Improving CT scan for lung cancer diagnosis with an integromic signature
Lung cancer is the leading cause of cancer-related mortality globally, making early detection crucial for reducing death rates. Low-dose computed tomography (LDCT) screening helps detect lung cancer early but often identifies indeterminate pulmonary nodules (PNs), leading to potential overtreatment. This study aimed to develop a diagnostic test that accurately differentiates malignant from benign PNs detected on LDCT scans by analyzing non-coding RNAs, DNA methylation, and bacterial DNA in patient samples. Using droplet digital polymerase chain reaction, we analyzed samples from a training set of 150 patients with malignant PNs and 250 smokers with benign PNs. Individual biomarkers in plasma and sputum showed moderate effectiveness, with sensitivities ranging from 62% to 77% and specificities from 54% to 87%. We developed an integromic signature by combining two plasma biomarkers and one sputum biomarker, along with additional clinical data, which demonstrated a sensitivity of 90% and specificity of 95%. The signature’s diagnostic performance was further validated in a cohort consisting of 30 patients with malignant PNs and 50 smokers with benign PNs. The integromic signature showed high sensitivity and specificity in distinguishing malignant from benign PNs identified through LDCT. This tool has the potential to significantly lower both mortality and health-care costs associated with the overtreatment of benign nodules, offering a promising approach to improving lung cancer screening protocols.
- Rashidi A, Kao R, Echeverria R, Sadigh G. Lung cancer screening updates: Impact of 2023 American Cancer Society’s guidelines for lung cancer screening. Clin Imaging. 2024;13:110229. doi: 10.1016/j.clinimag.2024.110229
- Wolf AMD, Oeffinger KC, Shih TYC, et al. Screening for lung cancer: 2023 guideline update from the American Cancer Society. CA Cancer J Clin. 2024;74:50-81. doi: 10.3322/caac.21811
- Aberle DR, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. doi: 10.1056/NEJMoa1911793
- Bonney A, Malouf R, Marchal C, et al. Impact of low-dose computed tomography (LDCT) screening on lung cancer-related mortality. Cochrane Database Syst Rev. 2022;8:CD013829. doi: 10.1002/14651858.CD013829.pub2
- Oudkerk M, Liu S, Heuvelmans MA, Walter JE, Field JK. Lung cancer LDCT screening and mortality reduction - evidence, pitfalls and future perspectives. Nat Rev Clin Oncol. 2021;18:135-151. doi: 10.1038/s41571-020-00432-6
- Reich JM. Estimated impact of LDCT-identified stage IA non-small-cell lung cancer on screening efficacy. Lung Cancer. 2006;52:265-271. doi: 10.1016/j.lungcan.2006.02.007
- McKee BJ, Regis SM, McKee AB, Flacke S, Wald C. Performance of ACR lung-RADS in a clinical CT lung screening program. J Am Coll Radiol. 2016;13:R25-R29.
- Su Y, Fang H, Jiang F. Integrating DNA methylation and microRNA biomarkers in sputum for lung cancer detection. Clin Epigenetics. 2016;8:109. doi: 10.1186/s13148-016-0275-5
- Zhou H, Liao J, Leng Q, Chinthalapally M, Dhilipkannah P, Jiang F. Circulating bacterial DNA as plasma biomarkers for lung cancer early detection. Microorganisms. 2023;11:582. doi: 10.3390/microorganisms11030582
- Gould MK, Ananth L, Barnett PG. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131:383-388. doi: 10.1378/chest.06-1261
- Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med. 1997;157:849-855.
- Feng Z, Pepe MS. Adding rigor to biomarker evaluations- EDRN experience. Cancer Epidemiol Biomarkers Prev. 2020;29:2575-2582. doi: 10.1158/1055-9965.EPI-20-0240
- McWilliams A, Tammemagi MC, Mayo RC, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013;369:910-919. doi: 10.1056/NEJMoa1214726
- Schultz EM, Sanders GD, Trotter PR, et al. Validation of two models to estimate the probability of malignancy in patients with solitary pulmonary nodules. Thorax. 2008;63:335-341. doi: 10.1136/thx.2007.084731
- Liang G, Li G, Wang Y, Lei W, Xiao Z. Aberrant miRNA expression response to UV irradiation in human liver cancer cells. Mol Med Rep. 2014;9:904-910. doi: 10.3892/mmr.2014.1901
- Lu LG, Zhang GM. Serum miR-205-5p level for non-small-cell lung cancer diagnosis. Thorac Cancer. 2022;13:1102-1103. doi: 10.1111/1759-7714.14356
- Zhao YL, Zhang JX, Yang JJ, et al. MiR-205-5p promotes lung cancer progression and is valuable for the diagnosis of lung cancer. Thorac Cancer. 2022;13:832-843. doi: 10.1111/1759-7714.14331
- Xu LB, Xiong J, Zhang YH, et al. miR2053p promotes lung cancer progression by targeting APBB2. Mol Med Rep. 2021;24:588. doi: 10.3892/mmr.2021.12227
- Zhu H, Xu Y, Li M, Chen Z. Inhibition sequence of miR-205 hinders the cell proliferation and migration of lung cancer cells by regulating PETN-mediated PI3K/AKT signal pathway. Mol Biotechnol. 2021;63:587-594. doi: 10.1007/s12033-021-00321-y
- Chen Q, Zhang H, Zhang J, et al. miR-210-3p promotes lung cancer development and progression by modulating USF1 and PCGF3. Onco Targets Ther. 2021;14:3687-3700. doi: 10.2147/OTT.S288788
- Eilertsen M, Andersen S, Al-Saad S, et al. Positive prognostic impact of miR-210 in non-small cell lung cancer. Lung Cancer. 2014;83:272-278. doi: 10.1016/j.lungcan.2013.11.005
- Puissegur MP, Mazure NM, Bertero T, et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2011;18:465-478. doi: 10.1038/cdd.2010.119
- Hisakane K, Seike M, Sugano T, et al. Exosome-derived miR-210 involved in resistance to osimertinib and epithelial-mesenchymal transition in EGFR mutant non-small cell lung cancer cells. Thorac Cancer. 2021;12:1690-1698. doi: 10.1111/1759-7714.13943
- Wang L, He J, Hu H, et al. Lung CSC-derived exosomal miR-210-3p contributes to a pro-metastatic phenotype in lung cancer by targeting FGFRL1. J Cell Mol Med. 2020;24: 6324-6339. doi: 10.1111/jcmm.15274
- Grosso S, Doyen J, Parks SK, et al. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013;4:e544. doi: 10.1038/cddis.2013.71
- Wang H, Bian S, Yang CS. Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1alpha. Carcinogenesis. 2011;32:1881-1889. doi: 10.1093/carcin/bgr218
- Xu W, Ye J, Cao Z, Zhao Y, Zhu Y, Li L. Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy. Heliyon. 2024;10:e32357. doi: 10.1016/j.heliyon.2024.e32357
- Bai Y, Wang Y, Qin J, et al. Systematic pan-cancer analysis identified RASSF1 as an immunological and prognostic biomarker and validated in lung cancer. Heliyon. 2024;10:e33304. doi: 10.1016/j.heliyon.2024.e33304
- Mashayekhi M, Asadi M, Hashemzadeh S, et al. Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients. Horm Mol Biol Clin Investig. 2023;44:145-152. doi: 10.1515/hmbci-2022-0007
- Walter RFH, Rozynek P, Casjens S, et al. Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer. PLoS One. 2018;13:e0195716. doi: 10.1371/journal.pone.0195716
- Xiao G, Zhang T, Yao J, Ren J, Cao W, Wu G. The association between RASSF1 gene polymorphisms and lung cancer susceptibility among people in Hubei Province of China. J Huazhong Univ Sci Technolog Med Sci. 2009;29:646-649. doi: 10.1007/s11596-009-0522-5
- Buckingham L, Faber LP, Kim A, et al. PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients. Int J Cancer. 2010;126:1630-1639. doi: 10.1002/ijc.24896
- Hridoy HM, Hossain MP, Ali MH, et al. Alocasia macrorrhiza rhizome lectin inhibits growth of pathogenic bacteria and human lung cancer cell in vitro and Ehrlich ascites carcinoma Zcell in vivo in mice. Protein Expr Purif. 2024;219:106484. doi: 10.1016/j.pep.2024.106484
- Wang W, Liang X, Kong H, et al. Correlation analysis of lung mucosa-colonizing bacteria with clinical features reveals metastasis-associated bacterial community structure in non-small cell lung cancer patients. Respir Res. 2023;24:129. doi: 10.1186/s12931-023-02420-7
- Shi H, Chen L, Liu Y, et al. Bacteria-driven tumor microenvironment-sensitive nanoparticles targeting hypoxic regions enhances the chemotherapy outcome of lung cancer. Int J Nanomedicine. 2023;18:1299-1315. doi: 10.2147/IJN.S396863
- Wong-Rolle A, Dong Q, Zhu Y, et al. Spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a distinct oncogenic signature. J Immunother Cancer. 2022;10:e004698. doi: 10.1136/jitc-2022-004698
- Qian X, Zhang HY, Li QL, et al. Integrated microbiome, metabolome, and proteome analysis identifies a novel interplay among commensal bacteria, metabolites and candidate targets in non-small cell lung cancer. Clin Transl Med. 2022;12:e947. doi: 10.1002/ctm2.947
- Chen Y, Wen F, Chen H, et al. Analysis of the pathogenic bacteria, drug resistance, and risk factors of postoperative infection in patients with non-small cell lung cancer. Ann Palliat Med. 2021;10:10005-10012. doi: 10.21037/apm-21-2364
- Liu H, Liu B, Zheng F, Chen X, Ye L, He Y. Distribution of pathogenic bacteria in lower respiratory tract infection in lung cancer patients after chemotherapy and analysis of integron resistance genes in respiratory tract isolates of uninfected patients. J Thorac Dis. 2020;12:4216-4223. doi: 10.21037/jtd-20-928
- Gui Q, Li H, Wang A, et al. The association between gut butyrate-producing bacteria and non-small-cell lung cancer. J Clin Lab Anal. 2020;34:e23318. doi: 10.1002/jcla.23318
- Sun M, Bai Y, Zhao S, et al. Gram-negative bacteria facilitate tumor progression through TLR4/IL-33 pathway in patients with non-small-cell lung cancer. Oncotarget. 2018;9:13462-13473. doi: 10.18632/oncotarget.24008
- Liu J, Wu Q, Li L, et al. Discovery of phylloseptins that defense against gram-positive bacteria and inhibit the proliferation of the non-small cell lung cancer cell line, from the skin secretions of Phyllomedusa frogs. Molecules. 2017;22:1428. doi: 10.3390/molecules22091428
- Ye M, Gu X, Han Y, Jin M, Ren T. Gram-negative bacteria facilitate tumor outgrowth and metastasis by promoting lipid synthesis in lung cancer patients. J Thorac Dis. 2016;8: 1943-1955. doi: 10.21037/jtd.2016.06.47
- Chow SC, Gowing SD, Cools-Lartigue JJ, et al. Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation. Int J Cancer. 2015;136:1341-1350. doi: 10.1002/ijc.29111
- Li N, Zhou H, Holden VK, et al. Streptococcus pneumoniae promotes lung cancer development and progression. iScience. 2023;26:105923. doi: 10.1016/j.isci.2022.105923
- Leng Q, Holden VK, Deepak J, Todd NW, Jiang F. Microbiota biomarkers for lung cancer. Diagnostics (Basel). 2021;11:407. doi: 10.3390/diagnostics11030407