Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring

Elena Kuzmin; Toby M Baker; Tom Lesluyes; Jean Monlong; Kento T Abe; Paula P Coelho; Michael Schwartz; Joseph Del Corpo; Dongmei Zou; Genevieve Morin; Alain Pacis; Yang Yang; Constanza Martinez; Jarrett Barber; Hellen Kuasne; Rui Li; Mathieu Bourgey; Anne-Marie Fortier; Peter G Davison; Atilla Omeroglu; Marie-Christine Guiot; Quaid Morris; Claudia L Kleinman; Sidong Huang; Anne-Claude Gingras; Jiannis Ragoussis; Guillaume Bourque; Peter Van Loo; Morag Park

doi:10.1016/j.celrep.2024.113988

Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring

Cell Rep. 2024 Apr 23;43(4):113988. doi: 10.1016/j.celrep.2024.113988. Epub 2024 Mar 22.

Authors

Elena Kuzmin¹, Toby M Baker², Tom Lesluyes², Jean Monlong³, Kento T Abe⁴, Paula P Coelho⁵, Michael Schwartz⁵, Joseph Del Corpo⁶, Dongmei Zou⁷, Genevieve Morin⁵, Alain Pacis⁸, Yang Yang⁹, Constanza Martinez¹⁰, Jarrett Barber¹¹, Hellen Kuasne⁷, Rui Li³, Mathieu Bourgey⁸, Anne-Marie Fortier⁷, Peter G Davison¹², Atilla Omeroglu¹³, Marie-Christine Guiot¹³, Quaid Morris¹⁴, Claudia L Kleinman¹⁵, Sidong Huang¹⁶, Anne-Claude Gingras⁴, Jiannis Ragoussis³, Guillaume Bourque¹⁷, Peter Van Loo¹⁸, Morag Park¹⁹

Affiliations

¹ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: elena.kuzmin@mcgill.ca.
² The Francis Crick Institute, NW1 1AT London, UK.
³ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON M5G 1X5, Canada.
⁵ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
⁶ Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada.
⁷ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada.
⁸ McGill Genome Centre, Montreal, QC H3A 0G1, Canada; Canadian Centre for Computational Genomics (C3G), McGill University, Montreal, QC H3A 0G1, Canada.
⁹ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
¹⁰ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Vector Institute, Toronto, ON M5G 1M1, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Computational and Systems Biology, Sloan Kettering Institute, New York City, NY 10065, USA.
¹² Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada; McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹³ Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
¹⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Vector Institute, Toronto, ON M5G 1M1, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Computational and Systems Biology, Sloan Kettering Institute, New York City, NY 10065, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁵ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada.
¹⁶ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
¹⁷ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada; Canadian Centre for Computational Genomics (C3G), McGill University, Montreal, QC H3A 0G1, Canada.
¹⁸ The Francis Crick Institute, NW1 1AT London, UK; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada. Electronic address: morag.park@mcgill.ca.

Abstract

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module we name PGCKA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames identify chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner, implicating network interactions. Together, these results shed light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.

Keywords: CP: Cancer; CP: Genomics; GCK-III; PDCD10; aneuploidy; basal breast cancer; cancer evolution; chromosomal arm copy number aberrations; chromosome 4p; triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Cell Line, Tumor
Cell Proliferation / genetics
Chromosome Aberrations
Chromosomes, Human, Pair 4 / genetics
Female
Gene Regulatory Networks*
Humans
Mice
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology