Germline Cancer Predisposition Variants in  Pediatric Rhabdomyosarcoma: A Report From the Children’s Oncology Group

Abstract

Background Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. Methods We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children’s Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided. Results We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10–22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10–4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis. Conclusions These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.

A case of primary CNS embryonal rhabdomyosarcoma with PAX3-NCOA2 fusion and systematic meta-review

“…Although our case harbors wildtype DICER1, which was con rmed by whole-exome and Sanger sequencing, DICER1 mutations have been reported in both primary CNS and non-CNS rhabdomyosarcoma [8][9][10][11]17]. A case of primary CNS rhabdomyosarcoma with NF1 was also reported, and an association between NF1 and non-CNS rhabdomyosarcoma is known [18][19][20]. We then further revealed the demographic similarities between CNS and non-CNS rhabdomyosarcoma.…”

Germline predisposition to pediatric Ewing sarcoma is uniquely characterized by inherited pathogenic variants in DNA damage repair genes

“…The presence of pathogenic germline variants was not significantly associated with age (mean 10.9 vs. 10.5 years, p = 0.42 by twosided t-test) or sex (p = 0.81 by Fisher's exact test). Across the pan-sarcoma discovery cohort, nominal enrichment signal at p < 0.05 was observed for multiple genes previously implicated in sarcoma pathogenesis, including TP53, NF1, and DICER1 5,18,25 ; nominal enrichment signal was also seen for MUTYH, PALB2, NTHL1, and FANCC, genes with less prior supporting evidence for their role in sarcoma germline predisposition. The enrichment in TP53 was greatest, reaching significance at FDR < 0.05 across the pan-sarcoma discovery cohort (Figure 2B; Table S7).…”

Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility

“…Two such RMS-specific cohort sequencing studies have recently explored both the frequency and identity of germline mutations in cancer predisposition genes in RMS patients. Our group completed the Genetics of Embryonal and Alveolar Rhabdomyosarcoma Study (GEARS), which performed germline WES analysis of 615 RMS patients from the Children’s Oncology Group in order to determine the prevalence of germline mutations in 70 known cancer predisposition genes [ 99 ]. We found that 45 of the 615 patients (7.3%) possessed cancer predisposition germline mutations.…”