Molecularly Defined Non-Small Cell Lung Cancer Subtypes

name: Molecularly Defined NSCLC Subtypes
display_name: Molecularly Defined Non-Small Cell Lung Cancer Subtypes
creation_date: "2026-06-14T00:00:00Z"
description: >-
  A curated grouping of non-small cell lung cancer (NSCLC) Disease entries
  defined by actionable oncogenic driver alterations. Members share lung
  adenocarcinoma-predominant NSCLC biology, oncogene addiction, increased MAPK
  signaling, tumor-cell proliferation, targeted-therapy sensitivity, and
  acquired resistance mechanisms, but differ by the specific driver gene and
  alteration class.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
- SHARED_TREATMENT_RESPONSE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped as an explicit curated union of molecularly defined NSCLC subtypes
  rather than as all lung cancer, all lung adenocarcinoma, or the generic NSCLC
  entry. These entries are kept separate because EGFR kinase-domain mutations,
  ALK/ROS1/RET fusions, BRAF V600E, KRAS G12C, and MET exon 14 skipping each
  define distinct diagnostic testing, first-line targeted therapy, resistance
  biology, and clinical-trial landscape. The shared grouping boundary is
  actionable oncogenic-driver dependence in NSCLC with convergent MAPK-driven
  proliferation and precision-oncology treatment selection.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005233
      label: non-small cell lung carcinoma
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      narrowMatch: this grouping is a molecularly defined subset of the MONDO
      non-small cell lung carcinoma class, restricted to current dismech Disease
      entries for actionable driver-positive NSCLC subtypes.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Listed members are curated NSCLC subtype entries whose disease_term is
        lung adenocarcinoma or whose parentage places them under non-small cell
        lung carcinoma. The grouping deliberately excludes generic NSCLC and
        metastatic NSCLC entries.
membership_criteria:
- description: >-
    A member is an explicit molecularly defined NSCLC Disease entry with
    oncogenic-driver signaling converging on MAPK activation and tumor-cell
    proliferation.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: Involves increased MAPK cascade signaling downstream of the driver.
      biological_processes:
      - preferred_term: MAPK cascade
        term:
          id: GO:0000165
          label: MAPK cascade
        modifier: INCREASED
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: Involves increased tumor-cell proliferation.
      biological_processes:
      - preferred_term: cell population proliferation
        term:
          id: GO:0008283
          label: cell population proliferation
        modifier: INCREASED
members:
- member: EGFR-Mutant Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Activating EGFR kinase-domain mutations, especially exon 19 deletions,
      L858R, exon 20 insertions, and acquired T790M/C797S resistance variants,
      drive ligand-independent EGFR signaling and define sensitivity or
      resistance to EGFR-directed tyrosine kinase inhibitors and antibodies.
    gene:
      preferred_term: EGFR
      term:
        id: hgnc:3236
        label: EGFR
- member: ALK-Rearranged Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALK fusions, most commonly EML4-ALK, provide partner-mediated dimerization
      of the ALK kinase domain, producing constitutive kinase signaling,
      oncogene addiction, sensitivity to ALK inhibitors, and recurrent ALK
      resistance mutations or bypass mechanisms.
    gene:
      preferred_term: ALK
      term:
        id: hgnc:427
        label: ALK
- member: ROS1-Rearranged Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ROS1 fusion proteins activate receptor tyrosine kinase signaling through
      partner-mediated dimerization, defining a rare NSCLC subtype with
      sensitivity to ROS1 inhibitors and characteristic ROS1 solvent-front or
      bypass resistance mechanisms.
    gene:
      preferred_term: ROS1
      term:
        id: hgnc:10261
        label: ROS1
- member: BRAF V600E-Mutant Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      BRAF V600E constitutively activates RAF-MEK-ERK signaling in NSCLC,
      distinguishing this subtype by MAPK-pathway dependence and sensitivity to
      combined BRAF/MEK inhibition.
    gene:
      preferred_term: BRAF
      term:
        id: hgnc:1097
        label: BRAF
- member: KRAS G12C-Mutant Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      KRAS G12C impairs GTPase cycling and creates a covalent inhibitor-binding
      cysteine pocket, distinguishing this smoking-associated adenocarcinoma
      subtype by RAS-MAPK dependence, KRAS G12C inhibitor sensitivity, and
      adaptive RTK or pathway reactivation resistance.
    gene:
      preferred_term: KRAS
      term:
        id: hgnc:6407
        label: KRAS
- member: MET Exon 14 Skipping Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MET exon 14 skipping removes the juxtamembrane CBL-binding regulatory
      domain, reducing receptor ubiquitination and degradation and producing
      prolonged MET signaling that is targetable with MET inhibitors.
    gene:
      preferred_term: MET
      term:
        id: hgnc:7029
        label: MET
- member: RET-Rearranged Non-Small Cell Lung Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      RET fusions join the RET kinase domain to dimerization partners such as
      KIF5B or CCDC6, causing constitutive RET signaling and defining an NSCLC
      subtype with selective RET inhibitor sensitivity and solvent-front or
      bypass resistance.
    gene:
      preferred_term: RET
      term:
        id: hgnc:9967
        label: RET
notes: >-
  Exclude the generic Non-Small Cell Lung Cancer and Metastatic NSCLC entries
  because they are not single actionable-driver subtypes. Also exclude small
  cell lung cancer, broad lung adenocarcinoma, pan-cancer NTRK fusion-positive
  cancer, non-lung BRAF/KRAS/RET cancers, and resistance-only states unless a
  standalone Disease entry is curated as a molecularly defined NSCLC subtype.