Abstract
Introduction
ALK-rearranged lung adenocarcinomas with TP53 mutations have more unstable genomic features, poorer ALK-TKI efficacy and a worse prognosis than ALK-rearranged lung adenocarcinomas with wild-type TP53. Here, we examine the gene variations that co-occur with ALK/RET/ROS1 rearrangements in NSCLC and the corresponding tumor immune microenvironment, as well as their association with prognosis.
Methods
A total of 155 patients with ALK/RET/ROS1 fusions were included retrospectively. Tumor genome mutation analysis was performed by next-generation sequencing. PD-L1 expression and tumor-infiltrating lymphocytes were assessed by multiplex immunohistochemistry. The correlations among gene covariation, the tumor immune microenvironment, and clinicopathological characteristics were analyzed.
Results
Among the 155 patients, concomitant TP53 mutation appeared most frequently (31%), followed by CDKN2A/B copy number loss (15%). The ALK/RET/ROS1 fusion and TP53 or CDKN2A/B covariation group had more males and patients with stage IV disease (p < 0.001, p = 0.0066). Patients with TP53 or CDKN2A/B co-occurrence had higher tumor mutation burdens and more neoantigens (p < 0.001, p = 0.0032). PD-L1 expression was higher in the tumor areas of the TP53 or CDKN2A/B co-occurring group (p = 0.00038). However, the levels of CD8+, CD8+PD1−, and CD8+PD-L1− TILs were lower in the tumor areas of this group (p = 0.043, p = 0.029, p = 0.025). In the TCGA NSCLC cohorts, the top 2 mutated genes were CDKN2A/B (24%) and TP53 (16%). The TP53 or CDKN2A/B co-occurring group had higher tumor mutation burdens and shorter OS (p < 0.001, p < 0.001).
Conclusions
Patients with co-occurring TP53/CDKN2A/B variations and ALK/RET/ROS1 rearrangements are associated with high TMB, more neoantigens, an immunosuppressive microenvironment and a worse prognosis.
Similar content being viewed by others
References
Aisner DL, Sholl LM, Berry LD et al (2018) The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin Cancer Res 24(5):1038–1047. https://doi.org/10.1158/1078-0432.CCR-17-2289
Alidousty C, Baar T, Martelotto LG et al (2018) Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations. J Pathol 246(1):67–76. https://doi.org/10.1002/path.5110
Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG (1998) Aberrant methylation of p16 INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci 95:11891–11896
Bergethon K, Shaw AT, Ou SHI et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870. https://doi.org/10.1200/JCO.2011.35.6345
Caccese M, Ferrara R, Pilotto S et al (2016) Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice. Expert Opin Pharmacother 11(17):2253–2266. https://doi.org/10.1080/14656566.2016.1242578
Carney BJ, Rangachari D, VanderLaan PA et al (2017) De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naive lung adenocarcinoma. Lung Cancer 114:108–110. https://doi.org/10.1016/j.lungcan.2017.08.018
Christopoulos P, Kirchner M, Bozorgmehr F et al (2019) Identification of a highly lethal V3(+) TP53(+) subset in ALK(+) lung adenocarcinoma. Int J Cancer 144(1):190–199. https://doi.org/10.1002/ijc.31893
Costa DB (2018) TP53 mutations are predictive and prognostic when co-occurring with ALK rearrangements in lung cancer. Ann Oncol 29(10):2028–2030. https://doi.org/10.1093/annonc/mdy339
Deneka AYB, Baca Y, Serebriiskii IG, Nicolas E, Parker MI, Xiu J, Korn WM, Demeure MJ, Wise-Draper T (2022) Association of T P53 and CDKN2A mutation profile with tumor mutation burden in head and neck cancer. Clinical Cancer Res 28:1925–1937
Dong ZY, Zhong WZ, Zhang XC et al (2017) Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res 23(12):3012–3024. https://doi.org/10.1158/1078-0432.CCR-16-2554
Gainor JF, Shaw AT (2013) Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18(7):865–875. https://doi.org/10.1634/theoncologist.2013-0095
Gainor JF, Shaw AT, Sequist LV et al (2016) EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res 22(18):4585–4593. https://doi.org/10.1158/1078-0432.CCR-15-3101
Jiang J, Gu Y, Liu J et al (2016) Coexistence of p16/CDKN2A homozygous deletions and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKIs. Lung Cancer 102:101–107. https://doi.org/10.1016/j.lungcan.2016.10.015
Klempner SJ, Bazhenova LA, Braiteh FS et al (2015) Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI. Lung Cancer 89(3):357–359. https://doi.org/10.1016/j.lungcan.2015.06.021
Koh J, Jang JY, Keam B et al (2016) EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1alpha and STAT3. Oncoimmunology. 5(3):e1108514. https://doi.org/10.1080/2162402X.2015.1108514
Kron A, Alidousty C, Scheffler M et al (2018) Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann Oncol 29(10):2068–2075. https://doi.org/10.1093/annonc/mdy333
Lin JJ, Ritterhouse LL, Ali SM et al (2017) ROS1 fusions rarely overlap with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 12(5):872–877. https://doi.org/10.1016/j.jtho.2017.01.004
Liu SY, Dong ZY, Wu SP et al (2018) Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. Lung Cancer 125:86–92. https://doi.org/10.1016/j.lungcan.2018.09.010
Liu Y, Zugazagoitia J, Ahmed FS et al (2020) Immune cell PD-L1 colocalizes with macrophages and is associated with outcome in PD-1 pathway blockade therapy. Clin Cancer Res 26(4):970–977. https://doi.org/10.1158/1078-0432.CCR-19-1040
Nakasuka T, Ohashi K, Watanabe H et al (2021) A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1(+) lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations. Lung Cancer 156:1–4. https://doi.org/10.1016/j.lungcan.2021.03.022
Nguyen B, Fong C, Luthra A et al (2021) Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell. https://doi.org/10.1101/2021.06.28.450217
Ota K, Azuma K, Kawahara A et al (2015) Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 21(17):4014–4021. https://doi.org/10.1158/1078-0432.CCR-15-0016
Piotrowska Z, Isozaki H, Lennerz JK et al (2018) Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov 8(12):1529–1539. https://doi.org/10.1158/2159-8290.CD-18-1022
Rich TA, Reckamp KL, Chae YK et al (2019) Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations. Clin Cancer Res 25(19):5832–5842. https://doi.org/10.1158/1078-0432.CCR-18-4049
Rikova K, Guo A, Zeng Q et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203. https://doi.org/10.1016/j.cell.2007.11.025
Shaw AT, Ou SH, Bang YJ et al (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971. https://doi.org/10.1056/NEJMoa1406766
Tokito T, Azuma K, Kawahara A et al (2016) Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 55:7–14. https://doi.org/10.1016/j.ejca.2015.11.020
Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954
Xu-Monette ZY, Zhang M, Li J, Young KH (2017) PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Front Immunol 8:1597. https://doi.org/10.3389/fimmu.2017.01597
Zhang SS, Nagasaka M, Zhu VW, Ou SI (2021) Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC. Lung Cancer 158:126–136. https://doi.org/10.1016/j.lungcan.2021.06.012
Funding
This research was funded by the Zhongnan Hospital of Wuhan University Science, Technology, and Innovation Seed Fund, Grant No. CXPY2019088.
Author information
Authors and Affiliations
Contributions
WH, BJ, and QL conceived and supervised the study. Bin Jiang, and Weikang Shao drafted the manuscript. LH, ZG, DD, WW, and WC collected the tissue samples and clinical data. WS, and TM performed the bioinformatics and statistical analyses. YC, QL, and WH provided critical comments and suggestions and revised the manuscript. All authors read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Weikang Shao, Ting Ma, Yanhui Chen and Qingyun Li are employees of Genecast Biotechnology Co., Ltd. The other authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jiang, B., Hu, L., Dong, D. et al. TP53 or CDKN2A/B covariation in ALK/RET/ROS1-rearranged NSCLC is associated with a high TMB, tumor immunosuppressive microenvironment and poor prognosis. J Cancer Res Clin Oncol 149, 10041–10052 (2023). https://doi.org/10.1007/s00432-023-04924-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-04924-7