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

A. Rose Brannon, Gowtham Jayakumaran, Monica Diosdado, Juber Patel, Anna Razumova, Yu Hu, Fanli Meng, Mohammad Haque, Justyna Sadowska, Brian J. Murphy, Tessara Baldi, Ian Johnson, Ryan Ptashkin, Maysun Hasan, Preethi Srinivasan, Anoop Balakrishnan Rema, Ivelise Rijo, Aaron Agarunov, Helen Won, Dilmi Perera, David N. Brown, Aliaksandra Samoila, Xiaohong Jing, Erika Gedvilaite, Julie L. Yang, Dennis P. Stephens, Jenna-Marie Dix, Nicole DeGroat, Khedoudja Nafa, Aijazuddin Syed, Alan Li, Emily S. Lebow, Anita S. Bowman, Donna C. Ferguson, Ying Liu, Douglas A. Mata, Rohit Sharma, Soo-Ryum Yang, Tejus Bale, Jamal K. Benhamida, Jason C. Chang, Snjezana Dogan, Meera R. Hameed, Jaclyn F. Hechtman, Christine Moung, Dara S. Ross, Efsevia Vakiani, Chad M. Vanderbilt, JinJuan Yao, Pedram Razavi, Lillian M. Smyth, Sarat Chandarlapaty, Gopa Iyer, Wassim Abida, James J. Harding, Benjamin Krantz, Eileen O’Reilly, Helena A. Yu, Bob T. Li, Charles M. Rudin, Luis Diaz, David B. Solit, Maria E. Arcila, Marc Ladanyi, Brian Loomis, Dana Tsui, Michael F. Berger, Ahmet Zehir () and Ryma Benayed ()
Additional contact information
A. Rose Brannon: Memorial Sloan Kettering Cancer Center
Gowtham Jayakumaran: Memorial Sloan Kettering Cancer Center
Monica Diosdado: Memorial Sloan Kettering Cancer Center
Juber Patel: Memorial Sloan Kettering Cancer Center
Anna Razumova: Memorial Sloan Kettering Cancer Center
Yu Hu: Memorial Sloan Kettering Cancer Center
Fanli Meng: Memorial Sloan Kettering Cancer Center
Mohammad Haque: Memorial Sloan Kettering Cancer Center
Justyna Sadowska: Memorial Sloan Kettering Cancer Center
Brian J. Murphy: Memorial Sloan Kettering Cancer Center
Tessara Baldi: Memorial Sloan Kettering Cancer Center
Ian Johnson: Memorial Sloan Kettering Cancer Center
Ryan Ptashkin: Memorial Sloan Kettering Cancer Center
Maysun Hasan: Memorial Sloan Kettering Cancer Center
Preethi Srinivasan: Memorial Sloan Kettering Cancer Center
Anoop Balakrishnan Rema: Memorial Sloan Kettering Cancer Center
Ivelise Rijo: Memorial Sloan Kettering Cancer Center
Aaron Agarunov: Memorial Sloan Kettering Cancer Center
Helen Won: Memorial Sloan Kettering Cancer Center
Dilmi Perera: Memorial Sloan Kettering Cancer Center
David N. Brown: Memorial Sloan Kettering Cancer Center
Aliaksandra Samoila: Memorial Sloan Kettering Cancer Center
Xiaohong Jing: Memorial Sloan Kettering Cancer Center
Erika Gedvilaite: Memorial Sloan Kettering Cancer Center
Julie L. Yang: Memorial Sloan Kettering Cancer Center
Dennis P. Stephens: Memorial Sloan Kettering Cancer Center
Jenna-Marie Dix: Memorial Sloan Kettering Cancer Center
Nicole DeGroat: Memorial Sloan Kettering Cancer Center
Khedoudja Nafa: Memorial Sloan Kettering Cancer Center
Aijazuddin Syed: Memorial Sloan Kettering Cancer Center
Alan Li: Memorial Sloan Kettering Cancer Center
Emily S. Lebow: Memorial Sloan Kettering Cancer Center
Anita S. Bowman: Memorial Sloan Kettering Cancer Center
Donna C. Ferguson: Memorial Sloan Kettering Cancer Center
Ying Liu: Memorial Sloan Kettering Cancer Center
Douglas A. Mata: Memorial Sloan Kettering Cancer Center
Rohit Sharma: Memorial Sloan Kettering Cancer Center
Soo-Ryum Yang: Memorial Sloan Kettering Cancer Center
Tejus Bale: Memorial Sloan Kettering Cancer Center
Jamal K. Benhamida: Memorial Sloan Kettering Cancer Center
Jason C. Chang: Memorial Sloan Kettering Cancer Center
Snjezana Dogan: Memorial Sloan Kettering Cancer Center
Meera R. Hameed: Memorial Sloan Kettering Cancer Center
Jaclyn F. Hechtman: Memorial Sloan Kettering Cancer Center
Christine Moung: Memorial Sloan Kettering Cancer Center
Dara S. Ross: Memorial Sloan Kettering Cancer Center
Efsevia Vakiani: Memorial Sloan Kettering Cancer Center
Chad M. Vanderbilt: Memorial Sloan Kettering Cancer Center
JinJuan Yao: Memorial Sloan Kettering Cancer Center
Pedram Razavi: Memorial Sloan Kettering Cancer Center
Lillian M. Smyth: Memorial Sloan Kettering Cancer Center
Sarat Chandarlapaty: Memorial Sloan Kettering Cancer Center
Gopa Iyer: Memorial Sloan Kettering Cancer Center
Wassim Abida: Memorial Sloan Kettering Cancer Center
James J. Harding: Memorial Sloan Kettering Cancer Center
Benjamin Krantz: Memorial Sloan Kettering Cancer Center
Eileen O’Reilly: Memorial Sloan Kettering Cancer Center
Helena A. Yu: Memorial Sloan Kettering Cancer Center
Bob T. Li: Memorial Sloan Kettering Cancer Center
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
Luis Diaz: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Maria E. Arcila: Memorial Sloan Kettering Cancer Center
Marc Ladanyi: Memorial Sloan Kettering Cancer Center
Brian Loomis: Memorial Sloan Kettering Cancer Center
Dana Tsui: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Ahmet Zehir: Memorial Sloan Kettering Cancer Center
Ryma Benayed: Memorial Sloan Kettering Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24109-5

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