Tuberous sclerosis complex: a complex case

• Published in: Cold Spring Harbor molecular case studies Vol. 8; no. 3; p. 1
• Main Authors: Powell, Ryan M, Pattison, Sharon, Moravec, Jiri C, Bhat, Basharat, Guirguis, Nada, Markie, David, Jones, Greg T, Copedo, Jason, Print, Cristin G, Morison, Ian M, Gavryushkin, Alex, Gray, Bronwyn, Wyeth, Lisa J, Eccles, Mike R, Macaulay, Erin C
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.04.2022
• Subjects: Adenocarcinoma; Angiomyolipoma; Angiomyolipoma - genetics; Angiomyolipoma - pathology; Cancer; Case studies; Complexity; Deoxyribonucleic acid; DNA; DNA methylation; DNA repair; Epithelial cells; Epithelium; Female; Gene sequencing; Genes; Genomes; Heterozygosity; Humans; Immunohistochemistry; Kidney Neoplasms; Leukemia, Myeloid, Acute; Loss of heterozygosity; Male; Mismatch repair; MLH1 protein; MSH2 protein; MSH6 protein; Mutation; Pathogenesis; Patients; Proteins; Repair; Research Report; Tuberous sclerosis; Tuberous Sclerosis - diagnosis; Tuberous Sclerosis - genetics; Tuberous Sclerosis - metabolism; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 2; Tuberous Sclerosis Complex 2 Protein - genetics; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; Whole genome sequencing; Wilms' tumor; pulmonary lymphangiomyomatosis; duodenal carcinoma; renal angiomyolipoma
• ISSN: 2373-2873
• DOI: 10.1101/mcs.a006182

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 (hamartin) or more frequently (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 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 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 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 , or 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.