Journal article
Identification of novel sarcoma risk genes using a two-stage genome wide DNA sequencing strategy in cancer cluster families and population case and control cohorts
BMC Medical Genetics, Vol.20(1), Article number 69
2019
Abstract
Background
Although familial clustering of cancers is relatively common, only a small proportion of familial cancer risk can be explained by known cancer predisposition genes.
Methods
In this study we employed a two-stage approach to identify candidate sarcoma risk genes. First, we conducted whole exome sequencing in three multigenerational cancer families ascertained through a sarcoma proband (n = 19) in order to prioritize candidate genes for validation in an independent case-control cohort of sarcoma patients using family-based association and segregation analysis. The second stage employed a burden analysis of rare variants within prioritized candidate genes identified from stage one in 560 sarcoma cases and 1144 healthy ageing controls, for which whole genome sequence was available.
Results
Variants from eight genes were identified in stage one. Following gene-based burden testing and after correction for multiple testing, two of these genes, ABCB5 and C16orf96, were determined to show statistically significant association with cancer. The ABCB5 gene was found to have a higher burden of putative regulatory variants (OR = 4.9, p-value = 0.007, q-value = 0.04) based on allele counts in sarcoma cases compared to controls. C16orf96, was found to have a significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003) of regulatory variants in controls compared to sarcoma cases.
Conclusions
Based on these genetic association data we propose that ABCB5 and C16orf96 are novel candidate risk genes for sarcoma. Although neither of these two genes have been previously associated with sarcoma, ABCB5 has been shown to share clinical drug resistance associations with melanoma and leukaemia and C16orf96 shares regulatory elements with genes that are involved with TNF-alpha mediated apoptosis in a p53/TP53-dependent manner. Future genetic studies in other family and population cohorts will be required for further validation of these novel findings.
Details
- Title
- Identification of novel sarcoma risk genes using a two-stage genome wide DNA sequencing strategy in cancer cluster families and population case and control cohorts
- Authors/Creators
- R.M. Jones (Author/Creator) - The University of Western AustraliaP.E. Melton (Author/Creator) - The University of Western AustraliaM. Pinese (Author/Creator) - Garvan Institute of Medical ResearchA.J. Rea (Author/Creator) - The University of Western AustraliaE. Ingley (Author/Creator) - Harry Perkins Institute of Medical ResearchM.L. Ballinger (Author/Creator) - Garvan Institute of Medical ResearchD.J. Wood (Author/Creator) - The University of Western AustraliaD.M. Thomas (Author/Creator) - Garvan Institute of Medical ResearchE.K. Moses (Author/Creator) - The University of Western Australia
- Publication Details
- BMC Medical Genetics, Vol.20(1), Article number 69
- Publisher
- BioMed Central Ltd
- Identifiers
- 991005543675707891
- Copyright
- © 2019 The Author(s)
- Murdoch Affiliation
- Harry Butler Institute; School of Veterinary and Life Sciences
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.189 Genome Studies
- 1.189.455 Genome-Wide Association Studies
- Web Of Science research areas
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics