Applying Proteogenomics to Characterize Molecular Features Associated With a High‐Risk HOXB13 Gene Variant in Prostate Cancer Tumors

The rare HOXB13 G84E variant is one of few established high‐risk prostate cancer (PrCa) variants, yet the underlying molecular mechanisms by which it drives tumor development remain unknown. Prostate tumors from six heterozygous G84E variant carriers and 18 non‐carriers (wild‐type) were examined using the Human AmpliSeq Transcriptome Gene Expression Panel, and proteomes were generated by mass spectrometry (SWATH). We identified a 799‐gene expression profile and a 75‐protein expression profile in G84E‐positive tumors when compared with wild‐type tumors. Cluster analysis revealed a top‐ranked 23 protein profile, which mapped to lipogenesis pathways. Integration of transcriptome and proteome data revealed overlapping differential expression of three genes ( NCLN , NFIB , and VASN ), two of which have an established link to lipid metabolic pathways. Examination of publicly available transcriptome data from 493 primary PrCa tumors from the The Cancer Genome Atlas (TCGA) tumors revealed 52 tumors with a similar differential expression profile for these three genes. Herein, an innovative proteogenomic approach was used to map molecular changes unique to HOXB13 perturbation in prostate tumors, revealing upregulation of genes in the steroid metabolic, lipid biosynthesis, and fatty acid metabolic pathways.