For nearly a century, scientists have known that the nervous system can influence tumors that arise within the brain itself. Neurons feed glioma growth, sensory experience can reshape brain tumor biology, and nerves thread through many solid tumors, modulating their microenvironments. What has remained far murkier is whether the brain exerts any influence over cancers that develop entirely outside the central nervous system. A new study published in Clinical Cancer Bulletin now offers the first genetically informed evidence that the physical architecture of the cerebral cortex may be causally linked to the risk of specific blood cancers, and that inherited differences in brain structure between populations could help explain one of the most striking disparities in cancer epidemiology.

The research, led by Yue Wang, Wanjing Feng, Bei Xu, and Peng Liu of Zhongshan Hospital, Fudan University, and collaborating institutions, focused on hematologic malignancies, a group of cancers that arise from blood-forming cells and include multiple myeloma, chronic lymphocytic leukemia, and several lymphomas and leukemias. The team was drawn to a long-standing epidemiological puzzle: the incidence of multiple myeloma and chronic lymphocytic leukemia differs by more than eight to ten times between Han Chinese and European or American populations, with Western populations showing dramatically higher rates. Conventional explanations, including genetic background, environmental exposures, lifestyle, and differences in healthcare access, have never fully accounted for a gap of this magnitude.

To probe whether the brain might be part of the answer, the researchers turned to Mendelian randomization, a statistical technique that uses naturally occurring genetic variants as instruments to test whether an exposure causally influences an outcome. Because genetic variants are randomly assorted at conception, this approach largely sidesteps the confounding and reverse causation that plague observational studies. The team drew brain imaging genetics from the ENIGMA3 cohort, a meta-analysis of 51,665 participants of European and American ancestry who underwent magnetic resonance imaging, in which the cerebral cortex was parcellated into 34 regions per hemisphere using the Desikan-Killiany atlas, each measured for average thickness and surface area. Cancer outcome data came from the FinnGen database, version R9, comprising 377,277 individuals, including hundreds of patients with each of eight hematologic malignancies. Cross-ancestry comparisons relied on CHIMGEN, a cohort of 7,009 Han Chinese individuals that represents the largest available brain structural genetics resource for that population.

The results were striking in their specificity. Multiple myeloma showed a positive causal association with the surface area of the pars triangularis, a region of the inferior frontal gyrus involved in language processing. Chronic lymphocytic leukemia was positively associated with the average thickness of two regions: the rostral anterior cingulate and the rostral middle frontal cortex. The effect estimates, expressed per one standard deviation increase in the cortical measurement, were modest for myeloma but considerably larger for the leukemia associations, and the authors emphasize that even small per-unit effects could accumulate into meaningful population-level differences in incidence when the distributions of these cortical traits differ between ancestries. Diffuse large B-cell lymphoma was linked to the thickness of the lingual region, while the remaining five malignancies appeared to be influenced by combinations of surface area and thickness across multiple cortical regions, defying simple single-region summaries.

Rigorous sensitivity analyses bolstered the credibility of these findings. The MR-PRESSO global test found no evidence of horizontal pleiotropy, the phenomenon in which genetic variants influence the outcome through pathways unrelated to the exposure, which would otherwise invalidate causal inference. Steiger directionality tests confirmed that the genetic instruments explained more variance in the cortical traits than in the cancer outcomes, supporting the proposed direction of causation from brain structure to cancer risk rather than the reverse. MR-Egger regression intercepts were non-significant across all primary associations, arguing against systematic directional pleiotropy, and the weighted median estimator provided consistent estimates even under scenarios in which a substantial fraction of instruments might be invalid. All instrumental variables exceeded conventional thresholds for instrument strength, with mean F-statistics well above the critical value of ten.

The second half of the study addressed the ancestry question directly. Comparing allele frequency distributions of the instrumental variants between ENIGMA3 and CHIMGEN, the researchers found statistically significant differences at every locus examined for the cortical traits linked to myeloma and leukemia. Bootstrap resampling with 10,000 iterations established non-overlapping 95 percent confidence intervals for the frequency distributions, and a post-hoc power analysis confirmed that the smaller Chinese cohort had more than 97 percent mean power to detect these differences, ruling out false negatives due to limited sample size. Critically, European and American populations exhibited a larger pars triangularis surface area and greater thickness of the rostral anterior cingulate and rostral middle frontal regions than Han Chinese individuals, precisely the cortical features that the Mendelian randomization analysis had tied to elevated risk of the very cancers that are far more common in Western populations.

Functional analyses added biological texture to the statistical signal. Gene-based association testing with MAGMA and VEGAS2 revealed that the genetic loci associated with the myeloma-linked pars triangularis feature were significantly enriched in pathways involving T cell regulation, DNA damage response, lymphatic endothelial cell differentiation, chemokine signaling, and cell motility, and notably showed upregulation of curated myeloma gene sets. The leukemia-associated cortical traits were enriched in pathways governing lymphocyte function and differentiation, DNA splicing and mutation, regulation of proto-oncogenes and tumor suppressors, extracellular matrix organization, and RAS-ERK signaling. Because these pathway analyses were conducted genome-wide and independently of the Mendelian randomization results, they provide convergent, rather than circular, support for a connection between cortical biology and hematologic cancer.

A transcriptome-wide association study integrating the cortical genetics with GTEx v8 whole blood expression data sharpened the picture further. The analysis identified shared regulatory genes linking specific cortical traits to specific cancers, including LAMC1, a laminin gene involved in cell adhesion and migration; TM2D2, which modulates cell death and proliferation signaling; CTNNAL1, a participant in Rho-mediated cell migration and cytokinesis; and ST5, a tumor suppressor that regulates ERK kinase activity. Most intriguingly, TTC37, a gene implicated in B-cell function, emerged as a regulatory gene shared across all three traits relevant to chronic lymphocytic leukemia, hinting at a molecular bridge between cortical development and B-cell biology, the very cell lineage from which the leukemia arises.

The authors are careful to frame their conclusions appropriately. Genetically inferred causality, they stress, does not demonstrate a direct physical mechanism, and the intermediate pathways, whether neuroendocrine signaling, immune modulation, or autonomic regulation, remain unknown. The FinnGen outcome definitions excluded patients with coexisting primary tumors to maximize diagnostic specificity, and future work with broader case definitions will test generalizability. Cross-ancestry comparisons also carry inherent limitations, including differences in linkage disequilibrium patterns and environmental contexts. Yet the convergence of three independent lines of evidence, causal genetic estimates, population differences in cortex-associated alleles, and functional pathway overlap, supports what the team calls a neuro-hematologic axis hypothesis: that inherited variation in the architecture of specific cortical regions constitutes an underappreciated source of biological diversity influencing population-specific blood cancer risk. If validated through trans-ancestry replication, neuroimaging studies of healthy individuals across ancestries, and experimental models connecting these cortical regions to plasma cell and B-cell function, the finding could reframe cancer disparities research, shifting attention from purely peripheral explanations toward the surprising possibility that the disease spectrum differs between populations partly because the brains look different.

Subject of Research: Causal relationships between cerebral cortical architecture and hematologic malignancies across ancestries

Article Title: Causal relationships between cerebral cortical architecture and blood cancers: the disease spectrum is different because the brains look different

Article References: Wang, Y., Feng, W., Xu, B., & Liu, P. (2026). Causal relationships between cerebral cortical architecture and blood cancers: the disease spectrum is different because the brains look different. Clinical Cancer Bulletin, 5(1), Article 6. https://doi.org/10.1007/s44272-026-00058-2

Image Credits: AI Generated

DOI: 10.1007/s44272-026-00058-2

Keywords: cerebral cortex, hematologic malignancies, multiple myeloma, chronic lymphocytic leukemia, Mendelian randomization, cortical thickness, cortical surface area, ancestry differences, ENIGMA3, CHIMGEN, FinnGen, neuro-hematologic axis

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Tags: ancestry differencesBlood cancer racial disparitiesbrain architecture and hematologic malignanciesbrain cortex structure and cancer riskbrain-cancer connection across ancestriescerebral cortexCHIMGENchronic lymphocytic leukemiacortical surface areacortical thicknessENIGMA3FinnGengenetic factors in blood cancer epidemiologyhematologic malignanciesinherited brain structure differencesMendelian randomizationMultiple Myelomaneural influence on blood malignanciesneural microenvironment and tumor developmentneuro-hematologic axisneuro-oncology and blood cancer disparitiesneurological contributions to blood cancerpopulation-based genetic studies on cancer riskracial variations in brain morphology