title: Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karageorgos
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Health Sciences, University of Malta, Msida, Malta.|Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Clint
authors.initials: C
authors.lastname: Mizzi
authors.affiliation: Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, Greece.
authors.forename: Efstathia
authors.initials: E
authors.lastname: Giannopoulou
authors.affiliation: Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pavlidis
authors.affiliation: Complete Genomics Inc., Mountain View, CA, USA.|BGI-Shenzhen, Shenzhen, 51803, China.
authors.forename: Brock A
authors.initials: BA
authors.lastname: Peters
authors.affiliation: Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Zagoriti
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.affiliation: The Golden Helix Foundation, London, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mitropoulos
authors.affiliation: Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta.|Department of Cell Biology and Genetics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.affiliation: Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, Greece.
authors.forename: Haralabos P
authors.initials: HP
authors.lastname: Kalofonos
authors.affiliation: Complete Genomics Inc., Mountain View, CA, USA.|BGI-Shenzhen, Shenzhen, 51803, China.
authors.forename: Radoje
authors.initials: R
authors.lastname: Drmanac
authors.affiliation: Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stubbs
authors.affiliation: Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Spek
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Katsila
authors.affiliation: Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece. gpatrinos@upatras.gr.|Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands. gpatrinos@upatras.gr.
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein