Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach

Karageorgos, Ioannis, Mizzi, Clint, Giannopoulou, Efstathia, Pavlidis, Cristiana, Peters, Brock A., Zagoriti, Zoi, Stenson, Peter D., Mitropoulos, Konstantinos, Borg, Joseph, Kalofonos, Haralabos P., Drmanac, Radoje, Stubbs, Andrew, van der Spek, Peter J., Cooper, David N., Katsila, Theodora and Patrinos, George P. (2015) Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach. Human Genomics, 9 (1) , 12. pp. 1-10. ISSN 1473-9542 [Article] (doi:10.1186/s40246-015-0034-2)

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Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences
Item ID: 29716
Notes on copyright: © 2015 Karageorgos et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
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Depositing User: Repository team
Date Deposited: 24 Apr 2020 14:31
Last Modified: 12 Dec 2020 22:06

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