Confounding factors affecting analysis of germline structural variants in pediatric solid tumors

Abstract We provide data showing the germline predisposition structural variants (SV) involving MYCN and RAF1::TMEM40 reported by Gillani et al. (2025) in pediatric solid tumors are confounded by circulating tumor DNA (ctDNA) and enrichment for Hispanic or Latino ancestry, respectively. We suggest that future germline studies should ensure analyses of tumor-in-normal contamination for non-polymorphic markers and careful examination of population stratification for polymorphic markers to ensure clinical relevance. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by National Institutes of Health R01 grants as follows. National Institutes of Health grant R01CA273326 (XM) National Institutes of Health grant R01CA237562 (SJD) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All raw genome sequencing data analyzed in this study is described in Gillani et al (2025) and are hosted by dbGaP (https://dbgap.ncbi.nlm.nih.gov/; cohorts: MESA, BioMe, GMKF), St. Jude Cloud (https://www.stjude.cloud/), The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All raw genome sequencing data analyzed in this study is described in Gillani et al (2025) and are hosted by dbGaP (https://dbgap.ncbi.nlm.nih.gov/; cohorts: MESA, BioMe, GMKF), St. Jude Cloud (https://www.stjude.cloud/), The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/). Accession numbers for respective cohort and cases are provided in the supplementary materials and methods or tables S1, S4, S5 and S7. https://dbgap.ncbi.nlm.nih.gov/