{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:16:59Z","timestamp":1783523819138,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) exhibits genomic heterogeneity that affects tumor immunogenicity and PD-L1 expression. Patient clustering based on shared mutational profiles using social network analysis (SNA) has been narrowly explored. The study aimed to identify subgroups of NSCLC patients with similar somatic mutation profiles using network-based modularity clustering, and to compare these groups with respect to PD-L1 expression, Tumor mutation burden (TMB), and clinical variables. Data of patients with stage 4 (metastatic) NSCLC, whose tumor tissue samples were collected between 2022 and 2024, were analyzed. This retrospective study included NSCLC patients harboring actionable driver mutations in genes such as EGFR, KRAS, ALK, BRAF, MET. A social network of 129 patients was constructed. Two distinct genomic clusters were identified. Cluster 2 (n = 55) showed a higher prevalence of KRAS, TP53, BRAF, STK11 and additional mutations, while cluster 1 (n = 74) displayed a limited number of driver mutations. Cluster 2 had significantly higher PD-L1 expression (29.8% vs. 13.7%, p = 0.001) and higher TMB (7.8 vs. 5.8, p = 0.021). In multivariate logistic regression, both PD-L1 and TMB were associated with cluster assignment (p &lt; 0.05). Mutation-based SNA clustering delineated two biologically distinct subgroups of NSCLC patients. The highly mutated cluster displayed higher PD-L1 expression and TMB, a profile consistent with a more immunogenic phenotype. This method offers a novel integrative approach that requires prospective validation before clinical implementation.<\/jats:p>","DOI":"10.3390\/life16071071","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:54:42Z","timestamp":1782694482000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Social Network Clustering Analysis for Detection of Associated Genetic Co-Mutations in Patients with Actionable Driver Mutations in NSCLC"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-2959","authenticated-orcid":false,"given":"Abed","family":"Agbarya","sequence":"first","affiliation":[{"name":"The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel"},{"name":"Department of Oncology, Bnai-Zion Medical Center, Haifa 3339419, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitham","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"The Joseph Fishman Oncology Center, Rambam Medical Center, Haifa 3525409, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Mhameed","sequence":"additional","affiliation":[{"name":"The Joseph Fishman Oncology Center, Rambam Medical Center, Haifa 3525409, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmond","family":"Sabo","sequence":"additional","affiliation":[{"name":"Pathology Institute, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7570-4550","authenticated-orcid":false,"given":"Walid","family":"Shalata","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 8457108, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esti","family":"Liani","sequence":"additional","affiliation":[{"name":"Pathology Institute, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salam","family":"Mazareb","sequence":"additional","affiliation":[{"name":"Pathology Institute, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Sheikh-Ahmad","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, Bnai-Zion Medical Center, Haifa 3339419, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5771-6569","authenticated-orcid":false,"given":"Leonard","family":"Saiegh","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, Bnai-Zion Medical Center, Haifa 3339419, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Radonjic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Dentistry, Palacky University, Hnevotinska Street 3, 77515 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Sebek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska Street 3, 77515 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4558-4858","authenticated-orcid":false,"given":"Dan","family":"Levy-Faber","sequence":"additional","affiliation":[{"name":"The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel"},{"name":"Department of Cardiothoracic Surgery, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.3390\/targets2030014","article-title":"Novel Combination of Therapeutic Approaches in Advanced NSCLC with EGFR Activating Mutations","volume":"2","author":"Rocco","year":"2024","journal-title":"Targets"},{"key":"ref_2","unstructured":"American Cancer Society (2025, October 02). Lung Cancer Survival Rates, by Stage. Available online: https:\/\/www.cancer.org\/cancer\/types\/lung-cancer\/detection-diagnosis-staging\/survival-rates.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.molmed.2023.03.007","article-title":"Cancer driver mutations: Predictions and reality","volume":"29","author":"Ostroverkhova","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Vicidomini, G. (2023). Current Challenges and Future Advances in Lung Cancer: Genetics, Instrumental Diagnosis and Treatment. Cancers, 15.","DOI":"10.3390\/cancers15143710"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"217","DOI":"10.5306\/wjco.v12.i4.217","article-title":"Oncogenic driver mutations in non-small cell lung cancer: Past, present and future","volume":"12","author":"Chevallier","year":"2021","journal-title":"World J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or carboplatin\u2013paclitaxel in pulmonary adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12943-023-01740-y","article-title":"Lung cancer immunotherapy: Progress, pitfalls, and promises","volume":"22","author":"Lahiri","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1\u2013positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ccell.2018.04.001","article-title":"Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"To, K.K.W., Fong, W., and Cho, W.C.S. (2021). Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.635007"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/2159-8290.CD-18-0099","article-title":"STK11\/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1111\/1759-7714.15336","article-title":"PD-L1 expression in patients with non-small-cell lung cancer is associated with sex and genetic alterations: A retrospective study within the Caucasian population","volume":"15","author":"Sarova","year":"2024","journal-title":"Thorac. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.jtho.2016.10.007","article-title":"Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis","volume":"12","author":"Lee","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.asjsur.2021.06.030","article-title":"A retrospective analysis of eleven gene mutations, PD-L1 expression and characteristics in non-small cell lung cancer patients","volume":"45","author":"Liu","year":"2022","journal-title":"Asian J. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41419-024-06563-3","article-title":"KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC","volume":"15","author":"Li","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s12672-025-02089-y","article-title":"The role of PD-L1 in EGFR-mutant non-small cell lung cancer","volume":"16","author":"Gao","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.lungcan.2018.09.010","article-title":"Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer","volume":"125","author":"Liu","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/1759-7714.15244","article-title":"Association of PD-L1 expression with driver gene mutations and clinicopathological characteristics in non-small cell lung cancer: A real-world study of 10441 patients","volume":"15","author":"Ruiz","year":"2024","journal-title":"Thorac. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Khalil, M., and Tsao, M.-S. (2025). Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1\/PD-L1 Inhibitors in Non-Small Cell Lung Cancer. Cancers, 17.","DOI":"10.3390\/cancers17132199"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chu, C.-H., Huang, Y.-H., Lee, P.-H., Hsu, K.-H., Chen, K.-C., Su, K.-Y., Yu, S.-L., Tseng, J.-S., Yang, T.-Y., and Chang, G.-C. (2022). Various impacts of driver mutations on the PD-L1 expression of NSCLC. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0273207"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, Y., Wang, P., Lian, R., Yuan, M., Yu, P., He, H., Chen, P., Zhou, H., Chen, W., and Zhang, D. (2025). Comprehensive characterization of PD-L1 expression and immunotherapy-related genomic biomarkers in early- versus advanced-stage non-small cell lung cancer. BMC Pulm. Med., 25.","DOI":"10.1186\/s12890-025-03687-w"},{"key":"ref_22","first-page":"54","article-title":"Prognostic value of KRAS mutations, TP53 mutations and PD-L1 expression among lung adenocarcinomas treated with immunotherapy","volume":"77","author":"Stougaard","year":"2023","journal-title":"J. Clin. Pathol."},{"key":"ref_23","first-page":"100767","article-title":"The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy","volume":"37","author":"Routy","year":"2023","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dan, A., Burtavel, L.-M., Coman, M.-C., Focsa, I.-O., Duta-Ion, S., Juganaru, I.-R., Zaruha, A.-G., Codreanu, P.-C., Strugari, I.-M., and Hotinceanu, I.-A. (2024). Genetic Blueprints in Lung Cancer: Foundations for Targeted Therapies. Cancers, 16.","DOI":"10.20944\/preprints202410.2445.v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e078872","DOI":"10.1136\/bmjopen-2023-078872","article-title":"Use of social network analysis in health research: A scoping review protocol","volume":"14","author":"Grewal","year":"2024","journal-title":"BMJ Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Agbarya, A., Shalata, W., Sabo, E., Saiegh, L., Shaham, Y., Nasrallah, H., Mhameed, K., Mazareb, S., Sheikh-Ahmad, M., and Faber, D.L. (2026). Investigation of the Prevalence of Associated Genetic Mutations (Co-Mutations) in Patients with Actionable Driver Mutations in Lung Cancer: A Retrospective Study. Diagnostics, 16.","DOI":"10.20944\/preprints202602.0780.v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities in large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9585614","DOI":"10.1155\/2018\/9585614","article-title":"Immunotherapies: Exploiting the Immune System for Cancer Treatment","volume":"2018","author":"Koury","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107308","DOI":"10.1016\/j.lungcan.2023.107308","article-title":"Gene-network analysis predicts clinical response to immunotherapy in patients affected by NSCLC","volume":"183","author":"Cucchiara","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/jcmm.12722","article-title":"Gene mutation-based and specific therapies in precision medicine","volume":"20","author":"Wang","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1097\/CM9.0000000000001455","article-title":"Co-mutations in tumor immune microenvironment and immunotherapy","volume":"134","author":"Ma","year":"2021","journal-title":"Chin. Med. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17588359211006950","DOI":"10.1177\/17588359211006950","article-title":"KRAS\/LKB1 and KRAS\/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas","volume":"13","author":"Gu","year":"2021","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.annonc.2024.06.014","article-title":"Interpatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer","volume":"35","author":"Alden","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jiang, L., Yu, H., Ness, S., Mao, P., Guo, F., Tang, J., and Guo, Y. (2022). Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis. Cancers, 14.","DOI":"10.3390\/cancers14020415"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12742","DOI":"10.1038\/s41598-023-39608-2","article-title":"Mutational landscape of cancer-driver genes across human cancers","volume":"13","author":"Sinkala","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e126908","DOI":"10.1172\/jci.insight.126908","article-title":"PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers","volume":"4","author":"Yarchoan","year":"2019","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/nmeth.2651","article-title":"Network-based stratification of tumor mutations","volume":"10","author":"Hofree","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e70090","DOI":"10.1002\/cncy.70090","article-title":"Unraveling the nexus: Tumor mutational burden, PD-L1 expression, and oncogenic alterations in non-small cell lung cancer cytology specimens","volume":"134","author":"Dai","year":"2026","journal-title":"Cancer Cytopathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1007\/s12539-025-00699-2","article-title":"Deep Clustering-Based Metabolic Stratification of Non-Small Cell Lung Cancer Patients Through Integration of Somatic Mutation Profile and Network Propagation Algorithm","volume":"17","author":"Luo","year":"2025","journal-title":"Interdiscip. Sci. Comput. Life Sci."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T14:37:32Z","timestamp":1783521452000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["life16071071"],"URL":"https:\/\/doi.org\/10.3390\/life16071071","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}