A TRIO APPROACH USING WHOLE EXOME SEQUENCING TO DISCOVER SHARED MUTATIONS IN TWO FIRST-DEGREE COUSINS WITH RHABDOMYOSARCOMA

Abstract

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma that arises in cells committed to the myogenic lineage but unable to achieve full differentiation. It occurs mainly in children and younger adults and is histologically classified into mainly the embryonal subtype (ERMS) and the alveolar subtype (ARMS). ARMS accounts for almost 30% of RMS cases overall, yet it is more aggressive and associated with worse prognosis due to two characteristic translocations of the FOXO1 gene with either the PAX3 or PAX7 genes. Such cases are described as fusion positive (FP). Although the vast majority of cases arise sporadically, almost 10% of children or adolescents diagnosed with RMS are considered genetically predisposed to develop this type of sarcoma. While a number of cancer predisposition syndromes have been previously reported in the literature as increasing the risk of RMS (e.g.: Li-Fraumeni Syndrome, Costello Syndrome...), many others are yet to be discovered. These syndromes are usually the result of point mutations inherited in an autosomal dominant manner. Although rare, familial cases of RMS can greatly inform about the biology and genetic basis of the sporadic disease, and this clears the floor for the discovery of new genes and/or gene variants associated with RMS specifically and cancer generally. Such a case has been recently reported whereby two first-degree cousins from a consanguineous family have been diagnosed with FP-ARMS at an early age. In order to identify the potential inherited single nucleotide variant(s) responsible for the RMS tumor growth in these two relatives, if any, whole-exome sequencing was performed on two trios each comprised of the patient and their respective parents. Sequencing outcome resulted in a large number of variants that were filtered according to a number of independent variables in order to narrow down the possible hits. Among forty-seven variants of interest, three were of particular relevance and were highly suspected of being responsible for the development of RMS in the two pediatric patients; the FANCL gene variant (rs62020347), the BRCA1 variant (rs1799950) and the NUMBL variant (rs536916726). Further research must be carried on each variant independently in order to determine its specific role in the etiology of RMS.