HATCHet2: Clone- and Haplotype-specific Copy Number Inference from Bulk Tumor Sequencing Data

Overview

Journal bioRxiv

Date 2023 Jul 28

PMID 37502835

Authors

Matthew A Myers

Brian J Arnold

Vineet Bansal

Katelyn M Mullen

Simone Zaccaria

Benjamin J Raphael

Affiliations

Soon will be listed here.

Abstract

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.

References

Gundem G, Van Loo P, Kremeyer B, Alexandrov L, Tubio J, Papaemmanuil E . The evolutionary history of lethal metastatic prostate cancer. Nature. 2015; 520(7547):353-357. PMC: 4413032. DOI: 10.1038/nature14347. View

Makohon-Moore A, Zhang M, Reiter J, Bozic I, Allen B, Kundu D . Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet. 2017; 49(3):358-366. PMC: 5663439. DOI: 10.1038/ng.3764. View

Zhou H, Hu Y, Luo R, Zhao Y, Pan H, Ji L . Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer. Nat Commun. 2021; 12(1):5431. PMC: 8440529. DOI: 10.1038/s41467-021-25787-x. View

Parisi F, Ariyan S, Narayan D, Bacchiocchi A, Hoyt K, Cheng E . Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies. BMC Genomics. 2011; 12:230. PMC: 3114747. DOI: 10.1186/1471-2164-12-230. View

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

Belsare S, Levy-Sakin M, Mostovoy Y, Durinck S, Chaudhuri S, Xiao M . Evaluating the quality of the 1000 genomes project data. BMC Genomics. 2019; 20(1):620. PMC: 6696682. DOI: 10.1186/s12864-019-5957-x. View

Minussi D, Nicholson M, Ye H, Davis A, Wang K, Baker T . Breast tumours maintain a reservoir of subclonal diversity during expansion. Nature. 2021; 592(7853):302-308. PMC: 8049101. DOI: 10.1038/s41586-021-03357-x. View

Fan X, Yang C, Li W, Bai X, Zhou X, Xie H . SMOOTH-seq: single-cell genome sequencing of human cells on a third-generation sequencing platform. Genome Biol. 2021; 22(1):195. PMC: 8247186. DOI: 10.1186/s13059-021-02406-y. View

Gerstung M, Jolly C, Leshchiner I, Dentro S, Gonzalez S, Rosebrock D . The evolutionary history of 2,658 cancers. Nature. 2020; 578(7793):122-128. PMC: 7054212. DOI: 10.1038/s41586-019-1907-7. View

10.

Al Bakir M, Huebner A, Martinez-Ruiz C, Grigoriadis K, Watkins T, Pich O . The evolution of non-small cell lung cancer metastases in TRACERx. Nature. 2023; 616(7957):534-542. PMC: 10115651. DOI: 10.1038/s41586-023-05729-x. View

11.

Favero F, Joshi T, Marquard A, Birkbak N, Krzystanek M, Li Q . Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data. Ann Oncol. 2014; 26(1):64-70. PMC: 4269342. DOI: 10.1093/annonc/mdu479. View

12.

Shen R, Seshan V . FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016; 44(16):e131. PMC: 5027494. DOI: 10.1093/nar/gkw520. View

13.

Scaravilli M, Koivukoski S, Latonen L . Androgen-Driven Fusion Genes and Chimeric Transcripts in Prostate Cancer. Front Cell Dev Biol. 2021; 9:623809. PMC: 7900491. DOI: 10.3389/fcell.2021.623809. View

14.

Li Y, Roberts N, Wala J, Shapira O, Schumacher S, Kumar K . Patterns of somatic structural variation in human cancer genomes. Nature. 2020; 578(7793):112-121. PMC: 7025897. DOI: 10.1038/s41586-019-1913-9. View

15.

Christodoulou E, Yellapantula V, OHalloran K, Xu L, Berry J, Cotter J . Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors. NPJ Precis Oncol. 2023; 7(1):21. PMC: 9941464. DOI: 10.1038/s41698-023-00357-0. View

16.

Rivlin N, Brosh R, Oren M, Rotter V . Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer. 2011; 2(4):466-74. PMC: 3135636. DOI: 10.1177/1947601911408889. View

17.

Dawson S, Tsui D, Murtaza M, Biggs H, Rueda O, Chin S . Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013; 368(13):1199-209. DOI: 10.1056/NEJMoa1213261. View

18.

Chiang D, Getz G, Jaffe D, OKelly M, Zhao X, Carter S . High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat Methods. 2008; 6(1):99-103. PMC: 2630795. DOI: 10.1038/nmeth.1276. View

19.

Nesta A, Tafur D, Beck C . Hotspots of Human Mutation. Trends Genet. 2020; 37(8):717-729. PMC: 8366565. DOI: 10.1016/j.tig.2020.10.003. View

20.

Wang G, Anastassiou D . Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis. Sci Rep. 2020; 10(1):17199. PMC: 7566486. DOI: 10.1038/s41598-020-74276-6. View