{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:09:20Z","timestamp":1788952160282,"version":"build-2803163510"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brain metastasis is a major cause of mortality in lung cancer, particularly in small-cell lung cancer (SCLC). Whether genetic susceptibility to lung cancer is associated with brain structural and functional traits relevant to metastatic vulnerability remains unclear. We investigated subtype-specific genetic associations with brain imaging phenotypes and explored the biological context of the SCLC-associated white-matter signal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bidirectional two-sample Mendelian randomization (MR) was performed using European genome-wide association study summary statistics for three lung cancer subtypes, 3,935 structural MRI phenotypes, and 191 resting-state functional MRI traits. MR findings were evaluated using genetic-correlation and sensitivity analyses. Public single-cell and spatial transcriptomic datasets from brain metastases, computational ligand-receptor inference, and virtual perturbation modeling were used to explore the SCLC-related findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SCLC genetic liability showed the clearest white-matter-related pattern, involving the superior cerebellar peduncle and cerebellar-related functional connectivity, whereas lung squamous cell carcinoma was mainly associated with frontal and parietal traits. Single-cell analysis identified mature-like, intermediate, and reactive-like oligodendrocyte states. Reactive-like cells exhibited reduced myelination-associated genes and enhanced stress-response programs. Computational analyses prioritized an FN1-associated tumor-oligodendrocyte interaction program, with neuronal-like malignant SCLC cells as the major predicted sender population. Cross-dataset, spatial, and virtual perturbation analyses provided additional exploratory support for tumor-derived FN1 as a candidate niche-organizing signal associated with reactive oligodendrocyte remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Lung cancer subtypes show distinct genetic associations with brain phenotypes. The SCLC findings and exploratory multi-omics analyses support an FN1-centered tumor-oligodendrocyte model that warrants experimental validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1890325","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:13:01Z","timestamp":1788948781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic associations link lung cancer liability to brain imaging phenotypes and nominate an FN1-associated tumor\u2013oligodendrocyte program in small-cell lung cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Kai","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Department of Thoracic Surgery, China Japan Friendship Hospital","place":["Beijing, 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