BUB1B germline mutation and predisposition to melanoma and multiple epithelial malignancies

Summary: Abstract Body: Although numerous melanoma predisposition syndromes have been identified, many remain genetically unexplained. Whole exome sequencing revealed a novel germline mutation, BUB1B c.2316C>G (p.Tyr772Ter), in a patient with multiple primary malignancies, including melanoma, breast, thyroid, and lung cancers, and an extensive family history of cancer. This truncating mutation likely leads to haploinsufficiency of the spindle assembly checkpoint protein, BUBR1, encoded by BUB1B, supported by reduced protein levels by immunofluorescence in tumor and non-malignant tissues compared with controls (p < 0.0001) and evidence of genomic instability, including increased premature chromatid separation in primary patient leukocytes (6.4% vs. normal ≤2%). Somatic mutation analysis of melanoma samples revealed concurrent mutations in established melanoma drivers, such as NRAS and CDKN2A, underscoring the multifactorial nature of tumorigenesis. RNA sequencing highlighted downregulation of genes implicated in the PI3K-Akt pathway and integrin binding, pathways critical to oncogenesis. This study establishes BUB1B as a putative novel melanoma predisposition gene and contributes to understanding the role of mitotic checkpoint defects in hereditary cancer syndromes. Further investigation into BUB1B mutations in cancer predisposition and tumorigenesis may also reveal therapeutic and prognostic insights, enhancing clinical management for at-risk individuals. Laura J. Young³, Tram T. Tran³, Maha Kazmi³, Marin P. Melloy^{3, 1}, Jessica Terrell³, Elanee Simmons³, Daniela Martinuic², Hidetoshi Mori², John D. McPherson⁴, Maija Kiuru^{3, 4} 1. University of Minnesota Medical School, Minneapolis, MN, United States. 2. Hereditary Cancer Program, Comprehensive Cancer Center, University of California Davis, Davis, CA, United States. 3. Dermatology, University of California Davis, Davis, CA, United States. 4. Pathology and Laboratory Medicine, University of California Davis, Davis, CA, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance