Tumor mutation burden estimated by a 69-gene-panel is associated with overall survival in patients with diffuse large B-cell lymphoma

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Tumor mutation burden (TMB) as estimated by cancer gene panels (CGPs) has been confirmed to be associated with prognosis and is effective in predicting clinical benefit from immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CGPs is associated with overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) is worth exploring.

Methods

The prognostic value of panel-TMB, calculated by a panel of 69 genes (GP69), for 87 DLBCL patients in our clinical center (GDPH dataset) was explored. The results were further validated using 37 DLBCL patients from the Cancer Genome Atlas (TCGA) database (TCGA dataset).

Results

Spearman correlation analysis suggested that panel-TMB is positively correlated with the TMB calculated by whole-exome sequencing (wTMB) in the TCGA dataset (R = 0.76, P < 0.0001). Both GDPH and TCGA results demonstrated that higher panel-TMB is significantly associated with a poor OS for DLBCL patients (P < 0.05) where a panel of 13 genes was associated with poor OS, and another panel of 26 genes was correlated with a favorable OS for DLBCL patients. Further subgroup analysis indicated that higher panel-TMB had shorter OS in DLBCL patients with younger than 60 years, elevated LDH, greater than one extranodal involvement, stage III/IV, an IPI score of 3–5, or HBsAg, anti-HBc, or HBV-DNA negativity (P < 0.05). Interestingly, the nomogram model constructed by panel-TMB, stage, and IPI could individually and visually predict the 1-, 2- and 3-year OS rates of DLBCL patients.

Conclusions

We established GP69 for the evaluation of OS for Chinese DLBCL patients. panel-TMB might be a potential predictor for prognostic stratification of DLBCL patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40164-021-00215-4.

Related collections

Most cited references 37

Record: found
Abstract: found
Article: found

Is Open Access

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Zachary Chalmers, Caitlin Connelly, David Fabrizio … (2017)

Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.

0 comments Cited 1152 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte.

Bertrand Coiffier, Catherine Thieblemont, Eric Van Den Neste … (2010)

We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.

0 comments Cited 460 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

Zheng Zhou, Laurie Sehn, Alfred Rademaker … (2014)

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low- and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.

0 comments Cited 304 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Yangqiu Li:

ORCID: http://orcid.org/0000-0002-0974-4036

yangqiuli@hotmail.com

Wenyu Li: lwy80411@163.com

Journal

Journal ID (nlm-ta): Exp Hematol Oncol

Journal ID (iso-abbrev): Exp Hematol Oncol

Title: Experimental Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 2162-3619

Publication date (Electronic): 15 March 2021

Publication date PMC-release: 15 March 2021

Publication date Collection: 2021

Volume: 10

Electronic Location Identifier: 20

Affiliations

[1 ]GRID grid.258164.c, ISNI 0000 0004 1790 3548, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, , Jinan University, ; Guangzhou, China

[2 ]GRID grid.79703.3a, ISNI 0000 0004 1764 3838, Department of Lymphoma, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, , South China University of Technology, ; Guangzhou, China

[3 ]Nanjing Geneseq Technology Inc, Nanjing, Jiangsu China

[4 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, School of Public Health, , Nanjing Medical University, ; Nanjing, Jiangsu China

Author information

Cunte Chen http://orcid.org/0000-0003-3733-9174

Yangqiu Li http://orcid.org/0000-0002-0974-4036

Article

Publisher ID: 215

DOI: 10.1186/s40164-021-00215-4

PMC ID: 7962318

PubMed ID: 33722306

SO-VID: 1ec32e74-7fc0-4f65-88f2-e4e03a4d7723

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 24 January 2021

Date accepted : 8 March 2021

Funding

Funded by: Guangdong Science and Technology Project

Award ID: 2020A0505100042

Award Recipient : Yangqiu Li

Funded by: the major program of Summit Project, Guangdong Province High-level Hospital Construction Project of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences

Award ID: DFJH2020025

Award Recipient : Wenyu Li

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tmb,gene panel,prognosis,biomarker,diffuse large b-cell lymphoma

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tmb, gene panel, prognosis, biomarker, diffuse large b-cell lymphoma

Comments

Comment on this article

scite_

Cited by 15

See all cited by

Most referenced authors 627

See all reference authors

Tumor mutation burden estimated by a 69-gene-panel is associated with overall survival in patients with diffuse large B-cell lymphoma

Read this article at

Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Karger: Oncology

Most cited references 37

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte.

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 254

Cited by 15

Most referenced authors 627