Biology subjects

Kaufmann, T. L.

Publications and source records attributed to Kaufmann, T. L..

6 recordsLinked to original sources

bioRxiv2026

Deciphering selection patterns of somatic copy-number events

Somatic copy-number alterations (SCNAs) are pervasive across cancers, arising through diverse mutational mechanisms and subsequently shaped by selection according to fitness advantages [1-4]. These alterations can drive tumourigenesis via gene-dosage changes in oncogenes and tumour suppressors [5, 6]. However, observed SCNA profiles do not uniquely define the genomic events that led to them, which is a major obstacle to understanding the selective forces shaping cancer genomes. Here we present SPICE, Selection Patterns In somatic Copy-number Events, an event-level framework that infers discrete copy-number events from allele-specific profiles and models focal selection from first principles, incorporating uniform breakpoint formation and locus-specific selective pressures. Applied to 5,966 samples from the TCGA dataset, SPICE quantifies the full spectrum of SCNA events, recapitulates known mutational processes, and tracks systematic shifts in event types before and after whole-genome duplication (WGD). Next, SPICE employs a generative selection model to identify the location of oncogenes and tumour-suppressors. Unlike previous approaches that detected peaks in aggregated copy-number signals, our model operates directly on inferred events and treats genome-wide breakpoint formation as a neutral reference against which locus-specific selection is detected. This analysis reveals 460 loci under selection which are highly enriched for known oncogenes and tumour suppressors, recapitulating most previously reported sites and uncovering many novel regions, and simultaneously showing that most internal copy-number events are not subject to focal selection. These results establish a unified framework that deconvolves copy-number profiles into their underlying evolutionary events and greatly expand the catalogue of loci implicated in cancer development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC="FIGDIR/small/708809v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@7d471corg.highwire.dtl.DTLVardef@c78feeorg.highwire.dtl.DTLVardef@1ba52a8org.highwire.dtl.DTLVardef@188ab0c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

PhytClust: efficient and optimal node clustering in phylogenetic trees

Phylogenetic trees play a fundamental role in elucidating evolutionary relationships among taxa. Clustering taxa remains a major challenge across diverse biological domains such as cancer genomics, microbial systematics, and phylogenomics. Several methods partition taxa in phylogenetic trees into clusters, but these approaches face key limitations. Many rely on user-defined distance thresholds, whose choice often depends on prior knowledge and may be difficult to justify consistently across datasets. More broadly, existing methods often differ in how clusters are defined and commonly rely on heuristics or user-specified criteria to make the search space tractable for large trees. Here, we present PhytClust, a threshold-free algorithm that partitions trees into monophyletic subtrees (clusters) by identifying groups of taxa with low within-cluster dispersion. For a fixed number of clusters, PhytClust finds the exact global optimum under this objective and then selects the optimal number of clusters using a cluster-validity index. The resulting partitions are reproducible and reflect both tree topology and branch lengths. In simulated datasets, PhytClust outperforms existing methods in both speed and accuracy and scales to trees with more than a hundred thousand taxa. We apply PhytClust across cancer genomics, avian phylogenomics, bacterial and archaea phylogenetics, and plant genomics to demonstrate PhytClusts varied applicability. By providing a standardized method for taxa clustering within phylogenetic trees, PhytClust yields reproducible, optimal and computationally efficient clusters.

evolutionary biology↗

bioRxiv2024

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily active mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

cancer biology↗

bioRxiv2024

Predictive biomarkers of breast ductal carcinoma in situ may underestimate the risk of recurrence due to de novo ipsilateral breast carcinoma development

Development of ipsilateral breast carcinoma following diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not be the case and it is important to know how often recurrences are new tumours. Ipsilateral primary-recurrence pairs (n=78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n=54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced by a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). Comparing primary DCIS with their recurrences found that evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo "recurrent tumours" of independent origin occur in patients who may be at high risk.

cancer biology↗

bioRxiv2022

Refphase: Multi-sample reference phasing reveals haplotype-specific copy number heterogeneity

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patients disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample reference phasing. We demonstrate Refphases ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.

bioinformatics↗

bioRxiv2022

Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma

Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either TERT activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only present in [~]50% of ALT tumors. To identify potential new pathways to telomere maintenance, we investigate allele-specific gene dosage effects from whole genomes and transcriptomes in 115 primary neuroblastomas. We show that copy-number dosage deregulates telomere maintenance, genomic stability, and neuronal pathways and identify upregulation of variants of histone H3 and H2A as a potential alternative pathway to ALT. We investigate the interplay between TERT activation, overexpression and copy-number dosage and reveal loss of imprinting at the RTL1 gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.

genomics↗