| Background:Familial nonmedullary thyroid carcinoma(FNMTC)refers to two or more first-degree relatives have nonmedullary thyroid carcinoma(NMTC),without other known associated familial syndromes or history of radiation exposure,accounting for approximately 5-15%of differentiated thyroid carcinoma cases.Despite accounting for a relatively small number of cases of NMTC,FNMTC is believed to be a distinct clinical entity.Whether the patients with FNMTC have clinical pathological features different from those of patients with sporadic NMTC(SNMTC)remains controversial.At the same time,the molecular genetic changes associated with familial patients are inconclusive.Objective:The primary objective of the first part of the study was to investigate whether the clinicopathological and prognostic features of FNMTC patients different from sporadic cases,and to further explore whether the number of NMTC patients in the family is related to the degree of malignancy of the tumors,analyse whether there is a difference between parent/offspring and sibling types of patients with FNMTC,and provide feasible suggestions in clinical treatment.The second part of the study is a part of a large study.We selected one site from the multiple mutation sites in previous studies:MUC5B,to validate,and analyse the frequency of germline mutations,explore whether the gene mutation was associated with the development of thyroid cancer,which laid the foundation for subsequent functional verification of the gene and the final result.Methods:Part I:Retrospective analysis of 209 cases with FNMTC and 1120 patients with SNMTC who underwent primary surgery in the same surgery group from January 1,2005 to December 30,2016 at the Department of Head and Neck Surgery,Cancer Hospital,Chinese Academy of Medical Sciences.Familial patients were further divided into the two affected members’ group and the three or more affected members’ group.The detaile clinical data of all the enrolled patients were collected.We plan to compare the differences of age,gender,tumor status,and prognosis factors between familial and sporadic patients,and the two affected members’ group and three or more affected members’ group were compared with sporadic patients respectively to analyze differences in clinical features and prognosis factors.Compare the parent/offspring and sibling types of patients with FNMTC to see if there are differences.Part Ⅱ:The MUC5B gene was tested in peripheral blood and tumor tissues of 100 patients with sporadic nomedullary thyroid carcinoma to observe whether there was a germline mutation in the patients.The frequency of MUC5B mutation was analyzed.Investigate whether germline mutations at this site are associated with thyroid cancer.Understand the relevant functions of the gene that have been studied and published.Observe the clinical features of patients with germline mutations in this gene.The author also completed the enrollment of the familial patients and the extraction of DNA.At the time of writing this paper,the verification results of familial patients were not yet available.Results:Part I:The FNMTC group had a significantly higher risk of bilateral growth,multifocality,extrathyroidal extension,and lateral lymph node metastasis than the SNMTC group.The results of comparison between the two subgroups of the familial group showed that the incidence of bilateral growth,multifocality,extrathyroidal extension,thyroid nodular goiter,and lateral lymph node metastasis in the group with ≥ 3 affected members was significantly higher than in the group with only two affected members(P<0.05).There was no significant difference in clinical features and prognosis factors between the 2 affected patients groups and sporadic patients,and the group with ≥3 affected members had a significantly higher risk of bilateral growth,multifocality,extrathyroidal extension,thyroid nodular goiter,and lateral lymph node metastasis than the SNMTC group(P<0.05).The former had a significantly higher relapse rate than the latter(P<0.05).Survival analysis showed that the rate of disease-free survival of familial patients was significantly lower than that of sporadic patients(90.43%vs 94.73%;P=0.008);the rate of disease-free survival of ≥3 affected patients was significantly lower than that of 2 affected patients(85.54%vs 93.65%;P=0.045).The age of onset in the second generation of parental pedigrees was significantly lower than that of the first generation(P<0.001).Part Ⅱ:One of the 100 patients with sporadic nonmedullary thyroid carcinoma had germline mutation of MUC5B,with a mutation frequency of 1.04%,which was much higher than the mutation frequency of 0.02%found in public databases.Therefor,it can be explained that germline mutations at this site are associated with thyroid cancer.MUC5B gene mutations are associated with proliferation,metastasis,and invasion of various tumors.Patients with this gene germline mutation have a strong ability of tumor metastasis and the patient has a clear family history of cancer.Conclusion:Familial nonmedullary thyroid carcinoma is a distinct clinical entity with high invasive biological behavior and poor prognosis.The true familial patient should be families with 3 or more patients with NMTC,and the families with only 2 affected patients may only be a family cluster of sporadic patients.The age of onset of the second generation is earlier and should be screened early.True familial patients should undergo more aggressive surgical procedures and rigorous postoperative monitoring.The molecular genetic studies on familial nonmedullary thyroid carcinoma have not been conclusive.In this paper,MUC5B mutation sites were verified in patients with sporadic nonmedullary thyroid carcinoma.The mutation frequency was found to be much higher than that recorded in the general population,and its function was more likely to be related to tumors.Therefor,it can be explained that germline mutations at this site are associated with thyroid cancer.The results combined with the verification results of the familial patients laid the foundation for follow-up research and provided ideas for follow-up studies. |
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