Open Access Repository

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


Downloads per month over past year

Jones, RM, Melton, PE ORCID: 0000-0003-4026-2964, Pinese, M, Rea, AJ, Ingley, E, Ballinger, ML, Wood, DJ, Thomas, DM and Moses, EK 2019 , '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, no. 1 , pp. 1-10 , doi: 10.1186/s12881-019-0808-9.

141389 - identi...pdf | Download (928kB)

| Preview


Background: Although familial clustering of cancers is relatively common, only a small proportion of familial cancerrisk 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, weconducted 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 patientsusing family-based association and segregation analysis. The second stage employed a burden analysis of rare variantswithin prioritized candidate genes identified from stage one in 560 sarcoma cases and 1144 healthy ageing controls, forwhich whole genome sequence was available.Results: Variants from eight genes were identified in stage one. Following gene-based burden testing and aftercorrection for multiple testing, two of these genes, ABCB5 and C16orf96, were determined to show statistically significantassociation with cancer. The ABCB5 gene was found to have a higher burden of putative regulatory variants (OR = 4.9, pvalue = 0.007, q-value = 0.04) based on allele counts in sarcoma cases compared to controls. C16orf96, was found to havea significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003) of regulatory variants in controls compared tosarcoma cases.Conclusions: Based on these genetic association data we propose that ABCB5 and C16orf96 are novel candidate riskgenes for sarcoma. Although neither of these two genes have been previously associated with sarcoma, ABCB5 has beenshown to share clinical drug resistance associations with melanoma and leukaemia and C16orf96 shares regulatoryelements with genes that are involved with TNF-alpha mediated apoptosis in a p53/TP53-dependent manner. Futuregenetic studies in other family and population cohorts will be required for further validation of these novel findings.

Item Type: Article
Authors/Creators:Jones, RM and Melton, PE and Pinese, M and Rea, AJ and Ingley, E and Ballinger, ML and Wood, DJ and Thomas, DM and Moses, EK
Keywords: cancer cluster families, genetic risk variants, sarcoma, whole exome sequencing, whole genome sequencing
Journal or Publication Title: BMC Medical Genetics
Publisher: BioMed Central
ISSN: 1471-2350
DOI / ID Number: 10.1186/s12881-019-0808-9
Copyright Information:

copyright The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated

Item Statistics: View statistics for this item

Actions (login required)

Item Control Page Item Control Page