{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:57:48Z","timestamp":1786118268493,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tumor mutational burden (TMB) summarizes the number of nonsilent mutations in a tumor but does not show whether these alterations cluster within a small set of pathways or extend across several oncogenic programs. To address this distinction, we developed a 10-pathway burden (10-PB) framework and defined the 10-PB score as the number of altered canonical oncogenic pathways per tumor. We then evaluated whether this mutation-based measure of pathway breadth provides information complementary to TMB in non-small cell lung cancer (NSCLC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Nonsilent mutations were mapped to 10 canonical oncogenic pathways to construct the 10-PB score. We first described pathway-level alteration patterns and then examined associations of 10-PB with survival and treatment response. Its incremental value relative to TMB was assessed using multivariable models, likelihood-ratio tests, and Akaike information criterion. Bootstrap resampling, continuous-risk analyses, and leave-one-pathway-out models were used to evaluate the stability and endpoint-specific structure of the findings. External MSK-based cohorts were used for validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Most tumors showed alterations in 2\u20134 pathways, indicating that multi-pathway involvement is common in NSCLC. LUAD and LUSC showed distinct pathway-level profiles. Higher 10-PB was associated with shorter overall survival and progression-free survival after adjustment for clinicopathologic factors and TMB. Model comparisons suggested that 10-PB adds prognostic information to TMB-based models. In the treatment-response analysis, higher 10-PB showed an exploratory association with unfavorable response. Leave-one-pathway-out analyses suggested endpoint-specific patterns, with NOTCH more closely associated with progression-free survival and adverse response, and TGF-\u03b2 and PI3K more closely associated with overall survival. External cohorts showed broadly consistent results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The 10-PB framework extends mutation-based assessment of NSCLC by describing how broadly nonsilent mutations involve canonical oncogenic pathways. This pathway-breadth measure complements TMB and may help refine prognosis-oriented stratification, while its treatment-response associations should be viewed as exploratory. Prospective validation and integration with functional pathway-activity data are needed before clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1882870","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T15:38:11Z","timestamp":1786030691000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A 10-pathway burden score complements tumor mutational burden for outcome stratification in non-small cell lung cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Feng","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingquan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of 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