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Highly recurrent, human syntenic CNAs characterize pediatric cancer models

ABSTRACT: Mouse models represent the gold standard for cancer-related preclinical in vivo trials. However, their molecular characterization has often been limited and lacks global DNA methylation profiling, which has emerged as a crucial classification tool for various human tumor entities. Therefore, the epigenetic tumor cell identity, proximity to respective human counterparts, and their underlying CNVs have mostly remained elusive. Here, we generate a comprehensive DNA methylation atlas of globally available mouse models for pediatric solid tumors, including an extensive, novel cohort of high-grade glioma models. We show that tumors cluster within dedicated tumor entities and exhibit previously suggested connections to putative cells of origin. Using tailor-made cross-species analysis, we highlight the epigenetic resemblance of analyzed models to the human disease and demonstrate entity-specific immune infiltration by custom deconvolution. Strikingly, we identified that specific mouse models harbor highly recurrent CNV signatures that are unique to the respective tumor subtype. We further show that these CNVs share syntenic regions with their respective human counterparts and occur reliably during multi-passage tumor evolution. Our results reveal epigenetic insights into a global conglomerate of mouse models for pediatric solid cancers and seminally showcase recurrent CNVs in murine tumors, granting long-awaited access to CNV research."

ORGANISM(S): Mus musculus

PROVIDER: GSE275151 | GEO | 2025/09/19

REPOSITORIES: GEO

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Project description:Background: Advances made in the area of microarray comparative genomic hybridization (aCGH) have enabled the interrogation of the entire genome at a previously unattainable resolution. This has lead to the discovery of a novel class of alternative entities called large-scale copy number variations (CNVs). These CNVs are often found in regions of closely linked sequence homology called duplicons that are thought to facilitate genomic rearrangements in some classes of neoplasia. Recently, it was proposed that duplicons located near the recurrent translocation break points on chromosomes 9 and 22 in chronic myeloid leukemia (CML) may facilitate this tumor-specific translocation. Furthermore, ~15-20% of CML patients also carry a microdeletion on the derivative 9 chromosome (der(9)) and these patients have a poor prognosis. It has been hypothesised that der(9) deletion patients have increased levels of chromosomal instability. Results: In this study aCGH was performed and identified a CNV (RP11-125A5, hereafter called CNV14q12) that was present as genomic gain or loss in 10% of control DNA samples derived from cytogenetically normal individuals. CNV14q12 was the same clone identified by Iafrate et al. as a CNV. Real-time polymerase chain reaction (Q-PCR) was used to determine the relative frequency of this CNV in DNA from a series of 16 CML patients (both with and without a der(9) deletion) together with DNA derived from 36 paediatric solid tumors in comparison to the incidence of CNV in control DNA. CNV14q12 was present in ~50% of both tumor and CML DNA, but was found in 72% of CML bearing a der(9) microdeletion. Chi square analysis found a statistically significant difference (p ≤ 0.001) between the incidence of this CNV in cancer and normal DNA and a slightly increased incidence in CML with deletions in comparison to those CML without a detectable deletion. Conclusions: The increased incidence of CNV14q12 in tumor samples suggests that either acquired or inherited genomic variation of this new class of variation may be associated with onset or progression of neoplasia. Keywords: CML, array CGH, aCGH, BAC array

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Highly recurrent, human syntenic CNAs characterize pediatric cancer models

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