Estimating tumor mutational burden across multiple cancer types using whole-exome sequencing

被引：16

作者：

Zhou, Chuang ^{[1
]}

Chen, Song ^{[2
]}

Xu, Fei ^{[3
]}

Wei, Jinwang ^{[3
]}

Zhou, Xiaoyu ^{[3
]}

Wu, Zhiqiang ^{[2
]}

Zhao, Longshuan ^{[1
]}

Liu, Jun ^{[3
]}

Guo, Wenbo ^{[2
]}

机构：

[1] Zhengzhou Univ, Affiliated Hosp 1, Dept Hepatobiliary Pancreat Surg, Zhengzhou, Peoples R China

[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Radiat Oncol, 58 Zhongshan 2nd Rd, Guangzhou, Peoples R China

[3] Genomicare Biotechnol Shanghai Co Ltd, Shanghai 201210, Peoples R China

来源：

ANNALS OF TRANSLATIONAL MEDICINE | 2021年 / 9卷 / 18期

关键词：

Tumor mutational burden (TMB); whole-exome sequencing (WES); immunotherapy; NIVOLUMAB;

D O I：

10.21037/atm-21-4227

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Tumor mutational burden (TMB) is emerging as a promising biomarker in immune checkpoint inhibitor (ICI) therapy. Despite whole-exome sequencing (WES) being the gold standard for quantifying TMB, TMB is determined by selected targeted panels in most cases, and WES-derived TMB data are lacking due to the greater cost and complexity. Determining TMB thresholds is another issue that needs attention. Methods: A total of 309 patients who had received ICI therapy, representing five cancers (listed in "Results"), were recruited. Among them, 269 patients were evaluable for survival analysis. Tumor and matched blood samples from the patients were analyzed using WES and somatic mutations were determined. TMB is defined as the total number of somatic nonsynonymous mutations in the tumor exome in our study. The patients were divided into different TMB subgroups according to a common fixed number (10 mutations/Mb) or the top tertile within each tumor type. Results: The distribution of WES-derived median TMBs was highly variable across different tumor types, ranging from 2.71 (cholangiocarcinoma) to 2.97 (nervous system tumor), 3.69 (gastric cancer), 4.31 (hepatocellular carcinoma), and 4.64 [colorectal cancer (CRC)] mutations/Mb. In CRC, the survival benefit of TMB-high patients was significant using both the top tertile and the 10 mutations/Mb threshold. In hepatocellular carcinoma, the 10 mutations/Mb threshold showed an advantage over the top tertile threshold. Among patients with nervous system tumors, cholangiocarcinoma, and gastric cancer, no obvious survival differences were observed between the TMB-high and TMB-low groups with either TMB stratification approach. Conclusions: The TMB threshold criterion may vary for different cancers. Our data suggest that TMB is unable to predict ICI benefit across all cancer types in Chinese patients. However, it may be an effective biomarker for predicting the clinical benefit of ICI therapy for patients with CRC.

引用

页数：10

共 24 条

[11] MSIsensor: microsatellite instability detection using paired tumor-normal sequence data [J].

Niu, Beifang ;

Ye, Kai ;

Zhang, Qunyuan ;

Lu, Charles ;

Xie, Mingchao ;

McLellan, Michael D. ;

Wendl, Michael C. ;

Ding, Li .

BIOINFORMATICS, 2014, 30 (07) :1015-1016

[12] Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer [J].

Overman, Michael J. ;

Lonardi, Sara ;

Wong, Ka Yeung Mark ;

Lenz, Heinz-Josef ;

Gelsomino, Fabio ;

Aglietta, Massimo ;

Morse, Michael A. ;

Van Cutsem, Eric ;

McDermott, Ray ;

Hill, Andrew ;

Sawyer, Michael B. ;

Hendlisz, Alain ;

Neyns, Bart ;

Svrcek, Magali ;

Moss, Rebecca A. ;

Ledeine, Jean-Marie ;

Cao, Z. Alexander ;

Kamble, Shital ;

Kopetz, Scott ;

Andre, Thierry .

JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (08) :773-+

[13] Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study [J].

Overman, Michael J. ;

McDermott, Ray ;

Leach, Joseph L. ;

Lonardi, Sara ;

Lenz, Heinz-Josef ;

Morse, Michael A. ;

Desai, Jayesh ;

Hill, Andrew ;

Axelson, Michael ;

Moss, Rebecca A. ;

Goldberg, Monica V. ;

Cao, Z. Alexander ;

Ledeine, Jean-Marie ;

Maglinte, Gregory A. ;

Kopetz, Scott ;

Andre, Thierry .

LANCET ONCOLOGY, 2017, 18 (09) :1182-1191

[14] First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers [J].

Ready, Neal ;

Hellmann, Matthew D. ;

Awad, Mark M. ;

Otterson, Gregory A. ;

Gutierrez, Martin ;

Gainor, Justin F. ;

Borghaei, Hossein ;

Jolivet, Jacques ;

Horn, Leora ;

Mates, Mihaela ;

Brahmer, Julie ;

Rabinowitz, Ian ;

Reddy, Pavan S. ;

Chesney, Jason ;

Orcutt, James ;

Spigel, David R. ;

Reck, Martin ;

O'Byrne, Kenneth John ;

Paz-Ares, Luis ;

Hu, Wenhua ;

Zerba, Kim ;

Li, Xuemei ;

Lestini, Brian ;

Geese, William J. ;

Szustakowski, Joseph D. ;

Green, George ;

Chang, Han ;

Ramalingam, Suresh S. .

JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (12) :992-+

[15] Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial [J].

Rosenberg, Jonathan E. ;

Hoffman-Censits, Jean ;

Powles, Tom ;

van der Heijden, Michiel S. ;

Balar, Arjun V. ;

Necchi, Andrea ;

Dawson, Nancy ;

O'Donnell, Peter H. ;

Balmanoukian, Ani ;

Loriot, Yohann ;

Srinivas, Sandy ;

Retz, Margitta M. ;

Grivas, Petros ;

Joseph, Richard W. ;

Galsky, Matthew D. ;

Fleming, Mark T. ;

Petrylak, Daniel P. ;

Perez-Gracia, Jose Luis ;

Burris, Howard A. ;

Castellano, Daniel ;

Canil, Christina ;

Bellmunt, Joaquim ;

Bajorin, Dean ;

Nickles, Dorothee ;

Bourgon, Richard ;

Frampton, Garrett M. ;

Cui, Na ;

Mariathasan, Sanjeev ;

Abidoye, Oyewale ;

Fine, Gregg D. ;

Dreicer, Robert .

LANCET, 2016, 387 (10031) :1909-1920

[16] Tumor mutational load predicts survival after immunotherapy across multiple cancer types [J].

Samstein, Robert M. ;

Lee, Chung-Han ;

Shoushtari, Alexander N. ;

Hellmann, Matthew D. ;

Shen, Ronglai ;

Janjigian, Yelena Y. ;

Barron, David A. ;

Zehir, Ahmet ;

Jordan, Emmet J. ;

Omuro, Antonio ;

Kaley, Thomas J. ;

Kendall, Sviatoslav M. ;

Motzer, Robert J. ;

Hakimi, A. Ari ;

Voss, Martin H. ;

Russo, Paul ;

Rosenberg, Jonathan ;

Iyer, Gopa ;

Bochner, Bernard H. ;

Bajorin, Dean F. ;

Al-Ahmadie, Hikmat A. ;

Chaft, Jamie E. ;

Rudin, Charles M. ;

Riely, Gregory J. ;

Baxi, Shrujal ;

Ho, Alan L. ;

Wong, Richard J. ;

Pfister, David G. ;

Wolchok, Jedd D. ;

Barker, Christopher A. ;

Gutin, Philip H. ;

Brennan, Cameron W. ;

Tabar, Viviane ;

Mellinghoff, Ingo K. ;

DeAngelis, Lisa M. ;

Ariyan, Charlotte E. ;

Lee, Nancy ;

Tap, William D. ;

Gounder, Mrinal M. ;

D'Angelo, Sandra P. ;

Saltz, Leonard ;

Stadler, Zsofia K. ;

Scher, Howard I. ;

Baselga, Jose ;

Razavi, Pedram ;

Klebanoff, Christopher A. ;

Yaeger, Rona ;

Segal, Neil H. ;

Ku, Geoffrey Y. ;

DeMatteo, Ronald P. .

NATURE GENETICS, 2019, 51 (02) :202-+

[17] Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer [J].

Topalian, Suzanne L. ;

Hodi, F. Stephen ;

Brahmer, Julie R. ;

Gettinger, Scott N. ;

Smith, David C. ;

McDermott, David F. ;

Powderly, John D. ;

Carvajal, Richard D. ;

Sosman, Jeffrey A. ;

Atkins, Michael B. ;

Leming, Philip D. ;

Spigel, David R. ;

Antonia, Scott J. ;

Horn, Leora ;

Drake, Charles G. ;

Pardoll, Drew M. ;

Chen, Lieping ;

Sharfman, William H. ;

Anders, Robert A. ;

Taube, Janis M. ;

McMiller, Tracee L. ;

Xu, Haiying ;

Korman, Alan J. ;

Jure-Kunkel, Maria ;

Agrawal, Shruti ;

McDonald, Daniel ;

Kollia, Georgia D. ;

Gupta, Ashok ;

Wigginton, Jon M. ;

Sznol, Mario .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2443-2454

[18] First-line pembrolizumab in programmed death ligand 1 positive non-small cell lung cancer [J].

Travert, Camille ;

Tomasini, Pascale ;

Jeanson, Arnaud ;

Greillier, Laurent ;

Barlesi, Fabrice .

TRANSLATIONAL CANCER RESEARCH, 2019, 8 (07) :2514-2516

[19] Genomic correlates of response to CTLA-4 blockade in metastatic melanoma [J].

Van Allen, Eliezer M. ;

Miao, Diana ;

Schilling, Bastian ;

Shukla, Sachet A. ;

Blank, Christian ;

Zimmer, Lisa ;

Sucker, Antje ;

Hillen, Uwe ;

Foppen, Marnix H. Geukes ;

Goldinger, Simone M. ;

Utikal, Jochen ;

Hassel, Jessica C. ;

Weide, Benjamin ;

Kaehler, Katharina C. ;

Loquai, Carmen ;

Mohr, Peter ;

Gutzmer, Ralf ;

Dummer, Reinhard ;

Gabriel, Stacey ;

Wu, Catherine J. ;

Schadendorf, Dirk ;

Garraway, Levi A. .

SCIENCE, 2015, 350 (6257) :207-211

[20] Tumor mutational and indel burden: a systematic pan-cancer evaluation as prognostic biomarkers [J].

Wu, Hao-Xiang ;

Wang, Zi-Xian ;

Zhao, Qi ;

Chen, Dong-Liang ;

He, Ming-Ming ;

Yang, Lu-Ping ;

Wang, Ying-Nan ;

Jin, Ying ;

Ren, Chao ;

Luo, Hui-Yan ;

Wang, Zhi-Qiang ;

Wang, Feng .

ANNALS OF TRANSLATIONAL MEDICINE, 2019, 7 (22)

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