Identification of Potentially Pathogenic Variants Associated with Recurrence in Medication-Related Osteonecrosis of the Jaw (MRONJ) Patients Using Whole-Exome Sequencing

Abstract

Background: Bisphosphonates are antiresorptive and antiangiogenic drugs that prevent and treat bone loss and mineralization in women with postmenopausal osteoporosis and cancer patients. Medication-related osteonecrosis of the jaw (MRONJ) is commonly caused by tooth extraction and dental trauma. Although genetic and pathological studies about MRONJ have been conducted, the pathogenesis of MRONJ still remains unclear. Methods: We aimed to identify genetic variants associated with MRONJ, using whole-exome sequencing (WES). Ten MRONJ patients prescribed bisphosphonates were recruited for WES, and jawbone tissue and blood samples were collected from the patients. Results: The analysis of the WES data found a total of 1866 SNP and 40 InDel variants which are specific to MRONJ. The functional classification assay using Gene Ontology and pathway analysis discovered that genes bearing the MRONJ variants are significantly enriched for keratinization and calcium ion transport. Some of the variants are potential pathogenic variants (24 missense mutations and seven frameshift mutations) with MAF < 0.01. Conclusions: The variants are located in eight different genes (KRT18, MUC5AC, NBPF9, PABPC3, MST1L, ASPN, ATN1, and SLAIN1). Nine deleterious SNPs significantly associated with MRONJ were found in the KRT18 and PABPC3 genes. It suggests that KRT18 and PABPC3 could be MRONJ-related key genes.

Analysis of SIRT1 Gene SNPs and Clinical Characteristics in Medication-Related Osteonecrosis of the Jaw

“…Consistent with the results in this work, the SIRT1 gene SNP rs932658 has also been demonstrated to be in association with MRONJ by regulating SIRT1 expression [17]. Other research groups have suggested potential roles of SNPs in the VEGF, CYP2C8, PPARG and other genes in the development of MRONJ [19,[24][25][26][27].…”

Disulfidptosis‐related PABPC3 promotes tumor progression and inhibits immune activity in osteosarcoma

“…[12][13][14] Using whole-exome sequencing, PABPC3 was found to be related to recurrence in patients with medication-related osteonecrosis of the jaw. 15 However, the interconnection between PABPC3 and osteosarcoma has not been explored.…”

“…mRNA polyadenylation, nonsense‐mediated decay, stress response, controlling mRNA translation initiation, mRNA quality surveillance and many other mRNA homeostasis‐related processes are regulated by the multifunctional proteins known as PABPs 12–14 . Using whole‐exome sequencing, PABPC3 was found to be related to recurrence in patients with medication‐related osteonecrosis of the jaw 15 . However, the interconnection between PABPC3 and osteosarcoma has not been explored.…”