Cybergenic
All findings

KRAS ⊥ EGFR

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

Inconclusive: differs between strataMutual exclusivity · Evidence: pattern across patients, not yet tested within subtypes

DataMSK-CHORD (2024) · Non-small cell lung cancer · 7,718 tumours · both altered in 8 (478 expected if independent)

Engine's conclusion

Inconclusive. Significant, but the effect differs between tumour types or subtypes, so it is not one general relationship across this cancer.

A well-studied pair (35,418 papers): on the map it is known biology, a positive control rather than an overlooked discovery.

Statistical support59%Significance (FDR q)2.8 × 10-200Signal (x)17%Efficacy (y)1%

Signal (x) is the corrected significance on the map's scale, discounted from 99% to 17% because the two genes act in one pathway, so their exclusivity is expected redundancy (known biology), not a new relationship. 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.

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 →

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.

EGFROncogeneApproved therapy

Epidermal growth factor receptor

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

Receptor tyrosine kinase; osimertinib for EGFR-mutant NSCLC, cetuximab in colorectal.

Pathway
RTK to RAS to MAPK
Hotspots in 3D
L858 · T790 · G719 · L861
Drives
NSCLC, Glioblastoma, Head & neck
EGFR mutations in non-small cell lung cancer →EGFR co-mutations by tumour type →Other findings with EGFR →

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)
6.1 × 10-205
Effect (log₂ odds ratio)
-6.7
Papers
35,418
Abstracts naming both
3,780
Trials
123
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 stateKRAS alteredKRAS wild-type
EGFR altered81,730
EGFR wild-type2,1163,864

both 8 (expected 478 if independent) · EGFR-only 1,730 · KRAS-only 2,116 · neither 3,864

Sources
cBioPortal / MSK-CHORD (2024)Genome NexusOmniPath / Reactome / STRINGUCSC XenaOpen TargetsPubTator3NIH iCiteEurope PMCClinicalTrials.gov
Anytime-valid evidence (e-value)e = 3.0e+99

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.

KRASOncogeneEGFROncogeneSotorasibAdagrasibOsimertinibCetuximab
Same question in other cohorts
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 depletion primarily reflects EGFR-mutant and KRAS-mutant tumors being selected into alternative driver states in NSCLC, rather than proving that a tumor carrying both is non-viable. Their shared RTK–RAS–MAPK signaling context makes this population-level explanation plausible, but the data do not establish a within-tumor interaction.

Argument strength (model self-report)30%
After adversarial review45%
The argument
  1. 1The depletion is large and survives burden-aware, multiple-testing-corrected analysis within the recorded lineage; only 8 tumors carry both alterations. It recurs across three patient sources, although those sources may share technical biases.E1E3E22
  2. 2A competing-driver-state hypothesis is biologically plausible because KRAS and EGFR are both connected to RTK–RAS–MAPK signaling in the supplied pathway and gene summaries. That overlap motivates the hypothesis but does not show that dual-altered cells have reduced fitness.E7E16E17
  3. 3The relationship is already extensively studied in NSCLC and across cancer research; the added measurement here is a burden-aware, same-panel, within-lineage estimate with a very strong depletion and cross-source recurrence. The supplied abstracts do not establish KRAS–EGFR mutual exclusivity or its mechanism: one concerns an NSCLC ctDNA landscape and the other immunotherapy.E1E3E6E12E13E14
  4. 4A specific compositional alternative is a mixture of never-smoker, EGFR-enriched adenocarcinoma and tobacco-associated, KRAS-enriched adenocarcinoma (textbook epidemiology, not measured in this cohort); that mixture could bias the pair toward apparent exclusivity. The control records lineage, not smoking etiology or molecular subtype, and subtype labels are unavailable, so it would not absorb this explanation. The reported stratum-specific heterogeneity also cautions against treating the pattern as uniform.E2E4E5
What would confirm or refute it

Run one isogenic competitive-fitness experiment in NSCLC adenocarcinoma organoids: engineer matched EGFR-mutant-only, KRAS-mutant-only, double-mutant, and unaltered clones, barcode them, and track clone abundance under the same growth conditions. A reproducible fitness disadvantage of double-mutant clones would support within-tumor negative selection; equal or greater fitness would weaken that explanation. The population association alone cannot establish this claim.

Strongest competing explanation (model)

No supplied Europe PMC paper studies the KRAS–EGFR relationship mechanistically, so a within-tumor redundancy or negative-selection mechanism is not asserted. Smoking-etiology or unlabelled molecular-subtype composition could account for some or all of the depletion; the cohort lacks the labels needed to test that. Cross-cohort recurrence does not rule out a shared panel or calling-pipeline artifact, and the measured heterogeneity argues against a single universal effect.

Adversarial review (second model pass)

Weakest link: The depletion is robust, but pathway overlap does not show that alternative-driver selection causes it; unmeasured smoking or subtype composition could explain the pattern, and the proposed isogenic test would not resolve that population-level confounding.

Cross-cohort agreement (intra-snapshot)3 sources agree

This mutual exclusivity recurs (same direction, survives FDR) in 3 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.

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/6b02ecbf-1ade-4f4e-a1bb-2cc4045c13b0
First seen
14 Aug 2026
Prediction registry
Locked 14 Aug 2026, row hash a2e9c2213fc29438e384c746f0ba41db (not testable out of sample). How the registry works
BibTeX
@misc{cybergenic_6b02ecbf,
  author       = {{Cybergenic}},
  title        = {{KRAS and EGFR mutual exclusivity in non-small cell lung cancer (MSK-CHORD)}},
  year         = {2026},
  howpublished = {\url{https://cybergenic.im/findings/6b02ecbf-1ade-4f4e-a1bb-2cc4045c13b0}},
  note         = {Research engine finding, first seen 2026-08-14; prediction locked 2026-08-14, registry row hash a2e9c2213fc29438e384c746f0ba41db},
  month        = aug
}
See it on the live map Mutations in non-small cell lung cancerEGFR and KRAS in every cohort

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