MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution

Tom L Kaufmann; Marina Petkovic; Thomas B K Watkins; Emma C Colliver; Sofya Laskina; Nisha Thapa; Darlan C Minussi; Nicholas Navin; Charles Swanton; Peter Van Loo; Kerstin Haase; Maxime Tarabichi; Roland F Schwarz

doi:10.1186/s13059-022-02794-9

MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution

Genome Biol. 2022 Nov 14;23(1):241. doi: 10.1186/s13059-022-02794-9.

Authors

Tom L Kaufmann^#^{1

2

3}, Marina Petkovic^#^{4

5

6}, Thomas B K Watkins^#⁷, Emma C Colliver⁷, Sofya Laskina⁸, Nisha Thapa⁹, Darlan C Minussi¹⁰, Nicholas Navin¹⁰, Charles Swanton^{7

11

12}, Peter Van Loo^{7

10

13}, Kerstin Haase^{6

14}, Maxime Tarabichi^{7

15}, Roland F Schwarz^{16

17

18}

Affiliations

¹ Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany. [email protected].
² Department of Electrical Engineering & Computer Science, Technische Universität Berlin, Marchstr. 23, 10587, Berlin, Germany. [email protected].
³ BIFOLD, Berlin Institute for the Foundations of Learning and Data, Berlin, Germany. [email protected].
⁴ Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
⁵ Department of Biology, Humboldt University of Berlin, Unter den Linden 6, 10099, Berlin, Germany.
⁶ Division of Oncology and Hematology, Department of Pediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
⁷ The Francis Crick Institute, London, UK.
⁸ Department of Mathematics and Computer Science, Free University of Berlin, Berlin, Germany.
⁹ UCL Medical School, University College London, London, UK.
¹⁰ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
¹² Department of Medical Oncology, University College London Hospitals, London, UK.
¹³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Institute for Interdisciplinary Research, Université Libre de Bruxelles, Brussels, Belgium.
¹⁶ Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany. [email protected].
¹⁷ BIFOLD, Berlin Institute for the Foundations of Learning and Data, Berlin, Germany. [email protected].
¹⁸ Institute for Computational Cancer Biology, Center for Integrated Oncology (CIO) and Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. [email protected].

^# Contributed equally.

Abstract

Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.

Keywords: Aneuploidy; Cancer evolution; Chromosomal instability; Intratumor heterogeneity; Phylogenetic reconstruction; Single-cell sequencing; Somatic copy-number alterations; Whole-genome doubling.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations
Exome
Genome, Human
Humans
Neoplasms* / genetics
Neoplasms* / pathology
Phylogeny

Abstract

Publication types

MeSH terms

Grants and funding