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

2024; Cell Press; Volume: 43; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2024.113988

2639-1856

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

Gene expression and cancer classification

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.