PIBF1 (p.R405Q) germline variant identified in cancer susceptibility family impairs protein stability and function

Approximately 5-10% of all cancer types are hereditary cancer syndromes, which are caused by pathogenic mutations in cancer susceptibility genes. In this investigation, a hereditary cancer pedigree was collected from a province in southern China, and the proband was a 31-year-old woman with breast cancer. Utilizing blood whole exome sequencing technology and bioinformatics analysis, the sole heterozygous missense mutation in PIBF1 that exhibits trait segregation was identified: PIBF1 (p.R405Q). The pedigree also included two other mutations that may be linked to carcinogenesis: RAD51D (p.K91Ifs*13) and BRCA2 (p.G3134Afs*29). This research concentrated on PIBF1 (p.R405Q) and employed breast cancer as a tumor model. In vitro and in vivo experiments showed that PIBF1-WT suppressed breast cancer cell proliferation, colony formation, invasive ability, and tumorigenesis. However, PIBF1 (p.R405Q) attenuated or inhibited the function of PIBF1-WT. Mechanistically, PIBF1-WT resisted cisplatin-induced DNA damage, significantly down-regulated the expression of γ-H2AX, and affected DNA damage repair, thus exerting a cancer inhibitory function. Interestingly, PIBF1 (p.R405Q) affects protein stability, thereby mitigating or eliminating the inhibitory effect of PIBF1. Furthermore, this family's polygenic risk factors for cancer are analyzed, and there is speculation about potential synergistic effects between PIBF1 and DNA damage repair genes like BRCA2 and RAD51D. In conclusion, PIBF1 regulates the cell cycle and DNA damage repair, PIBF1(p.R405Q) increases susceptibility to cancer, multiple DNA damage repair gene mutations may synergistically promote cancer progression in this cancer family lineage, and PIBF1(p.R405Q) may be one of the polygenic risk factors for familial hereditary cancer syndromes.