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

• DOI: 10.1016/j.celrep.2024.113988
• Publication Date: 2024-03-22T11:32:25Z
• Authors: 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 G...; Quaid Morris; Claudia L. Kleinman; Sidong Huang; Anne-Claude Gingras; Jiannis Ragoussis; Guillaume Bourque; Peter Van Loo; Morag Park
• Keywords: Triple-negative breast cancer

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