KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma
Abstract
Objectives The efficacy of anti- programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) immune checkpoint inhibitors remains controversial in patients with KRAS mutation. In addition, whether and how KRAS gene and its mutant subtypes might influence immunity has not been clarified yet. Here we examine some important biomarkers for the efficacy of immunotherapy in specific KRAS subtypes.Materials and methods We conducted a bioinformatics analysis on somatic mutations data, transcriptome sequencing data and proteomic data from The Cancer Genome Atlas (TCGA) database. CIBERSORT was used to provide an estimation of the abundances of immune cells using gene expression data.Results From a cohort of 567 patients with lung adenocarcinoma (LUAD) based on TCGA, the overall mutation rate of KRAS was 26.29 %, including KRAS/TP53 co-mutation rate of 9.7 %. We observed increased Tumor mutation burden (TMB) in KRAS mutant group compared with wild type, while no difference in PD-L1 expression and immune cell infiltration. More importantly, TP53 and KRAS/TP53 co-mutation group not only significantly increased tumor mutation burden, but also had higher PD-L1 protein level and immune cell infiltration. We further focused on influence of KRAS mutant subtype on immune biomarker. The most prevalent mutant subtype of KRAS in lung adenocarcinoma was G12C(9.88 %,56/567), followed by G12 V(5.82 %,33/567), G12D(3.00 %,17/567), G12A(3.00 %,17/567), respectively. Among them, G12D mutation appeared to be a special mutant subtype with an obviously lower TMB. This low mutation load was more significant when co-mutation with TP53. Besides, our results also revealed significantly decreased expressions of PD-L1 protein level and immune cell infiltration (activated CD4 memory T cell, helper T cell, M1 macrophage and NK cell) in KRAS G12D/TP53 mutant group.Conclusion KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma.
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Early data suggest KRAS alleles other than G12C, especially with TP53 co-mutation, may be negative predictive biomarkers for anti-PD-1/PD-L1 inhibitors in NSCLC.
“Early data suggests that the presence of KRAS alleles other than G12C mutations (75), especially in conjunction with a TP53 co-mutation, may represent a negative predictive biomarkers for anti-PD-1/PD-L1 immune checkpoint inhibitors in NSCLC patients (76).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [76]
Cites
Robust enumeration of cell subsets from tissue expression profiles
Newman, A. M., Liu, C. L., Green, M. R., Gentles, A. J., Feng, W., Xu, Y., Hoang, C. D., Diehn, M., & Alizadeh, A. A. (2015) · Nature Methods · doi:10.1038/nmeth.3337 · Cited by 12,116 · see citing works
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380 · see citing works
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639 · see citing works
First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer
Carbone, D. P., Reck, M., Paz-Ares, L., Creelan, B., Horn, L., Steins, M., Felip, E., van den Heuvel, M. M., Ciuleanu, T.-E., Badin, F., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1613493 · Cited by 2,503 · see citing works
<i>STK11/LKB1</i> Mutations and PD-1 Inhibitor Resistance in <i>KRAS</i> -Mutant Lung Adenocarcinoma
Skoulidis, F., Goldberg, M. E., Greenawalt, D. M., Hellmann, M. D., Awad, M. M., Gainor, J. F., Schrock, A. B., Hartmaier, R. J., Trabucco, S. E., Gay, L., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0099 · Cited by 1,641 · see citing works
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer
Tran, E., Robbins, P. F., Lu, Y.-C., Prickett, T. D., Gartner, J. J., Jia, L., Pasetto, A., Zheng, Z., Ray, S., Groh, E. M., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1609279 · Cited by 1,368 · see citing works
Dong, Z.-Y., Zhong, W.-Z., Zhang, X.-C., Su, J., Xie, Z., Liu, S.-Y., Tu, H.-Y., Chen, H.-J., Sun, Y.-L., Zhou, Q., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2554 · Cited by 959 · see citing works
KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer
Liao, W., Overman, M. J., Boutin, A. T., Shang, X., Zhao, D., Dey, P., Li, J., Wang, G., Lan, Z., Li, J., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.02.008 · Cited by 617 · see citing works
Self-citationMyc Cooperates with Ras by Programming Inflammation and Immune Suppression
Kortlever, R. M., Sodir, N. M., Wilson, C. H., Burkhart, D. L., Pellegrinet, L., Brown Swigart, L., Littlewood, T. D., & Evan, G. I. (2017) · Cell · doi:10.1016/j.cell.2017.11.013 · Cited by 553 · see citing works
Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., & Wakelee, H. A. (2019) · Lung Cancer · doi:10.1016/j.lungcan.2019.05.015 · Cited by 132 · see citing works
KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures
Friedlaender, A., Drilon, A., Weiss, G. J., Banna, G. L., & Addeo, A. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.101978 · Cited by 118 · see citing works
Cheng, H., Fan, K., Luo, G., Fan, Z., Yang, C., Huang, Q., Jin, K., Xu, J., Yu, X., & Liu, C. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.01.013 · Cited by 83 · see citing works
KRAS-Driven Lung Adenocarcinoma and B Cell Infiltration: Novel Insights for Immunotherapy
Rosamaria, P., Petriella, D., Lacalamita, R., Montrone, M., Catino, A., Pizzutilo, P., Antonietta, B. M., Zito, A. F., Bene, G. D., Zonno, A., et al. (2019) · Cancers · doi:10.3390/cancers11081145 · Cited by 37 · see citing works
Lanman, B. A., Chen, J. J., Liu, L., Lopez, P., Pickrell, A. J., Reed, A. B., Wang, H., Achanta, P., Canon, J. R., Erlanson, D. A., et al. (2019) · Cancer Research · doi:10.1158/1538-7445.am2019-4455 · Cited by 9 · see citing works
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Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336 · see citing works
Ricciuti, B., Alessi, J. V., Elkrief, A., Wang, X., Cortellini, A., Li, Y. Y., Vaz, V. R., Gupta, H., Pecci, F., Barrichello, A., et al. (2022) · Annals of Oncology · doi:10.1016/j.annonc.2022.07.005 · Cited by 112 · see citing works
- Authors
- Gao, G., Liao, W., Ma, Q., Zhang, B., Chen, Y., & Wang, Y.
- Affiliations
- West China Hospital of Sichuan University (CN)
- Sichuan University (CN)
- Corresponding author
- Wang, Yongsheng
- Venue
- Lung Cancer
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 149
- Pages
- 41-45
- ISSN
- 0169-5002 (ISSN-L)
- OpenAlex
- W3085963549
- Cited by
- 71
- References
- 14
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 10 · 2023: 16 · 2022: 18 · 2021: 8 · 2020: 1
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Lung Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Major Science and Technology Projects of China
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS G12D mutation, lung adenocarcinoma, tumor mutational burden, TP53 co-mutation, PD-L1 expression, immune cell infiltration, immunosuppression, PD-1/PD-L1 blockade, predictive biomarkers, tumor immune microenvironment
- MeSH terms
- Adenocarcinoma of Lung, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Proteomics, B7-H1 Antigen
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