ESPEYB21 4. Growth and Growth Factors New Perspectives (2 abstracts)
4.13. Saturation genome editing of BAP1 functionally classifies somatic and germline variants
Waters AJ , Brendler-Spaeth T , Smith D , Offord V , Tan HK , Zhao Y , Obolenski S , Nielsen M , van Doorn R , Murphy JE , Gupta P , Rowlands CF , Hanson H , Delage E , Thomas M , Radford EJ , Gerety SS , Turnbull C , Perry JRB , Hurles ME & Adams DJ
Nat Genet. 2024 Jul;56(7):1434-1445. doi: 10.1038/s41588-024-01799-3. PMID: 38969833
Brief Summary: These authors performed exhaustive saturation genome editing (SGE) of BAP1 (BRCA1-associated protein 1), the disruption of which is linked to tumorigenesis and altered neurodevelopment. 18,108 unique variants were characterized, of which 6,196 were found to have abnormal functions. These were then used to evaluate phenotypic associations in the UK Biobank. BAP1 variants were also characterized in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar. Disruptive germline BAP1 variants were associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and a therapeutic target.
BAP1 is a widely expressed deubiquitinating enzyme that plays a critical role in several cellular processes, including transcriptional regulation, cell cycle, response to DNA damage and regulation of chromatin dynamics. Germline BAP1 variants were associated with increased levels of IGF-1. This finding suggests a possible pathogenic mechanism involving a close cross-talk between BAP1 and IGF system and suggests potential therapeutic targets.
This study functionally characterised 18,108 unique BAP1 variants, achieving near-complete coverage of the possible variants of the gene. This extensive and detailed mapping is unprecedented in genetic research. The authors developed a variant classifier based on the SGE data with over 98% sensitivity and specificity. This represents a significant advance in the interpretation of genetic variants, particularly those categorised as “variants of uncertain significance” (VUS), which pose challenges in clinical practice. A significant difference in the effect of different BAP1 variants was observed, particularly between those associated with cancer and those associated with neurodevelopmental disorders.
Disruptive germline BAP1 variants are associated with increased levels of IGF-1, a mitogen that promotes tumour growth. This suggests a possible pathogenic mechanism and highlights potential therapeutic targets. The use of SGE allowed a more precise differentiation between variants that contribute to cancer and those associated with neurodevelopmental disorders.
These innovative findings significantly advance our understanding of BAP1’s role in diseases and provide advanced tools for precision medicine, enabling more accurate prediction of disease risk and guiding therapeutic decisions.
References: 1. Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067 (2018).2. Carbone, M. et al. BAP1 and cancer. Nat. Rev. Cancer 13, 153–159 (2013).3. Nishikawa, H. et al. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 69, 111–119 (2009).4. Pollak, M. N., Schernhammer, E. S. & Hankinson, S. E. Insulin-like growth factors and neoplasia. Nat. Rev. Cancer 4, 505–518 (2004).
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ESPE Yearbook of Paediatric Endocrinology
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