Biology subjects

Haglund de Flon, F.

Publications and source records attributed to Haglund de Flon, F..

3 recordsLinked to original sources

bioRxiv2026

Genetic profiling of soft tissue and bone tumors using SarcDBase

To streamline molecular profiling of tumor biopsies, we developed SarcDBase, an openly accessible tool that extracts and interprets clinically relevant genetic alterations from next-generation sequencing data. By automatically linking identified variants to curated, user-defined reference lists, SarcDBase minimizes the need for specialized expertise and reduces the burden of manual data processing. The platform delivers detailed molecular profiles, diagnostic insights and an intuitive interface for comprehensive interpretation. SarcDBases performance was evaluated in a heterogeneous cohort of 204 deep-sequenced bone and soft tissue tumors. In most cases (81%), its interpretation closely matched the curated post-sequencing diagnosis. Discrepancies mainly occurred in samples lacking diagnostically informative mutations. In some instances, SarcDBase flagged rare or unexpected alterations, including previously unreported gene fusions. This highlights SarcDBases dual potential as both an interrogative research tool and facilitator of molecular diagnostics, especially for reclassification of diagnostically challenging tumor types.

genomics↗

bioRxiv2026

Principles of subclonal gene dosage across human cancer

Intratumor heterogeneity drives disease progression, but even though subclonal copy number variation (CNV) is a major contributor to this heterogeneity1, its impact on cell phenotype is not fully understood. Here, by applying high-quality joint whole genome sequencing and mRNA profiling in single cells (DNTR-seq2) to solid tumors and leukemias from 57 patients, we have analyzed the in vivo transcriptional effect of subclonal CNVs within a tumor. We found that gene dosage is generally additive in low and moderate copy states, but that cancer-type-specific compensation is common, and core promoter elements are associated with reduced additivity. We find that different classes of subclonal CNV impose varying degrees of transcriptional constraints on a cell, with highly amplified megabase-size regions associated with a strong effect both in cis and trans, while arm level CNVs generally exert a milder effect. We also describe a previously unappreciated class of tumors with transient clonality, where every cell is genetically highly distinct. We find that transient clonality is common in ovarian cancer and soft tissue sarcoma, that it is preceded by a whole genome duplication event, and that gene dosage in these tumors affects transcript abundance to a similar degree as in cancer with stable subclones.

cancer biology↗

bioRxiv2024

CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma

Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We identified four major subgroups: (i) low-grade osteosarcoma with chromosome 12 amplicons as the sole acquired alteration, (ii) high- and low-grade tumours with CDK4 and MDM2 amplification along with few changes affecting other chromosomes, (iii) high-grade osteosarcomas with heavily rearranged genomes including either CDK4 and MDM2 amplification or (iv) CDK4 amplification and TP53 structural alterations. The amplicons involving MDM2 exhibited signs of an initial chromothripsis event affecting chromosome 12. In contrast, there was no indication of a chromothripsis event on chromosome 12 in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus resulted in breakage and repair processes that co-amplified the CDK4 locus. Furthermore, our investigation revealed recurring promoter swapping events that involved the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events led to the ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions, respectively, in two distinct cases.

cancer biology↗