Hepatocellular　carcinoma　(HCC)　is　a　widespread　primary　liver　cancer　with　a　high　fatality　rate.　Despite　several　genes　with　oncogenic　effects　in　HCC　have　been　identified,　many　remain　undiscovered.　In　this　study,　we　conducted　a　comprehensive　computational　analysis　to　explore　the　involvement　of　genes　within　the　same　families　as　known　driver　genes　in　HCC.　Specifically,　we　expanded　the　concept　beyond　single-gene　mutations　to　encompass　gene　families　sharing　homologous　structures,　integrating　various　omics　data　to　comprehensively　understand　gene　abnormalities　in　cancer.　Our　analysis　identified　74　domains　with　an　enriched　mutation　burden,　404　domain　mutation　hotspots,　and　233　dysregulated　driver　genes.　We　observed　that　specific　low-frequency　somatic　mutations　may　contribute　to　HCC　occurrence,　potentially　overlooked　by　single-gene　algorithms.　Furthermore,　we　systematically　analyzed　how　abnormalities　in　the　ubiquitinated　proteasome　system　(UPS)　impact　HCC,　finding　that　abnormal　genes　in　E3,　E2,　DUB　families,　and　Degron　genes　often　result　in　HCC　by　affecting　the　stability　of　oncogenic　or　tumor　suppressor　proteins.　In　conclusion,　expanding　the　exploration　of　driver　genes　to　include　gene　families　with　homologous　structures　emerges　as　a　promising　strategy　for　uncovering　additional　oncogenic　alterations　in　HCC.　©　2024