@article {1285431, title = {Prevalence and detection of low-allele-fraction variants in clinical cancer samples}, journal = {Nat Commun}, volume = {8}, number = {1}, year = {2017}, month = {2017 Nov 09}, pages = {1377}, 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.}, issn = {2041-1723}, doi = {10.1038/s41467-017-01470-y}, author = {Shin, Hyun-Tae* and Choi, Yoon-La* and Yun, Jae Won* and Kim, Nayoung K D* and Kim, Sook-Young and Jeon, Hyo Jeong and Nam, Jae-Yong and Lee, Chung and Ryu, Daeun and Kim, Sang Cheol and Park, Kyunghee and Lee, Eunjin and Bae, Joon Seol and Son, Dae Soon and Joung, Je-Gun and Lee, Jeeyun and Kim, Seung Tae and Ahn, Myung-Ju and Lee, Se-Hoon and Ahn, Jin Seok and Lee, Woo Yong and Oh, Bo Young and Park, Yeon Hee and Lee, Jeong Eon and Lee, Kwang Hyuk and Kim, Hee Cheol and Kim, Kyoung-Mee and Im, Young-Hyuck and Park, Keunchil and Park, Peter J** and Park, Woong-Yang**} }