A novel RBBP8(p.E281*) germline mutation is a predisposing mutation in familial hereditary cancer syndrome

Abstract

Background: Screening tumor susceptibility genes will be found powerful biomarkers for hereditary cancer monitoring, prevention and diagnosis, which providing opportunities for understanding the potential molecular mechanism and biomarker for precise treatment of hereditary cancer syndromes.Methods: Whole blood exon sequencing and bioinformatics analysis uncovers a novel RBBP8 (c.841G>T) germline mutation in this familial hereditary cancer syndrome, and veri ed by sanger sequencing. Cell proliferation, clone formation, cell migration, in vivo tumorigenesis were investigated by CCK8, clone formation assays, transwell, in vivo xenograft. The protein localization and interaction were detected by immuno uorescence, nuclear and cytoplasmic protein extraction kit and Co-IP .Results: A new heterozygous germline mutation of RBBP8 (c.841G>T) gene was associated with familial hereditary cancer syndrome. Unlike RBBP8-WT is mainly detected in the nucleus and could interact with BRCA1. Opposite, RBBP8(c.841G>T) is mainly located in the cytoplasm and lost interact with BRCA1, which may gain some new functions in the cytoplasm to promote breast cancer proliferation, in vivo tumorigenesis and migration. Meanwhile, patients with RBBP8(c.841G>T) germline mutation maybe bene t from PARP inhibitors (Olaparib) and platinum (Cisplatin).Conclusions: A de novo RBBP8 (c.841G>T) germline mutation was identi ed from familial hereditary cancer syndrome. RBBP8 (c.841G>T) lost its ability to enter the nucleus and the BRCA1 binding motif, which may gain some new functions to promote tumorigeneses in the cytoplasm. RBBP8 (c.841G>T) is a tumor susceptibility gene and candidate precision medicine biomarker in this familial hereditary cancer syndrome.