Pan‐cancer proteogenomic landscape of whole‐genome doubling reveals putative therapeutic targets in various cancer types

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Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer typesDear Editor, Whole-genome doubling (WGD) occurs in various cancer types and plays a crucial role in tumour development and genomic instability.1,2 However, the proteogenomic characteristics and molecular regulators governing WGD have yet to be elucidated.By integrating large-scale multiomics data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), 3 we classified three types of WGD tumours across cancer types.This study elucidates the mutational signatures, molecular pathways, transcription factor (TF) regulation and kinase phosphorylation networks enriched in tumours with WGD to explore potential drug targets.Our study integrated genomic, transcriptomic, proteomic and phosphoproteomic data from 1060 samples representing 10 cancer types including breast cancer (BRCA), clear cell renal cell carcinoma (CCRCC), colon adenocarcinoma (COAD), glioblastoma (GBM), highgrade serous carcinoma (HGSC), head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma (LSCC), lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC) and uterine corpus endometrial carcinoma (UCEC) (Figure 1A).WGD was found to be prevalent in 42% of tumours, with the highest in HGSC (83%) and the lowest in PDAC (9.4%) (Figure 1B,C; Table S1A).Although no clinical phenotypes were associated with WGD status across pan-cancer, the advanced tumour stage was linked to WGD status in HNSCC (false discovery rate [FDR] < .05)(Figure S1A,B).Mutation signature analyses showed that WGD was associated with specific copy number (CN) signatures (Figure 1D; Table S1B).WGD in LSCC, LUAD and HNSCC showed enrichment for either or both CN7 and CN15 signatures (FDR < .05).Since CN7 indicates chromothripsis amplification and CN15 indicates chromosomal lossof-heterozygosity (LOH) with twice-genome-doubling, 4 WGD in LSCC, LUAD and HNSCC may have occurred within a highly unstable genome.WGD in BRCA and

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