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

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

doi:10.1101/2022.10.13.511885

Cited by 3 publications

(7 citation statements)

References 72 publications

(107 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mirrored-subclonal CNAs are differential gains or losses of the maternal and paternal chromosomes in different subpopulations of cancer cells from the same tumor. In contrast to earlier reports of mirrored-subclonal allelic imbalance [39,[48][49][50] in bulk samples, HATCHet2 identifies haplotype imbalance in specific clones. We show using simulated data that HATCHet2 accurately identifies mirrored-subclonal CNAs (Additional file 1: Section S9).…”

Section: Identification Of Clone-specific Mirrored-subclonal Cnasmentioning

confidence: 76%

“…We refer to such events as mirrored-subclonal CNAs because the more-abundant haplotype is opposite ("mirrored") between the two clones. Previous efforts to detect these events have been limited to the identification of mirrored-subclonal allelic imbalance [39,[48][49][50], a sample-level rather than clone-level feature, in which the more abundant haplotype on average in a sample is different between samples. This analysis treated samples as homogeneous and did not identify haplotype-specific copy-number states nor assign them to specific tumor clones.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Myers,

Arnold,

Bansal

et al. 2024

Genome Biol

View full text Add to dashboard Cite

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.

show abstract

Section: Identification Of Clone-specific Mirrored-subclonal Cnasmentioning

confidence: 76%

mentioning

confidence: 99%

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

Myers,

Arnold,

Bansal

et al. 2024

Genome Biol

View full text Add to dashboard Cite

show abstract

“…Mirrored-subclonal CNAs are differential gains or losses of the maternal and paternal chromosomes in different subpopulations of cancer cells from the same tumor. In contrast to earlier reports of mirroredsubclonal allelic imbalance [41,[50][51][52] in bulk samples, HATCHet2 identifies haplotype imbalance in specific clones. Our HATCHet2 analysis of the 10 prostate cancer patients from [44] reveals numerous mirrored-subclonal CNAs that were missed in both the original published analysis of these patients [44] as well as in the reanalysis using HATCHet [32].…”

Section: Identification Of Clone-specific Mirrored-subclonal Cnasmentioning

confidence: 77%

“…The mhBAF is also a more robust estimator of mirroredsubclonal CNAs, compared to earlier approaches [25,41,51,52] 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: Mirrored Haplotype B-allele Frequency (Mhbaf)mentioning

confidence: 99%

“…We refer to such events as mirrored-subclonal CNAs because the more-abundant haplotype is opposite ("mirrored") between the two clones. Previous efforts to detect these events have been limited to the identification of mirrored-subclonal allelic imbalance [41,[50][51][52], a sample-level rather than clone-level feature, in which the more abundant haplotype on average in a sample is different between samples. This analysis treated samples as homogeneous and did not identify haplotype-specific copy-number states nor assign them to specific tumor clones.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Myers

Arnold

Bansal

et al. 2023

Preprint

View full text Add to dashboard Cite

Multi-region DNA sequencing of primary tumors and metastases from individual patients helps identify somatic aberrations driving cancer development. However, most methods to infer copy-number aberrations (CNAs) analyze individual samples. We introduce HATCHet2 to identify haplotype- and clone-specific CNAs simultaneously from multiple bulk samples. HATCHet2 introduces a novel statistic, the mirrored haplotype B-allele frequency (mhBAF), to identify mirrored-subclonal CNAs having different numbers of copies of parental haplotypes in different tumor clones. HATCHet2 also has high accuracy in identifying focal CNAs and extends the earlier HATCHet method in several directions. We demonstrate HATCHet2's improved accuracy using simulations and a single-cell sequencing dataset. HATCHet2 analysis of 50 prostate cancer samples from 10 patients reveals previously-unreported mirrored-subclonal CNAs affecting cancer genes.

show abstract

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

Sahm,

Patel,

Göbel

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 3 publications

References 72 publications

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

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

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

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

Contact Info

Product

Resources

About