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J Transl Med. 2019 Nov 20;17(1):381. doi: 10.1186/s12967-019-2129-3.

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

Author information

1
Center for Precision Medicine, Seoul National University Hospital, Seoul, 03082, South Korea.
2
Department of Periodontics, Asan Medical Center, Seoul, 05505, South Korea.
3
Department of Dentistry, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
4
Department of Oral and Maxillofacial Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
5
Division of Biomedical Informatics, Seoul National University Biomedical Informatics (SNUBI) and Systems Biomedical Informatics Research Center, Seoul National University College of Medicine, Seoul, 03080, South Korea.
6
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
7
Department of Oral and Maxillofacial Surgery, University of Ulsan College of Medicine, Seoul, 05505, South Korea. ahnkangmin@ulsan.ac.kr.
8
Center for Precision Medicine, Seoul National University Hospital, Seoul, 03082, South Korea. juhan@snu.ac.kr.
9
Division of Biomedical Informatics, Seoul National University Biomedical Informatics (SNUBI) and Systems Biomedical Informatics Research Center, Seoul National University College of Medicine, Seoul, 03080, South Korea. juhan@snu.ac.kr.

Abstract

BACKGROUND:

Bisphosphonate-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.

METHODS:

This 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.

RESULTS:

The 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.

CONCLUSION:

This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.

KEYWORDS:

Angiogenesis; Bioinformatics; Cancer biology; Osteoporosis; Pharmacogenomics

PMID:
31747953
DOI:
10.1186/s12967-019-2129-3
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