Tuberous sclerosis complex: a complex case

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• Tuberous sclerosis complex (TSC) is an inheritable disorder caused by mutations in TSC1 or TSC2 genes.
• Malignant manifestations like LAM and AML can occur sporadically, complicating diagnosis in TSC patients.
• This case involves a patient with LAM, duodenal adenocarcinoma, and a history of Wilms' tumor reclassified as AML.

Purpose of the Study:

• To investigate the origins and relatedness of multiple tumors in a patient with a complex medical history.
• To identify the genetic basis for tumor development in the presented case.
• To explore the mechanisms of tumor suppressor loss in TSC-related and sporadic tumors.

Main Methods:

• Germline whole-genome sequencing to identify genetic mutations.
• Immunohistochemistry to assess protein expression (tuberin).
• Analysis for somatic loss of heterozygosity and DNA methylation.
• Clonal deconvolution analyses for tumor pathogenesis.

Main Results:

• A premature truncation in one TSC2 allele was identified via germline sequencing.
• Loss of tuberin expression was observed in AML and LAM tissues.
• No somatic LOH or epimutations at the TSC2 locus were found, suggesting alternative loss mechanisms.
• No causative mutations in mismatch repair genes were found in the duodenal adenocarcinoma.

Conclusions:

• Germline TSC2 mutation contributes to tumor development in this complex case.
• The study underscores the challenges in distinguishing TSC from sporadic tumors.
• Multiple sequencing techniques are crucial for interpreting complex clinical data.