Tuberous sclerosis complex: a complex case

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI:10.1101/mcs.a006182
Ryan M Powell, S. Pattison, Jiří C. Moravec, B. Bhat, Nada Guirguis, D. Markie, G. Jones, Jason Copedo, C. Print, I. Morison, A. Gavryushkin, Bronwyn Gray, Lisa J. Wyeth, M. Eccles, E. Macaulay
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引用次数: 1

Abstract

Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.
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结节性硬化症:一个复杂的病例
结节性硬化症(TSC)是一种遗传性疾病,其特征是在多器官系统中形成良性但无组织的肿瘤。种系突变的TSC1(错构体)或更常见的TSC2 (tuberin)基因是TSC的病因。TSC的恶性表现,肺淋巴管平滑肌瘤病(LAM)和肾血管平滑肌脂肪瘤(AML),也可能以独立的散发性血管周围上皮细胞瘤(PEComa)为特征,以体细胞TSC2突变为特征。因此,在缺乏其他特征的TSC患者中,从散发性LAM和散发性AML的表现中识别TSC可能会变得模糊。在本报告中,我们提出了一个病例研究,一个患者最初报告有散发性LAM和缺乏DNA错配修复蛋白的粘液十二指肠腺癌。此外,患者有Wilms肿瘤病史,在LAM诊断后被重新分类为AML。因此,我们研究了这些肿瘤的起源和相关性。利用种系全基因组测序,我们在患者的一个TSC2等位基因中发现了一个过早截断。免疫组化观察到AML和LAM组织中tuberin表达缺失。然而,没有证据表明在TSC2位点存在杂合性缺失或DNA甲基化突变,这表明可能有其他机制导致肿瘤抑制蛋白的缺失。在十二指肠粘液腺癌中,未发现DNA错配修复基因MLH1、MSH2、MSH6或PMS2的致病突变。相反,克隆反褶积分析用于鉴定导致发病的突变。该报告强调了使用多种测序技术的实用性和在临床环境中解释数据的复杂性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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