Why are some blood cancers up to ten times more common in Western populations than in Han Chinese?

A new study from Clinical Cancer Bulletin suggests the answer may lie not in lifestyle or environment alone, but in the very structure of the brain.

The study published in Clinical Cancer Bulletin by Professor Peng Liu and colleagues from Zhongshan Hospital, Fudan University provides the first genetically informed evidence that specific features of the human cerebral cortex—namely, the surface area of the pars triangularis and the thickness of two frontal regions—are causally linked to multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL), respectively.

“The brain is the most complex organ, and its role in extracerebral tumours has been largely overlooked,” said Professor Liu.

“We found that European/American populations have a significantly larger pars triangularis surface area and greater rostral anterior cingulate and rostral middle frontal thickness compared with Han Chinese individuals—and these very same traits are genetically associated with higher risks of MM and CLL.”

The team used Mendelian randomization (MR), drawing on large-scale datasets from the ENIGMA3, CHIMGEN, and FinnGen cohorts.

The analysis revealed that:

(1) A one‑standard‑deviation increase in pars triangularis surface area was associated with a significantly higher risk of MM (OR=1.0035, P=0.01846).

(2) Greater rostral anterior cingulate thickness and rostral middle frontal thickness were each linked to increased CLL risk (OR=519.12 and 19662, respectively; both P<0.05).

These associations withstood rigorous sensitivity tests, including MR‑PRESSO for pleiotropy, Steiger directionality tests, and weak‑instrument diagnostics.

Critically, the researchers observed that the same cortical structures that predict cancer risk also differ markedly between ancestries.

Bootstrapped allele frequency analyses of cortex‑associated SNPs showed that European/American populations carry genetic variants favouring larger pars triangularis surface area and thicker frontal cortices—differences the study had sufficient statistical power to detect (mean power 97.88%).

This “neuro‑hematologic axis” hypothesis shifts the focus of cancer disparities from purely peripheral or environmental explanations to one that may involve central nervous system biology.

To explore potential mechanisms, the team conducted pathway analyses and a transcriptome‑wide association study (TWAS).

The pathways enriched for MM‑associated cortical loci included T‑cell regulation, DNA damage response , among others.

CLL‑associated cortical loci were enriched in lymphocyte function, ECM organisation, RAS/ERK signalling, among others.

The TWAS identified shared regulatory genes between cortical traits and blood cancers.

Notably, TTC37 was common to both CLL-associated cortical regions.

Additionally, LAMC1, TM2D2, CTNNAL1, OR7E14P, ST5, and L3HYPDH were found to link pars triangularis surface area to MM.

“These findings do not prove direct biological causation—yet,” Professor Liu cautioned.

“But they offer a testable, genetically grounded hypothesis: that inherited differences in brain architecture may contribute to population‑level disparities in specific hematologic malignancies.”

The study opens several promising research avenues, including trans‑ancestry MR with harmonised instruments, neuroimaging comparisons of healthy individuals from high‑ versus low‑incidence populations, and experimental models probing how cortical regions modulate systemic B‑cell or plasma cell function.

For now, the message is clear: when it comes to cancer risk, the brain may be more than a bystander—and the roots of well‑known health disparities may reach much deeper than previously thought.

Source: Editorial Office and Clinical Cancer Bulletin