Cybergenic
All findings

TP53 ⊥ KRAS

TP53 and KRAS mutual exclusivity in non-small cell lung cancer (MSK-CHORD)

Strengthened: held up under a stratified controlMutual exclusivity · Evidence: pattern across patients, not yet tested within subtypes

DataMSK-CHORD (2024) · Non-small cell lung cancer · 7,718 tumours · both altered in 692 (1,018 expected if independent)

Engine's conclusion

Strengthened. Significant, with a real effect in a consistent direction, and it still holds when tumours are compared only within the same tumour type (and within the same molecular subtype, wherever this cancer's subtypes are known in the data). No artifact check failed.

A well-studied pair (38,138 papers): on the map it is known biology, a positive control rather than an overlooked discovery.

Not called novel: a PubTator3 search finds 1,581 papers naming both TP53 and KRAS in non-small cell lung cancer in the title or abstract. See the PubTator3 search.

Statistical support57%Significance (FDR q)3.6 × 10-44Signal (x)44%Efficacy (y)12%

Signal (x) is the corrected significance on the map's scale, discounted from 97% to 44% because the cohort-composition confound is not yet controlled. Efficacy (y) is credibility times actionability.

Structure & site3D structure: AlphaFold

These genes are rarely altered in the same tumour: mutual exclusivity, often a sign they hit one shared pathway so a tumour needs only one broken.

Primary site

Lung

This finding's tumour type arises in the highlighted organ.

Drag to rotate. Dark marks the hotspot residues on the predicted fold. For a fuller read of this same model, open the interactive structure workbench for this protein on Nanoverse (a companion site we also run), which maps its binding pockets, per-region confidence, and the likely effect of a mutation.

TP53Tumor suppressorIndirect

Tumor protein p53

Tumour suppressor: normally restrains growth; cancer switches it OFF.

Guardian of the genome: DNA-damage-induced arrest, apoptosis, and senescence. The most-mutated gene in cancer.

Pathway
p53 / DNA-damage
Hotspots in 3D
R175 · R248 · R273 · R282 · G245 · R249
Drives
Pan-cancer, Li-Fraumeni
TP53 mutations in non-small cell lung cancer →TP53 co-mutations by tumour type →Other findings with TP53 →

Drag to rotate. Dark marks the hotspot residues on the predicted fold. For a fuller read of this same model, open the interactive structure workbench for this protein on Nanoverse (a companion site we also run), which maps its binding pockets, per-region confidence, and the likely effect of a mutation.

KRASOncogeneApproved therapy

KRAS proto-oncogene GTPase

Oncogene: when altered it gets stuck ON and drives growth.

Central RAS signal transducer. G12C is now druggable (sotorasib, adagrasib); G12D inhibitors are emerging.

Pathway
RTK to RAS to MAPK
Hotspots in 3D
G12 · G13 · Q61 · A146
Drives
Pancreatic, Colorectal, NSCLC
KRAS mutations in non-small cell lung cancer →KRAS co-mutations by tumour type →Other findings with KRAS →

Anatomical figure from the EBI Expression Atlas anatomogram, and predicted structures from the AlphaFold Protein Structure Database (both CC-BY-4.0). A model shows the protein's healthy fold; a highlighted residue marks a recurrent cancer position, not a prediction of a specific mutation's effect.

Statistical evidence
Test p (raw)
3.9 × 10-48
Effect (log₂ odds ratio)
-1.1
Papers
38,138
Abstracts naming both
1,581
Trials
14
Contingency table: the source of the q7,718 tumours

The raw 2×2 the FDR q and log₂ odds ratio above were computed from. It is the immutable evidence the score re-derives from: every number on this page traces back to these four counts.

Gene stateTP53 alteredTP53 wild-type
KRAS altered6921,432
KRAS wild-type3,0062,588

both 692 (expected 1,018 if independent) · KRAS-only 1,432 · TP53-only 3,006 · neither 2,588

Sources
cBioPortal / MSK-CHORD (2024)Genome NexusOmniPath / Reactome / STRINGUCSC XenaOpen TargetsPubTator3NIH iCiteEurope PMCClinicalTrials.gov
Anytime-valid evidence (e-value)e = 2.6e+21

Decisive evidence. Exceeds the α=0.05 reject threshold (e≥20). Unlike a single-look p, this stays valid under the engine's continuous re-testing.

Why it sits here on the map

Molecular-subtype certification is unresolved. Recorded lineage only. Within-lineage molecular subtype remains unresolved. The association remains visible, but does not qualify as a subtype-controlled discovery.

Opacity: novelty (display only)0%

The two axes are variables: signal (x) and efficacy (y = credibility × actionability). A point high on both lands in the frontier (top-right). A strong signal with low credibility sits low and to the right: statistically strong, not worth pursuing.

TP53Tumor suppressorKRASOncogeneSotorasibAdagrasib
HypothesisModel-generated hypothesis (not evidence)
Written by gpt-6-luna

A language model wrote this from the evidence listed below. It is annotation: the engine's verdict above comes only from the measured statistics, never from this text.

I hypothesize that the observed TP53–KRAS depletion is chiefly driven by histologic composition within NSCLC: pooling adenocarcinoma, where KRAS alterations are more characteristic, with squamous carcinoma, where TP53 alterations are more characteristic, could bias the pooled association toward mutual exclusivity. This is a testable population-level explanation, not a claim that the genes interact within individual tumors.

Argument strength (model self-report)20%
After adversarial review20%
The argument
  1. 1The depletion is statistically strong but moderate in size: the within-lineage log2 odds ratio of -1.1 corresponds to an odds ratio of about 0.47, and 692 tumors carry both alterations, so the pattern is not absolute incompatibility. The burden-aware test and FDR correction support a real association in this dataset, not its cause.E1E21
  2. 2Histologic composition is my leading explanation to test: as textbook lung-cancer context, KRAS alterations are characteristic of lung adenocarcinoma, whereas TP53 alterations are common in squamous carcinoma. Pooling those histologies could bias this pair toward exclusivity. The recorded control is lineage-only, and the supplied cross-check says there are no molecular-subtype labels, so this specific histology contrast was not absorbed by a subtype-adjusted comparison.E2E5
  3. 3A simple functional-redundancy account is not directly indicated by the supplied gene-role annotations: they place TP53 in the p53/DNA-damage pathway and KRAS in RTK–RAS–MAPK signaling. Partial negative selection remains possible, but the many double-altered tumors argue against a strict incompatibility.E1E15E16
  4. 4The pair is already extensively studied in NSCLC, so this result should not be called unexplored; what this measurement adds is a burden-aware, within-lineage estimate in this cohort, with a moderate depletion that recurs in two independent patient sources. The supplied paper abstracts do not establish TP53–KRAS mutual exclusivity or a mechanism: one is a high-level NSCLC ctDNA landscape description and the other concerns PDLIM2 metastasis. The literature counts indicate extensive study, not that these abstracts establish the specific relationship.E1E3E6E11E12E13
What would confirm or refute it

Profile a sufficiently powered, consecutively accrued NSCLC cohort with central pathology adjudication and same-panel TP53/KRAS sequencing, then perform a burden-aware comparison separately in adenocarcinoma and squamous carcinoma. The histology-composition hypothesis would be supported if the pooled depletion substantially attenuates within both histologies and their differing alteration frequencies reconstruct the pooled pattern; it would be weakened if a similar depletion persists within each histology.

Strongest competing explanation (model)

The histology explanation is plausible but not demonstrated by the supplied measurements, which contain no subtype labels or histology-specific TP53/KRAS frequencies. Thus no specific explanation is established here. The provided paper abstracts do not study this pair's mutual exclusivity, so no within-tumor cooperation or redundancy mechanism is proposed. The cross-cohort recurrence reduces concern about cohort-specific noise, but shared panels or calling pipelines could still produce a systematic artifact.

Adversarial review (second model pass)

Weakest link: The evidence gives no histology-specific TP53/KRAS frequencies or stratified association, so the composition account is plausible but unsupported as the chief cause of the observed depletion.

Cross-cohort agreement (intra-snapshot)2 sources agree

This mutual exclusivity recurs (same direction, survives FDR) in 2 independent sources of this tumour type. This controls cohort-specific noise only. Several of these cohorts share a sequencing panel, a pipeline or even patients (the MSK cohorts overlap), so a systematic artifact can recur across them. It is not external or prospective validation, and it grants no confidence on its own. The same direction is also significant in 2 other tumour types: the pattern in a different tissue, not replication of this one.

Evidence the argument cites

Model-written annotation, not a finding. The statistics it cites are real and are shown above; the argument connecting them is a hypothesis that needs wet-lab or clinical validation before it means anything.

Cite this finding
Permalink
https://cybergenic.im/findings/a13a712e-cc7f-4b13-a056-aec6ea1eca03
First seen
14 Aug 2026
Prediction registry
Locked 14 Aug 2026, row hash b329f185823617f4dd239ef5928cfa15 (not testable out of sample). How the registry works
BibTeX
@misc{cybergenic_a13a712e,
  author       = {{Cybergenic}},
  title        = {{TP53 and KRAS mutual exclusivity in non-small cell lung cancer (MSK-CHORD)}},
  year         = {2026},
  howpublished = {\url{https://cybergenic.im/findings/a13a712e-cc7f-4b13-a056-aec6ea1eca03}},
  note         = {Research engine finding, first seen 2026-08-14; prediction locked 2026-08-14, registry row hash b329f185823617f4dd239ef5928cfa15},
  month        = aug
}
See it on the live map Mutations in non-small cell lung cancerKRAS and TP53 in every cohort

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