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

Watkins, Thomas B. K.; Colliver, Emma C.; Huska, Matthew R.; Kaufmann, Tom L.; Lim, Emilia L.; Duncan, Cody B.; Haase, Kerstin; Van Loo, Peter; Swanton, Charles; McGranahan, Nicholas; Schwarz, Roland F.

doi:10.1371/journal.pcbi.1011379

Cited by 4 publications

(2 citation statements)

References 72 publications

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“…Rapid-CNS 2 utilizes single-molecule sequencing to identify genetic and epigenetic modifications on the same molecule. Leveraging this technology for integrated analysis of mutations, copy number variants, and methylation -especially with long readsholds promise for detecting subclonal reads accurately 28,30,31 . Subclonal methylation classes could also be identified by a robust MNP-Flex model providing further insights for potential targeted therapies of heterogeneous samples.…”

Section: Discussionmentioning

confidence: 99%

Versatile, accessible cross-platform molecular profiling of central nervous system tumors: web-based, prospective multi-center validation

Sahm,

Patel,

Göbel

et al. 2024

Preprint

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The 2021 WHO classification underscores the importance of molecular data integration in Central Nervous System (CNS) tumor diagnostics. However, currently used assays have disadvantages due to technical complexity, required equipment and reagent cost, as well as lengthy turnaround times. In response to these challenges, we introduce Rapid-CNS2 and MNP-Flex. Rapid-CNS2, an adaptive sampling-based nanopore sequencing workflow, offers real-time methylation classification and DNA copy-number information within a 30-minute window, suitable for intra-operative settings, followed by comprehensive molecular profiling within 24 h, covering the complete spectrum of diagnostically and therapeutically relevant information for the respective entity. We have prospectively validated Rapid-CNS2 in a multi-center setting on 223 samples. For even more widespread use of methylation-based CNS tumor classification, we developed MNP-Flex, a platform-agnostic methylation classifier encompassing 184 CNS tumor classes. MNP-flex achieved 92% accuracy across a global validation cohort of 78,000 samples spanning five different technologies. These innovations represent a significant advancement in CNS tumor diagnostics, making rapid, actionable molecular insights more widely and more rapidly available, which is crucial for personalized treatment strategies. Their integration streamlines the diagnostic process, broadening access to accurate molecular classification and promising improved patient outcomes in neurooncology on a global scale. MNP-Flex is available as a web-service https://mnp-flex.org and the Rapid-CNS2 workflow is available on Github.

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Section: Discussionmentioning

confidence: 99%

Versatile, accessible cross-platform molecular profiling of central nervous system tumors: web-based, prospective multi-center validation

Sahm,

Patel,

Göbel

et al. 2024

Preprint

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“…The mhBAF is also a more robust estimator of mirrored-subclonal CNAs, compared to earlier approaches [ 23 , 39 , 49 , 50 ] that identify imbalanced segments that differ across samples in a post-hoc analysis. These methods are unable to detect regions of mirrored-subclonal allelic imbalance that are not identified by the input segmentation.…”

Section: Methodsmentioning

confidence: 99%

HATCHet2: clone- and haplotype-specific copy number inference from bulk tumor sequencing data

Myers,

Arnold,

Bansal

et al. 2024

Genome Biol

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Bulk DNA sequencing of multiple samples from the same tumor is becoming common, yet most methods to infer copy-number aberrations (CNAs) from this data analyze individual samples independently. We introduce HATCHet2, an algorithm to identify haplotype- and clone-specific CNAs simultaneously from multiple bulk samples. HATCHet2 extends the earlier HATCHet method by improving identification of focal CNAs and introducing a novel statistic, the minor haplotype B-allele frequency (mhBAF), that enables identification of mirrored-subclonal CNAs. We demonstrate HATCHet2’s improved accuracy using simulations and a single-cell sequencing dataset. HATCHet2 analysis of 10 prostate cancer patients reveals previously unreported mirrored-subclonal CNAs affecting cancer genes.

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Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

Hynds,

Huebner,

Pearce

et al. 2024

Nat Commun

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Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

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

Cited by 4 publications

References 72 publications

Versatile, accessible cross-platform molecular profiling of central nervous system tumors: web-based, prospective multi-center validation

Versatile, accessible cross-platform molecular profiling of central nervous system tumors: web-based, prospective multi-center validation

HATCHet2: clone- and haplotype-specific copy number inference from bulk tumor sequencing data

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

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