CT Scans Reveal Hidden Tumour Chaos That May Signal KRAS Mutations in Lung Cancer

Every tumour is not one thing. Under the microscope, a lung cancer is a patchwork of genetically distinct cell populations competing for space and resources, and that internal chaos — known as intratumoural heterogeneity — has long been suspected of leaving fingerprints on medical images. A new exploratory study published in BMC Medical Imaging by Lihao Wu, Xiang Liu, Yongjie Zhou and colleagues at Nanchang University and collaborating institutions now reports that a measure of spatial heterogeneity extracted from routine computed tomography scans is strongly associated with KRAS mutation status in lung adenocarcinoma, one of the most common and lethal human cancers. But the researchers are equally candid about what their data do not show: the heterogeneity signal may largely ride along with tumour size, and it added no measurable predictive power beyond simpler clinical and volume-based models.

The finding matters because KRAS, once considered undruggable, is now one of the most consequential genes in lung oncology. Mutations in this gene define a distinct biological subtype of non-small cell lung cancer with specific treatment implications, and knowing a tumour’s KRAS status before tissue sampling or molecular testing could, in principle, sharpen clinical decision-making. Molecular profiling currently requires biopsy material or liquid biopsy assays, which take time and are not always available. If a non-invasive imaging signature could reliably hint at mutation status, it could help prioritise patients for targeted testing or clinical trial enrolment. The new study tests that idea with unusual statistical rigour for an exploratory radiomics analysis, and its results are a masterclass in why that rigour matters.

The team assembled a retrospective, single-centre cohort of 271 candidate records that had been intentionally enriched for KRAS-positive tumours. After a final eligibility review excluded 71 patients, 200 patients remained: 101 with KRAS-mutant lung adenocarcinomas and 99 with KRAS-wildtype tumours. The cohort was split 140 for training and 60 for internal testing, and the researchers deliberately preserved that original partition without re-partitioning, a choice that guards against the subtle optimism that creeps in when datasets are repeatedly reshuffled until a model looks good. The near-even balance of mutant and wildtype tumours was by design, since a KRAS-enriched cohort gives far more statistical power to detect mutation-associated imaging features than the roughly one-in-four prevalence seen in unselected populations.

The core of the analysis is a quantity the authors call the ITHscore, computed in both two-dimensional and three-dimensional versions from CT images. Radiomics approaches like this one convert the grayscale texture of a tumour on a scan into quantitative descriptors: regions of viable tissue, necrosis, mucin, haemorrhage and varying cell density all attenuate X-rays differently, and spatial variation in those attenuation patterns can be summarised mathematically. The intuition is straightforward. A tumour whose cells are genetically diverse tends to be physically diverse too, and that physical diversity — uneven density, irregular internal structure, heterogeneous enhancement — is exactly what CT is built to detect. The researchers asked whether the spatial arrangement of these patterns, not just their average intensity, differed between KRAS-mutant and KRAS-wildtype tumours.

The headline association was striking. Tumour volume correlated strongly with both ITH scores, with Spearman correlation coefficients of 0.658 for the 2D score and 0.679 for the 3D score — meaning bigger tumours were substantially more heterogeneous on imaging, which is biologically plausible since larger lesions have had more time to evolve subclones. After adjusting for log2-transformed tumour volume, T category, age, sex and smoking history in logistic regression models, each standard deviation increase in the 2D ITHscore was associated with 3.84-fold higher odds of harbouring a KRAS mutation (95% confidence interval, 2.23 to 6.59), while the 3D score yielded an odds ratio of 3.45 (95% CI, 1.98 to 6.00). Those are large effects for an imaging biomarker, and they held in both 2D and 3D formulations.

But the authors then did something that many radiomics studies skip: they stress-tested the association against the possibility that it was simply a proxy for tumour burden. Because ITH scores rise with volume, and volume itself differs systematically between KRAS-mutant and wildtype tumours, any apparent independence could be an artefact of comparing big heterogeneous tumours with small homogeneous ones. When the analysis was restricted to the overlapping tumour-volume range — 102 patients whose tumours fell within sizes shared by both mutation groups — the odds ratios attenuated to 2.39 (95% CI, 1.14 to 5.00) for the 2D score and 2.28 (95% CI, 0.999 to 5.22) for the 3D score. The association weakened but did not vanish, leaving the question genuinely open.

A second sensitivity analysis used overlap weighting, a statistical technique that reweights patients so that the modelled covariates are balanced between mutation groups, achieving absolute standardised mean differences below 0.001 — essentially perfect balance on the measured variables. Under this weighting, the odds ratios were 3.94 (95% CI, 2.53 to 10.91) for the 2D score and 3.07 (95% CI, 1.96 to 6.57) for the 3D score, stronger than in the restricted analysis. The authors interpret this carefully: attenuation occurred in one analysis but not the other, so independence from measured tumour burden was neither confirmed nor excluded. They also note that the restricted cohorts were not matched, and residual imbalance in sex and smoking history persisted in that subset — a reminder that even careful subgroup analyses carry their own confounders.

The predictive question got an equally sober answer. The team fitted six logistic-regression reference models in the training cohort and compared them in the internal-test partition using paired bootstrap confidence intervals, which account for the fact that the same patients are being scored by competing models. A clinical-plus-volume model achieved an area under the receiver operating characteristic curve of 0.844 (95% CI, 0.726 to 0.941) — respectable discrimination. Adding both ITH scores actually nudged performance down slightly, to 0.833 (95% CI, 0.725 to 0.925), with a paired difference in AUC of −0.011 (95% CI, −0.099 to 0.077), a change indistinguishable from zero. In plain terms, the heterogeneity scores carried no incremental information about KRAS status once tumour size and basic clinical variables were known.

This pattern — a robust association that fails to translate into added predictive value — is increasingly recognised as a signature of confounding by tumour burden in radiomics research. Heterogeneous imaging features often simply flag larger, more advanced tumours, and any molecular association they show can dissolve once size and stage are properly accounted for. What makes this study notable is that the authors report that dissolution themselves rather than burying it. Their conclusions state plainly that the findings do not establish molecular specificity or clinical utility, and that validation in representative external cohorts is required. In a field where single-centre radiomics models are frequently oversold, that restraint is itself a kind of scientific signal.

The study, approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University and funded in part by the National Natural Science Foundation of China, arrives at a moment when the radiomics community is reckoning with reproducibility. Its lessons are twofold. First, CT-derived spatial heterogeneity is genuinely and strongly linked to KRAS mutation biology in lung adenocarcinoma, an observation that may illuminate tumour evolution even if it does not yet serve as a diagnostic shortcut. Second, the path from association to clinical tool runs through exactly the kind of adversarial statistics this team deployed — volume restriction, overlap weighting, paired bootstrap comparison — and through external validation in cohorts that reflect real-world KRAS prevalence rather than deliberately enriched samples. Until that work is done, the chaotic texture visible on a lung CT remains a compelling biological clue, but not yet a substitute for the molecular test.

Subject of Research: Association between CT-derived spatial intratumoural heterogeneity and KRAS mutation status in lung adenocarcinoma

Article Title: CT-derived spatial intratumoural heterogeneity and KRAS mutation status in a predominantly lung adenocarcinoma cohort: an exploratory study of association and incremental discrimination

Article References: Wu, L., Liu, X., Zhou, Y., Rao, Z., Su, R., Xu, F., Zhang, L., Peng, C., Li, H., Li, L., & Peng, D. (2026). CT-derived spatial intratumoural heterogeneity and KRAS mutation status in a predominantly lung adenocarcinoma cohort: an exploratory study of association and incremental discrimination. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02962-4

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02962-4

Keywords: lung adenocarcinoma, KRAS mutation, intratumoural heterogeneity, radiomics, CT imaging, tumour burden, non-small cell lung cancer, biomarker, machine learning, cancer imaging, molecular testing, CT-derived