title: Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing.
abstract: Hereditary cancers occur because of inherited gene mutations. Genetic testing has been approved to provide information for risk assessment and rationale for appropriate intervention. Testing methods currently available for clinical use have some limitations, including sensitivity and testing throughput, etc. Next generation sequencing (NGS) has been rapidly evolving to increase testing sensitivity and throughput. It can be potentially used to identify inherited mutation in clinical diagnostic setting. Here we develop an effective method employing target enrichment and NGS platform to detect common as well as rare mutations for all common hereditary cancers in a single assay. Single base substitution across 115 hereditary cancer related genes using YH (the first Asian genome) was characterized to validate our method. Sensitivity, specificity and accuracy of 93.66, 99.98 and 99.97 %, were achieved, respectively. In addition, we correctly identified 53 SNVs and indels of BRCA1 and BRCA2 in two breast cancer specimens, all confirmed by Sanger sequencing. Accuracy in detecting copy number variation (CNV) was corroborated in 4 breast cancer specimens with known CNVs in BRAC1. Application of the method to 85 clinical cases revealed 22 deleterious mutations, 11 of which were novel. In summary, our studies demonstrate that the target enrichment combined with NGS method provides the accuracy, sensitivity, and high throughput for genetic testing for patients with high risk of hereditary or familial cancer.
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, Tianjin, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Guan
authors.forename: Hong
authors.initials: H
authors.lastname: Hu
authors.forename: Yin
authors.initials: Y
authors.lastname: Peng
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Gong
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yi
authors.forename: Libin
authors.initials: L
authors.lastname: Shao
authors.forename: Tengfei
authors.initials: T
authors.lastname: Liu
authors.forename: Gairui
authors.initials: G
authors.lastname: Li
authors.forename: Rongjiao
authors.initials: R
authors.lastname: Wang
authors.forename: Pingping
authors.initials: P
authors.lastname: Dai
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xiao
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Feng
authors.initials: F
authors.lastname: Mu
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.forename: Zeming
authors.initials: Z
authors.lastname: Xie
authors.forename: Wenhui
authors.initials: W
authors.lastname: Yan
authors.forename: Nan
authors.initials: N
authors.lastname: Xu
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012680:Sensitivity and Specificity