BIK – Prostate Cancer

Prostate cancer is the second most common malignancy in men worldwide. Recent exome‐wide collapsing analysis of 37,184 prostate cancer cases and 331,329 male controls identified that rare damaging germline variants in the BH3‐only apoptosis regulator BIK are significantly associated with overall prostate cancer risk (PMID:38766261).

Inheritance of BIK risk alleles appears consistent with an autosomal dominant predisposition model, where heterozygous rare non‐synonymous variants confer moderate susceptibility. Case–control enrichment of rare missense BIK variants provides genetic evidence in the absence of reported familial segregation.

Although no segregating pedigrees have been described, the large sample size and robust case–control signal support a substantive contribution of rare BIK variants to prostate cancer risk. Variant spectrum was dominated by missense changes within functional domains, consistent with perturbation of proapoptotic activity.

Functionally, BIK encodes a proapoptotic BH3‐only protein that binds and antagonizes anti‐apoptotic Bcl-2 family members to trigger mitochondrial apoptosis. Split‐luciferase interaction mapping confirms key BH3 interface residues critical for Bik binding, and mutation of conserved BH4 region residues in Bcl-2 family proteins underscores the functional importance of these interfaces (PMID:9303307; PMID:25844633).

Transcriptional regulation studies demonstrate that PAR bZIP factors (TEF, DBP) directly activate the bik promoter, and loss of Bik expression in knockout fibroblasts impairs oxidative stress–induced apoptosis, supporting a tumor suppressor mechanism via haploinsufficiency (PMID:19219069).

Collectively, genetic association and functional assays provide moderate clinical validity for BIK in prostate cancer predisposition. Further familial segregation, variant‐specific penetrance assessment, and prostate‐specific functional models are needed. Key Take-home: BIK genetic testing may refine risk stratification in precision oncology.

References

• medRxiv • 2024 • Characterising the contribution of rare protein‐coding germline variants to prostate cancer risk and severity in 37,184 cases. PMID:38766261
• The EMBO journal • 1997 • The anti‐apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. PMID:9303307
• Biochemistry • 2015 • Mapping the BH3 Binding Interface of Bcl-xL, Bcl-2, and Mcl-1 Using Split‐Luciferase Reassembly. PMID:25844633
• Cell death and differentiation • 2009 • PAR bZIP-bik is a novel transcriptional pathway that mediates oxidative stress-induced apoptosis in fibroblasts. PMID:19219069

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