and oucomes of MEN1 patients,furthermore,to explore the genetic and molecular mechanism for tumoriogenesis of MEN1.Patients and Methods 1.From 2001 to 2016,68 families and 121 patients fulfilled the criteria for diagnosis of MEN1 and their clinical information and follow-up data were collected.2.A meta analysis of patients treated for TC(thymic carcinoid)associated to MEN1 from eight institutions was performed and we used a fixed effect model to pool results across studies to evaluate the prevalence,clinical features,and prognosis.3.We performed direct sequencing for the 121 MEN1 patients.For negative patients in direct sequencing,multiplex ligation-dependent probe amplification was performed to explore gross deletions of MEN1 and the comparison between MEN1 mutation-positive and mutation-negative patients was made.4.Total genomic DNA was extracted from tumor tissue for PCR.PCR products of MEN1 gene were purified and direct gene sequencing was performed.Meanwhile,LOH(loss of heterzygosity)analysis was performed using DNA from MEN1 associated endocrine tumors and corresponding peripheral leukocytes.The expression level of menin was also detected in MEN1 associated endocrine tumors through immunohistochemical staining and immunofluorescence staining.Results 1.The average onset age of MEN1 patients was 36.9±18.1 years and the average age of diagnosis was 40.1±16.6 years.The most common manifestations were pHPT(primary hyperparathyrodism),PIT(pituitary tumor)and PNET(pancreatic neuroendocrine tumor)and the prevalence of which was 84.8%,73.5% and 58.6%,respectively.The five-year survival and ten-year survival rate of MEN1 was 90.7%and 84.1%,respectively.Patients with TC had a higher risk of death(HR=16.1,P<0.0001).2.A thorough systematic review including eight studies was performed,of which 2711 MEN1 patients were found and the prevalence of TC was 3.7%(n=99).Older age at diagnosis(HR=1.4,P=0.03),larger maximum tumor diameter(HR=1.5,P=0.04)and with metastasis(HR=1.6,P=0.04)were associated with poor outcome.There was marginal gender difference in Asian population while it was obvious in European and American population.3.ACC(adrenocortical carcinoma)might be a rare component of MEN1.The tumor tissue of ACC had homozygous somatic mutation of MEN1 gene and LOH of chromosome 11q13 was found.4.70.2% of the121 MEN1 patients had MEN1 germ-line mutation,and the most mutated exons resulted to be exon 2 and 10(57.1%),truncating mutation(frame-shift mutation,nonsense mutation and gross deletion)represented the highest rate(82.9%).Mutation-positive group(n=85)and mutation-negative group(n=36)had a different tumor prevalence.Mutation-positive patients were more susceptible to pHPT and PNET,while mutation-negative were more likely to develop PIT(P<0.05).Meanwhile,mutation-negative patients seemed to have a longer life expectancy compared with that of mutation-positive patients.5.In all PNETs,LOH of MEN1 gene and loss of menin expression were found,while in 66.7% of parathyroid tumors and 75.0% of TCs,neither LOH nor menin absence was found.Conclusions 1.The average onset age of MEN1 patients was 36.6±18.0 years and the average age of diagnosis was 40.1±17.2 years.The most common manifestation was pHPT and the prevalence of PIT was higher than that of PNET in MEN1 patients.Five-year and ten-year survival rate of MEN1 patients was 90.7% and 84.1%,respectively.Besides,patients with TC had a significant higher risk of death.2.TC was a rare but fatal component of MEN1.Patients with older age,larger tumor size,or with metastasis were associated with poorer outcome and should be managed aggressively.3.ACC might be a rare component of MEN1 with rapid progress and poor prognosis.4.Exon 2 and exon 10 might be the hot regions of MEN1 mutation.The severity of MEN1 in mutation-negative patients were better than that in mutation-positive patients.5.Tumor formation of MEN1 might have tissue specialty.PNET conformed to the “two-hit” hypothysis,while haploinsufficiency might be involved in the tumorigenesis of pHPT and TC formation might require other mechanisms in addition to the germ-line mutation of MEN1. |
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