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- Title
Prevalence and detection of low-allele-fraction variants in clinical cancer samples.
- Authors
Hyun-Tae Shin; Yoon-La Choi; Jae Won Yun; Kim, Nayoung K. D.; Sook-Young Kim; Hyo Jeong Jeon; Jae-Yong Nam; Chung Lee; Daeun Ryu; Sang Cheol Kim; Kyunghee Park; Eunjin Lee; Joon Seol Bae; Dae Soon Son; Je-Gun Joung; Jeeyun Lee; Seung Tae Kim; Myung-Ju Ahn; Se-Hoon Lee; Jin Seok Ahn
- Abstract
Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay.
- Subjects
GENETIC mutation; RITUXIMAB; INDIVIDUALIZED medicine; DISEASE prevalence; CANCER
- Publication
Nature Communications, 2017, Vol 8, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-01470-y