Comparative oncology / research surface

Pulmonary adenocarcinoma: a never-smoker lung-cancer model, driven by HER2 not EGFR.

Canine pulmonary adenocarcinoma is a low-mutation-burden, never-smoker-like lung cancer. It reaches the erbB axis through HER2 (the V659E transmembrane hotspot) where human lung adenocarcinoma uses EGFR, a reciprocal-driver divergence. TP53 and KRAS are shared drivers but occur far less often in the dog.

These are somatic tumor alterations, not a germline carrier status. Every number here is a cohort frequency, the fraction of sequenced tumors somatically altered in a gene, reported by a published study. It is not a variant a dog inherits or carries, and it is not a prediction about any individual dog. Cross-species labels (concordant, divergent, canine-enriched) come from a commensurability-gated concordance map (INV-81), not a coarse shared flag.

This is the molecular driver landscape for this cancer. all cancers →

The conserved core

concordant · 2 genes

Drivers where dog and human agree on status for this comparable cancer (commensurability-gated). That agreement is the evidence the dog models the human disease here.

TP53 concordant

tumor suppressor

Dog

12.5%

of 88 tumors · missense + stop-gain SNVs

Lorch et al. 2019

Human

46%

of 230 tumors · SNVs

TCGA 2014

A shared driver; the markedly lower canine frequency (12.5% vs 46%) is consistent with the low-mutation-burden, never-smoker-like biology of cPAC (median TMB 2.04 mut/Mb). The canine figure is from the full lung-carcinoma cohort (n=88).

fused signature constraint LOEUF 0.449 ortholog dog↔human high-corroborated germline 11 ClinVar syndromes

KRAS concordant

RAS-family oncogene

Dog

4.5%

of 88 tumors · hotspot activating: G12V, G12D, Q61K

Lorch et al. 2019

Human

33%

of 230 tumors · hotspot activating

TCGA 2014

A genuine activating driver in both, at very different frequency (4.5% vs 33%). The human 33% is heavily smoking-associated; the low canine rate mirrors human never-smoker lung adenocarcinoma where KRAS is likewise infrequent.

fused signature constraint LOEUF 0.264 ortholog dog↔human high-corroborated germline 4 ClinVar syndromes

Where dog and human diverge

divergent · 2

Both sides characterized for a commensurable lesion, and they disagree. The honest limit of the model, not darkness and not a missing rate filled with zero.

ERBB2 divergent

HER2 receptor tyrosine kinase; the dominant cPAC driver

Dog

37.8%

of 74 tumors · HER2 V659E transmembrane-domain missense (93% of all HER2 mutations)

Lorch et al. 2019

Human

1.7%

of 1478 tumors · exon-20 kinase-domain insertions (YVMA), NOT the transmembrane V659E

Arcila et al. 2012

Dog (cited): 37.8% (28/74), 93% V659E transmembrane hotspot (Lorch 2019)

Human (cited): 1.7% (25/1478), exon-20 kinase-domain insertions (Arcila 2012)

HER2 drives both cancers but diverges on frequency (~20-fold) AND mutated domain (canine transmembrane V659E vs human kinase-domain insertions). Both sides cited, same gene + cancer.

HER2 is a driver in both, but profoundly divergent: canine cPAC is roughly 20-fold enriched and dominated by the V659E transmembrane allele, whereas the rarer human HER2-mutant lung adenocarcinoma uses exon-20 kinase-domain insertions. Both the frequency and the mutated protein domain differ.

fused signature constraint LOEUF 0.518 ortholog high-corroborated

EGFR divergent

the dominant human lung-adenocarcinoma driver

Dog

—

see cited basis

Human

14%

of 230 tumors · activating kinase-domain mutations

TCGA 2014

Dog (cited): reported rare / not recurrently mutated in cPAC (Lorch 2019, Mariotti 2014); erbB activated via HER2 instead

Human (cited): 14% in human lung adenocarcinoma (TCGA n=230)

Reciprocal driver usage: the human lung-ADC driver EGFR is rare in the dog, which reaches the same axis through HER2. Both sides characterized (canine as sequenced-and-rare, human 14%).

The reciprocal-driver signal: canine cPAC activates the erbB axis through HER2 with EGFR reported rare (Lorch 2019, in lieu of EGFR mutation), whereas human lung adenocarcinoma is EGFR-mutated in 14% (much higher in never-smokers). Canine EGFR is reported qualitatively rare, not quantified as a percent.

Canine-enriched drivers

darkness · 2

Recurrent in the canine cohort; the human side is not established as a recurrent driver here or is unquantified. Coverage darkness, not a measured disagreement (INV-81 / INV-77).

PTEN canine-enriched

5.7% of 88

PI3K-pathway tumor suppressor · potentially-pathogenic SNVs · Lorch et al. 2019

Recurrent in canine cPAC and mechanistically plausible (PI3K/AKT, consistent with the constitutive AKT phosphorylation in HER2-V659E cPAC cell lines). The human lung-adenocarcinoma PTEN frequency was not table-verifiable and is left unquantified rather than guessed.

VHL canine-enriched

3.4% of 88

tumor suppressor (canonical in renal/CNS tumors, not lung) · potentially-pathogenic SNVs · Lorch et al. 2019

An unusual recurrent hit of uncertain significance: VHL is not an established human lung-adenocarcinoma driver (it drives clear-cell renal carcinoma and CNS hemangioblastoma), so this canine recurrence is a divergent, low-confidence finding, not a shared mechanism.