RT Journal Article
SR Electronic
T1 Development and validation of a 36-gene sequencing assay for hereditary cancer risk assessment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 088252
DO 10.1101/088252
A1 Valentina S. Vysotskaia
A1 Gregory J. Hogan
A1 Genevieve M. Gould
A1 Xin Wang
A1 Alex D. Robertson
A1 Kevin R. Haas
A1 Mark R. Theilmann
A1 Lindsay Spurka
A1 Peter V. Grauman
A1 Henry H. Lai
A1 Diana Jeon
A1 Genevieve Haliburton
A1 Matt Leggett
A1 Clement S. Chu
A1 Kevin Lori
A1 Jared R. Maguire
A1 Kaylene Ready
A1 Eric A. Evans
A1 H. Peter Kang
A1 Imran S. Haque
YR 2016
UL http://biorxiv.org/content/early/2016/11/17/088252.abstract
AB The past two decades have brought many important advances in our understanding of the hereditary susceptibility to cancer. Numerous studies have provided convincing evidence that identification of germline mutations associated with hereditary cancer syndromes can lead to reductions in morbidity and mortality through targeted risk management options. Additionally, advances in gene sequencing technology now permit the development of multigene hereditary cancer testing panels. Here, we describe the 2016 revision of the Counsyl Inherited Cancer Screen for detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy number variants (CNVs) in 36 genes associated with an elevated risk for breast, ovarian, colorectal, gastric, endometrial, pancreatic, thyroid, prostate, melanoma, and neuroendocrine cancers. To determine test accuracy and reproducibility, we performed a rigorous analytical validation across 341 samples, including 118 cell lines and 223 patient samples. The screen achieved 100% test sensitivity across different mutation types, with high specificity and 100% concordance with conventional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). We also demonstrated the screen’s high intra-run and inter-run reproducibility and robust performance on blood and saliva specimens. Furthermore, we showed that pathogenic Alu element insertions can be accurately detected by our test. Overall, the validation in our clinical laboratory demonstrated the analytical performance required for collecting and reporting genetic information related to risk of developing hereditary cancers.