University of Tasmania
141389 - identification of novel sarcoma.pdf (906.67 kB)

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

Download (906.67 kB)
journal contribution
posted on 2023-05-20, 18:41 authored by Jones, RM, Phillip MeltonPhillip Melton, Pinese, M, Rea, AJ, Ingley, E, Ballinger, ML, Wood, DJ, Thomas, DM, Eric MosesEric Moses

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, pvalue = 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.


Publication title

BMC Medical Genetics








Menzies Institute for Medical Research


BioMed Central

Place of publication

United Kingdom

Rights statement

copyright The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the 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

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

Usage metrics

    University Of Tasmania


    Ref. manager