Germline predisposition to genitourinary rhabdomyosarcoma

Abstract

Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the location or the pathology of the sarcomas. Therefore, there are limited data on genitourinary specific associations with certain genetic syndromes. We summarize, here, the primary differential considerations for rhabdomyosarcoma of the genitourinary system. Primary considerations include DICER1 pathogenic variation, Li-Fraumeni syndrome, constitutional mismatch repair deficiency, mosaic variegated aneuploidy, neurofibromatosis type 1, Noonan syndrome, other RASopathies, Costello syndrome, and Beckwith-Wiedemann syndrome. Some conditions may present with specific pathological, clinical and/or family history features, but for others, the genitourinary tumor may be the only presenting sign at the time of diagnosis. Genetic evaluation with counseling and/or testing may help identify an underlying tumor predisposition. This manuscript serves as an introduction to germline considerations for children with genitourinary rhabdomyosarcoma.

A Case of Pheochromocytoma as a Subsequent Neoplasm in a Survivor of Childhood Embryonal Rhabdomyosarcoma

“…Neumann et al12 found almost 25% of patients with a pheochromocytoma and negative family history had a germline mutation in RET , VHL , or SDHx and over 90% of those patients had no symptomatology of a pheochromocytoma. Several cancer predisposition syndromes are also associated with rhabdomyosarcoma including Li-Fraumeni ( TP53 mutations), Beckwith-Weidemann, DICER1 mutations, and syndromes involving RAS mutations including Noonan syndrome, neurofibromatosis type 1, and Costello syndrome 8,13,14. Recently, a study by Li et al9 used whole exome sequencing to estimate the prevalence of germline mutations in known cancer predisposition genes in 615 pediatric patients with newly diagnosed rhabdomyosarcoma, and found 7.3% of patients had germline mutations in 15 genes.…”

“…Several cancer predisposition syndromes are also associated with rhabdomyosarcoma including Li-Fraumeni (TP53 mutations), Beckwith-Weidemann, DICER1 mutations, and syndromes involving RAS mutations including Noonan syndrome, neurofibromatosis type 1, and Costello syndrome. 8,13,14 Recently, a study by Li et al 9 used whole exome sequencing to estimate the prevalence of germline mutations in known cancer predisposition genes in 615 pediatric patients with newly diagnosed rhabdomyosarcoma, and found 7.3% of patients had germline mutations in 15 genes. Survivors of rhabdomyosarcoma may be particularly at risk for subsequent neoplasms because chemotherapy and radiation exposure can further increase the cancer risk from underlying genetic predisposition.…”

Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

“…5 10 Additionally, recent studies focused on reviewing tumour syndromes or searching for germline variants related to specific sarcoma histologies, such as osteosarcomas and rhabdomyosarcomas, have pinpointed the relevance of GPVs in cancer predisposing genes (CPGs) in sarcoma aetiology. [11][12][13][14] However, due to the rarity of both sarcomas and most HCPS, establishing gene-disease associations is challenging, and there may be undiscovered associations, especially in populations underrepresented in genomic studies.…”

Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility

“…The protein neurofibromin, encoded by NF1 , typically negatively regulates the Ras pathway [ 61 ], thus inactivating mutations in NF1 also in hyperactivation of the Ras pathway. Urogenital, and to a lesser extent, orbital, ERMS have been associated with NF1 [ 62 ]. Although studies have shown that the prevalence of RMS amongst NF1 patients is less than 1%, it is still greater than in individuals without NF1 [ 63 ].…”