Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS Journal Article

   

Authors:	Brannon, A. R.; Jayakumaran, G.; Diosdado, M.; Patel, J.; Razumova, A.; Hu, Y.; Meng, F.; Haque, M.; Sadowska, J.; Murphy, B. J.; Baldi, T.; Johnson, I.; Ptashkin, R.; Hasan, M.; Srinivasan, P.; Rema, A. B.; Rijo, I.; Agarunov, A.; Won, H.; Perera, D.; Brown, D. N.; Samoila, A.; Jing, X.; Gedvilaite, E.; Yang, J. L.; Stephens, D. P.; Dix, J. M.; DeGroat, N.; Nafa, K.; Syed, A.; Li, A.; Lebow, E. S.; Bowman, A. S.; Ferguson, D. C.; Liu, Y.; Mata, D. A.; Sharma, R.; Yang, S. R.; Bale, T.; Benhamida, J. K.; Chang, J. C.; Dogan, S.; Hameed, M. R.; Hechtman, J. F.; Moung, C.; Ross, D. S.; Vakiani, E.; Vanderbilt, C. M.; Yao, J. J.; Razavi, P.; Smyth, L. M.; Chandarlapaty, S.; Iyer, G.; Abida, W.; Harding, J. J.; Krantz, B.; O’Reilly, E.; Yu, H. A.; Li, B. T.; Rudin, C. M.; Diaz, L.; Solit, D. B.; Arcila, M. E.; Ladanyi, M.; Loomis, B.; Tsui, D.; Berger, M. F.; Zehir, A.; Benayed, R.
Article Title:	Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS
Abstract:	Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients. © 2021, The Author(s).
Keywords:	adult; human tissue; major clinical study; cancer patient; sensitivity and specificity; gene frequency; germ line; patient care; clinical evaluation; clonal hematopoiesis; human; male; female; article; protein fingerprinting
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-01-01
Start Page:	3770
Language:	English
DOI:	10.1038/s41467-021-24109-5
PUBMED:	34145282
PROVIDER:	scopus
PMCID:	PMC8213710
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108164115&doi=10.1038%2fs41467-021-24109-5&partnerID=40&md5=533a530e2e9171a3fc8e3d6ba869e49c
Notes:	Article -- Export Date: 1 July 2021 -- Source: Scopus