Whole genome sequencing of apparently mutation-negative MEN1 patients
Whole genome sequencing of apparently mutation-negative MEN1 patients
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DOI：
10.1530/eje-19-0522
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Stalberg, Peter
中科院分区：
文献类型：
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作者：
Backman, Samuel;Bajic, Duska;Stalberg, Peter
目的：多发性内分泌瘤1型（MEN1）是一种常染色体显性遗传综合征，通常由MEN1基因功能缺失突变引起。然而，少数符合MEN1标准的患者未发现MEN1突变。此外，这些个体中的一些个体呈现出提示散发性疾病的微妙不同的表型。本研究的目的是探讨突变阴性的MEN1的遗传结构。设计：14例临床诊断为MEN1（n = 13）或怀疑为MEN1（n = 1）且MEN1基因筛查阴性的患者。体质变异对人口数据库和体细胞变异进行了研究下的肿瘤抑制model.Results：3例患者携带致病性变异（两个剪接位点的变异，一个错义变异）在MEN1，没有被检测到在常规临床测序，一名患者携带致病性变异CASR和一名患者携带一个总缺失染色体1 q，其中包括CDC 73基因。匹配的肿瘤DNA从6例无突变的分析没有检测到任何复发的基因，满足Knudson的两次击中model.Conclusion：这些结果突出了生殖系突变的可能性错过了常规筛查，考虑表型在非典型或突变阴性的情况下的重要性。缺乏明显的致病突变表明，一小部分MEN1突变阴性的MEN1病例可能是由于一个患者中几种内分泌肿瘤的偶然发生。
Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1.Design: Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included.Methods: Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model.Results: Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1 q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model.Conclusion: These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent diseasecausing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.