Identifying genetic variants underlying medication-induced osteonecrosis of the jaw in cancer and osteoporosis: a case control study

Abstract

BackgroundBisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer.MethodsThis study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods.ResultsThe stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-β signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes.ConclusionThis study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.

Gene-Wise Burden of Coding Variants Correlates to Noncoding Pharmacogenetic Risk Variants

“…Thus, the establishment of an in silico method can be important and beneficial to the field, which enable us to narrow down and focus on those potentially critical gene-drug combinations. Ab initio GVB may be applied to discover unknown pharmacogenes with significant inter-individual drug response variabilities [6][7][8]. Further improvements and molecular validations should be required before use GVB as a supportive tool for drug safety scoring for a given drug for an individual or population, using NGS.…”

“…This enables alternative approaches for predicting the inter-individual drug response differences. Gene-wise variant burden (GVB), an integrated gene-level measure of the cumulative impact of the multitude of deleterious variants, including common, rare, and even novel variants on a given gene, has been successfully applied to address many pharmacogenetic problems [5][6][7][8]. Pharmacokinetic and pharmacodynamic genes associated with withdrawn, precautionary, and the US FDA-approved pharmacogenomics biomarker drugs exhibited significantly lower GVBs than those associated with safe drugs [5].…”

Pathogenesis and multidisciplinary management of medication-related osteonecrosis of the jaw

“…40 The expression of TGF-β and angiogenesis-related signalling have been shown to be possible consequences of MRONJ. 41 Altered VEGF expression has been observed following treatment with BPs, 42 possibly related to the expression of TGF-β. 16 Soft tissue toxicity Although osteoclasts and bone are the primary targets following their exposure to BPs, it has been reported that the toxicity of BPs to soft tissue is closely related to MRONJ.…”

“… 40 The expression of TGF-β and angiogenesis-related signalling have been shown to be possible consequences of MRONJ. 41 Altered VEGF expression has been observed following treatment with BPs, 42 possibly related to the expression of TGF-β. 16 …”

“…Multiple signalling pathways may be involved in the pathogenesis of MRONJ. At present, it is relatively certain that the TGF-β1 signalling pathway has a key role in the development of MRONJ, 16 , 29 , 41 potentially representing a future research direction. Therefore, the study of the TGF-β pathway and specific downstream sites may lead to a breakthrough in the pathogenesis of MRONJ.…”