School of Pathology (ETDs)

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    Germline Cancer Predisposition Variants in Paediatric Rhabdomyosarcoma
    (University of the Witwatersrand, Johannesburg, 2023) Pillhofer, Gabriella Peta; Lamola, Lindie; Mnika, Khuthala
    Rhabdomyosarcoma (RMS) is cancer that originates from undifferentiated skeletal muscle cells. RMS is the most common tissue sarcoma in children and adolescents and has over 50% of cases occurring in individuals under the age of 10 and thus there is reason to suspect that RMS may have a hereditary predisposition. However, much of the existing research of germline predisposition in paediatric RMS is focused on ethnically European populations, and currently very little data is available from African populations. In this study, we aimed to identify RMS predisposition variants by performing whole exome sequencing (WES) on germline DNA from eight paediatric patients diagnosed with RMS. Following WES, variant annotation and filtering was performed to identify variants in genes of interest that were potentially germline causes of malignancy. Filtered variants were then classified according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. This study identified four variants of uncertain significance (VUSs) in four patients. Two of these were in genes that have previously been associated with an RMS phenotype (SDHB and BRCA1), and two were in genes that have been associated with a hereditary cancer syndrome that is not linked to RMS (CBL and CREBBP). While the highlighted variants are not of clinical significance, this study emphasises the importance of cataloguing and reporting VUSs in research in Africa. By expanding the genomic database on African patients, the analysis of variants on the continent may be made more accurate and efficient. It is the goal that the knowledge gained from this study will contribute to the information base of hereditary paediatric cancers in Africa, and that it may encourage similar research so that the field may continue to expand.
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    RB1 and Beyond: Determining genetic causes of retinoblastoma in South African patients
    (University of the Witwatersrand, Johannesburg, 2024) Beukman, Danielle; Lamola, Lindie
    Retinoblastoma is the most common solid tumour of the retina, affecting mainly paediatric patients. Although loss-of-function germline variants the RB1 gene is the tumour suppressor gene most often associated with heritable retinoblastoma, two contradictory research findings complicate the assumption that a pathogenic germline variant in RB1 will lead to the development of heritable retinoblastoma. Firstly, heritable retinoblastoma has been observed in cohorts with biallelic wild-type RB1 genes, secondly, biallelic loss-of-function is not always sufficient to lead to retinoblastoma tumorigenesis. By investigating germline variants in additional cancer predisposition genes to discover candidate driver genes in heritable retinoblastoma, the full germline mutational spectrum of heritable retinoblastoma can be established. In this study we investigate sequence germline variants in cancer predisposition genes beyond RB1 in South African retinoblastoma patients with an African ancestry by performing whole exome sequencing on eight patients diagnosed with retinoblastoma. Whole exome sequencing data for genes previously associated with retinoblastoma was subjected to variant annotation by means of a variant effect predictor and filtering criteria applied manually. Variant classification was performed according to guidelines proposed by The American College of Medical Genetics and Genomics and the Association of Molecular Pathology. The highest degree of variant classification was variants of unknown significance. The absence of sequence variants capable of describing the retinoblastoma phenotype in this cohort demonstrates the necessity of looking beyond RB1, combining next generation sequencing with copy number analysis pipelines and additional genome mapping technologies capable of detecting structural variants. The detection of sequence variants previously reported to be possibly damaging but now considered polymorphisms highlights the importance of revisiting variant classification. In closing, this study adds genomic information from patients with a South African ancestry to mounting genomic data, ensuring that previously underrepresented populations can also benefit from future cancer predisposition and precision medicine research.