Renal cell carcinoma of acquired cystic disease in 2 patients with TSC2/PKD1 contiguous gene syndrome

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2020

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Mansfield, Brett Stephen

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Introduction The genes for tuberous sclerosis complex and autosomal dominant polycystic kidney disease lie adjacent to each other on chromosome 16p13.3. Rarely, a large deletion can result in a contiguous gene syndrome which leads to early, severe polycystic kidney disease and the development of end stage renal disease (ESRD) in the third decade of life. Acquired cystic disease is most frequently seen in the dialysis population and predisposes the affected individual to acquired cystic disease associated renal cell carcinoma (ACD-RCC), a new subtype of renal cell carcinoma (RCC).Methods Two patients with phenotypic characteristics of TSC2/PKD1 contiguous gene syndrome with ESRD who developed ACD-RCC will be described. The Affymetrix® OncoScan® chromosomal microarray was performed on DNA extracted from whole blood from both participants to assess for genetic changes across the genome. The NanoString® nCounter® Cancer CN Assay was used to identify copy number variations (CNVs) in 87 common cancer genes.Results No mutation was identified by conventional genetic testing to account for the TSC2/PKD1 contiguous gene syndrome in both participants. Mutations in the BRCA2, KRAS and MDM4 genes were common to both patients and identified by means of the NanoString® nCounter® Cancer CN Assay. One participant was found to have CNVs in 3p22.1 and 3q26.2, important loci in RCC. Discussion The absence of a mutation in TSC2/PKD1 contiguous gene syndrome occurs in 10-25% of affected individuals. The most common cause of which is somatic mosaicism. Further genetic testing would be required to confirm mosaicism in each of the cases described. Alteration observed in the three cancer causing genes (BRCA2, KRAS and MDM4) were present in both cases, however, these are not known to predispose to RCC. One participant was found to have CNVs in 3p22.1 and 3q26.2, important susceptibility loci in RCC which may have contributed to cancer development. Further, targeted gene sequencing studies are needed to identify mutations that may predispose individuals with ESRD to ACD-RCC.

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A research report submitted in partial fulfilment of the requirements for the degree of Master of Medicine to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2020

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