Prevalence and detection of low-allele-fraction variants in clinical cancer samples

被引:86
作者
Shin, Hyun-Tae [1 ,2 ]
Choi, Yoon-La [2 ]
Yun, Jae Won [1 ,2 ]
Kim, Nayoung K. D. [1 ]
Kim, Sook-Young [1 ]
Jeon, Hyo Jeong [1 ]
Nam, Jae-Yong [1 ,2 ]
Lee, Chung [1 ,2 ]
Ryu, Daeun [1 ,2 ]
Kim, Sang Cheol [1 ]
Park, Kyunghee [1 ]
Lee, Eunjin [1 ]
Bae, Joon Seol [1 ]
Son, Dae Soon [1 ]
Joung, Je-Gun [1 ]
Lee, Jeeyun [4 ]
Kim, Seung Tae [4 ]
Ahn, Myung-Ju [4 ]
Lee, Se-Hoon [4 ]
Ahn, Jin Seok [4 ]
Lee, Woo Yong [5 ]
Oh, Bo Young [5 ,6 ]
Park, Yeon Hee [4 ]
Lee, Jeong Eon [5 ]
Lee, Kwang Hyuk [7 ]
Kim, Hee Cheol [5 ]
Kim, Kyoung-Mee [3 ]
Im, Young-Hyuck [4 ]
Park, Keunchil [4 ]
Park, Peter J. [8 ]
Park, Woong-Yang [1 ,2 ,9 ]
机构
[1] Samsung Med Ctr, Samsung Genome Inst, Seoul 06351, South Korea
[2] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Seoul 06351, South Korea
[3] Sungkyunkwan Univ, Dept Pathol & Translat Genom, Samsung Med Ctr, Sch Med, Seoul 06351, South Korea
[4] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Hematol & Oncol,Dept Med, Seoul 06351, South Korea
[5] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Surg, Seoul 06351, South Korea
[6] Ewha Womans Univ, Sch Med, Dept Surg, Seoul 07985, South Korea
[7] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Gastroenterol,Dept Med, Seoul 06351, South Korea
[8] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA
[9] Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Seoul 16419, South Korea
来源
NATURE COMMUNICATIONS | 2017年 / 8卷
关键词
CELL LUNG-CANCER; GENERATION SEQUENCE DATA; EGFR T790M; MUTATIONS; RESISTANT; GENOME; HETEROGENEITY; GEFITINIB; AZD9291; TUMORS;
D O I
10.1038/s41467-017-01470-y
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:10
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