Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients

Abstract

Background Anaplastic lymphoma kinase (ALK) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to explore the landscape of ALK fusion-positive and ALK fusion-negative in a large cohort of NSCLC patients.
Methods The formalin-fixed paraffin-embedded specimens of NSCLC patients who underwent next-generation sequencing from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. Clinical laboratory were included in this study.
Results In the current study, a total of 180 (3.20%) patients tested positive for ALK fusions in 5,622 NSCLC samples. Within the ALK-positive cohort, a total of 228 ALK fusions were identified. Furthermore, five novel ALK fusion partners, including DAB1-ALK, KCMF1-ALK, KIF13A-ALK, LOC643770-ALK, and XDH-ALK were identified. In cases with ALK fusion-positive, TP53 alterations were the most prevalent (26.3%), followed by CDKN2A (8.4%), epidermal growth factor receptor (EGFR, 5.6%), and ALK (5.6%). By contrast, EGFR alterations were most prevalent (51%) in patients with ALK fusion-negative NSCLC, followed by TP53 (42.7%), KRAS (11.6%), and CDKN2A (11.3%). A total of 10 cases where ALK fusion co-occurred with EGFR mutations were also identified. Notably, the ALK fusion positivity rate was higher in younger patients (p < 0.0001) and in female patients (p = 0.0429). Additionally, positive ALK test results were more prevalent in patients with high programmed death-ligand 1 expression, especially when applying a 50% cutoff.
Conclusions Collectively, these findings offer valuable genomic insights that could inform the personalized clinical care of patients with NSCLC harboring ALK fusions within the context of precision medicine.

Keywords

NSCLC / ALK fusion / next-generation sequencing / genomic landscape

Author Contributions

W.X. collected and organized the data. J.Y. wrote the manuscript. H.L. prepared the figures. L.L. and J.L. critically revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

None.

Conflict of Interest

None declared.

Acknowledgments

Authors thank to the support of Yinfeng Gene Technology Co., Ltd. in next-generation sequencing and bioinformatics data arrangement.

References

[1] Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA.Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008; 83[phone]

[2] de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res 2018; 7[phone]

[3] Soda M, Choi YL, Enomoto M.et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448(7153): 561-566

[4] Solomon B, Varella-Garcia M, Camidge DR.ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009; 4(12) 1450-1454

[5] Hallberg B, Palmer RH.Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 2013; 13(10) 685-700

[6] He Y, Sun LY, Gong R.et al.The prevalence of EML4-ALK variants in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Biomarkers Med 2019; 13(12) 1035-1044

[7] Takeuchi K, Choi YL, Togashi Y.et al.KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15[phone]

[8] Rikova K, Guo A, Zeng Q.et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131[phone]

[9] Togashi Y, Soda M, Sakata S.et al.KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7(02) e31323

[10] Feng T, Chen Z, Gu J, Wang Y, Zhang J, Min L.The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma. Lung Cancer 2019; 137: 19-22

[11] Rodig SJ, Shapiro GI.Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs 2010; 11(12) 1477-1490

[12] Markham A.Brigatinib: first global approval. Drugs 2017; 77(10) 1131-1135

[13] Kuang S, Leighl NB.Lorlatinib in ALK-rearranged lung cancer. Cancer Cell 2021; 39(01) 25-27

[14] Li W, Liu Y, Li W, Chen L, Ying J.Intergenic breakpoints identified by DNA sequencing confound targetable kinase fusion detection in NSCLC. J Thorac Oncol 2020; 15[phone]

[15] Kang J, Zhang XC, Chen HJ.et al.Complex ALK fusions are associated with better prognosis in advanced non-small cell lung cancer. Front Oncol 2020; 10: 596937

[16] Zhao R, Zhang J, Han Y.et al.Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 2019; 23[phone]

[17] Ke L, Xu M, Jiang X, Sun X.Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase/oncogene or c-ros oncogene 1 (ALK/ROS1) fusions inflict non-small cell lung cancer (NSCLC) female patients older than 60 years of age. Med Sci Monit 2018; 24(24) 9364-9369

[18] Ota K, Azuma K, Kawahara A.et al.Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 2015; 21(17) 4014-4021

[19] Chen WS, Bindra RS, Mo A.et al.CDKN2A copy number loss is an independent prognostic factor in HPV-negative head and neck squamous cell carcinoma. Front Oncol 2018; 8: 95

[20] Yin J, Li Y, Zhao H.et al.Copy-number variation of MCL1 predicts overall survival of non-small-cell lung cancer in a Southern Chinese population. Cancer Med 2016; 5[phone]

[21] Sawada R, Maehara R, Oshikiri T.et al.MDM2 copy number increase: a poor prognostic, molecular event in esophageal squamous cell carcinoma. Hum Pathol 2019; 89: 1-9

[22] Huang F, Chang H, Greer A.et al.IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. Mol Cancer Ther 2015; 14[phone]

[23] Gainor JF, Varghese AM, Ou SH.et al.ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19(15) 4273-4281

[24] Li Y, Li Y, Yang T.et al.Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One 2013; 8(01) e52093

[25] Popat S, Vieira de Araújo A, Min T. et al. Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 2011; 6(11) 1962-1963

[26] Tiseo M, Gelsomino F, Boggiani D.et al.EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011; 71[phone]

[27] Marusyk A, Almendro V, Polyak K.Intra-tumour heterogeneity: a looking glass for cancer?. Nat Rev Cancer 2012; 12[phone]

[28] Ulivi P, Puccetti M, Capelli L.et al.Molecular determinations of EGFR and EML4-ALK on a single slide of NSCLC tissue. J Clin Pathol 2013; 66[phone]

[29] Yang JJ, Zhang XC, Su J.et al.Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014; 20[phone]

[30] Imamura F, Inoue T, Kimura M, Nishino K, Kumagai T.A long-term survivor of non-small-cell lung cancer harboring concomitant EGFR mutation and ALK translocation. Respir Med Case Rep 2016; 19: 137-139

[31] Christopoulos P, Kirchner M, Bozorgmehr F.et al.Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma. Int J Cancer 2019; 144[phone]

[32] Yoneshima Y, Ijichi K, Anai S.et al.PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer 2018; 118: 36-40

[33] Kim SJ, Kim S, Kim DW.et al.Alterations in PD-L1 expression associated with acquisition of resistance to ALK inhibitors in ALK-rearranged lung cancer. Cancer Res Treat 2019; 51[phone]

[34] Yang CY, Liao WY, Ho CC.et al.Association of programmed death-ligand 1 expression with fusion variants and clinical outcomes in patients with anaplastic lymphoma kinase-positive lung adenocarcinoma receiving crizotinib. Oncologist 2020; 25[phone]

[35] Li M, Hou X, Chen J.et al.ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061). Lung Cancer 2022; 165: 54-62

[36] Zhou Y, Song L, Xu Q.et al.Investigation on the survival implications of PD-L1 expression status in ALK- rearranged advanced non-small cell lung cancer treated with first-line crizotinib. Lung Cancer 2022; 167: 58-64

[37] Chang GC, Yang TY, Chen KC.et al.ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep 2020; 10(01) 21063

[38] Tian X, Li Y, Huang Q, Zeng H, Wei Q, Tian P.High PD-L1 expression correlates with an immunosuppressive tumour immune microenvironment and worse prognosis in ALK-rearranged non-small cell lung cancer. Biomolecules 2023; 13(06) 991

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Global Medical Genetics