Processes of - molecular and cellular oncogenesis

Overview

Cancer = accumulated genetic and epigenetic change conferring the hallmarks: sustained proliferative signalling, evasion of growth suppressors, resistance to apoptosis, replicative immortality, angiogenesis, invasion/metastasis, immune evasion, altered metabolism, genome instability, tumour-promoting inflammation

	Oncogene	Tumour suppressor
Effect of mutation	Gain of function	Loss of function
Alleles needed	One (dominant)	Both (two-hit)
Germline example	RET (MEN2), MET	RB1, TP53, APC, BRCA1/2, VHL, NF1
Druggable?	Yes - inhibit the active product	Hard - you cannot restore a missing protein

*This is why targeted therapy exists for EGFR/ALK/BRAF but not for TP53 or RB1*

~5-10% of cancers arise from a high-penetrance germline mutation
Mutational burden varies ~1000-fold: highest in melanoma and lung cancer (UV, tobacco), lowest in paediatric tumours
Most cancers require 2-8 driver mutations accumulated over years to decades

Point mutation - KRAS G12C, BRAF V600E, EGFR L858R, PIK3CA
Amplification - HER2, MYCN (neuroblastoma), EGFR
Chromosomal translocation -> fusion gene
- BCR-ABL (t(9;22), CML), PML-RARA (APL), EWSR1-FLI1 (Ewing), IGH-MYC (Burkitt)
- Often arises from erroneous repair of DNA double-strand breaks by non-homologous end joining
Chromosomal inversion -> fusion
- *EML4-ALK in NSCLC is an inversion of chromosome 2p, not a point mutation* - hence it is detected by FISH/NGS fusion panels, not by a hotspot mutation assay
Insertion - EGFR exon 20 insertion (resistant to standard EGFR TKIs)

Germline first hit + somatic second hit -> earlier, multifocal, bilateral disease (retinoblastoma is the paradigm)
Second hit mechanisms: point mutation, deletion, loss of heterozygosity, promoter hypermethylation (epigenetic - e.g. MLH1 in sporadic MSI colorectal cancer)

VHL (chromosome 3p) is part of the cellular oxygen-sensing machinery
- Normoxia: VHL ubiquitinates HIF-1alpha/HIF-2alpha -> proteasomal degradation
- VHL loss (clear cell RCC, von Hippel-Lindau syndrome) -> HIF accumulates even in normoxia
- -> transcription of hypoxia-response genes: VEGF, PDGF, TGF-alpha, EPO, GLUT1, CAIX
- -> angiogenesis (explains why clear cell RCC is hypervascular and why VEGF TKIs work), and polycythaemia
- -> belzutifan directly inhibits HIF-2alpha - drugging the consequence of a tumour suppressor loss

Mismatch repair deficiency -> MSI, hypermutation, high neoantigen load -> immunotherapy sensitivity
Homologous recombination deficiency (BRCA1/2, PALB2, RAD51) -> PARP inhibitor synthetic lethality
Chromosomal instability -> aneuploidy
Nucleotide excision repair defect -> xeroderma pigmentosum

Alteration	Test
Point mutation	Targeted PCR, NGS panel
Fusion/translocation/inversion	FISH, RNA-based NGS, IHC surrogate (ALK, ROS1)
Amplification	FISH/ISH, IHC (HER2)
Protein loss	IHC (MMR proteins, BAP1, p16)
Global genomic state	MSI PCR, HRD score, tumour mutational burden

Liquid biopsy (ctDNA) - detects mutations and resistance alterations without tissue; a negative result does not exclude (shedding varies)
*Germline vs somatic matters* - germline findings trigger cascade testing of relatives and change risk-reducing surgery decisions

Inhibit the activated kinase - imatinib (BCR-ABL, KIT), osimertinib (EGFR), alectinib (ALK), dabrafenib (BRAF)
Block the downstream consequence - MEK inhibitors, VEGF inhibitors, belzutifan (HIF-2alpha)
Exploit the repair defect - synthetic lethality (PARP inhibitors in BRCA-mutant disease)
Exploit the immune consequence - checkpoint inhibitors in MSI-H/TMB-high disease
Differentiate rather than kill - ATRA + arsenic in PML-RARA APL

A. Point mutation in the drug target altering conformation/ATP-binding affinity
- ABL T315I (-> ponatinib, asciminib), EGFR T790M (-> osimertinib), then C797S
B. Activation of a bypass/alternative pathway
- MET amplification in EGFR-mutant NSCLC; HER2 amplification
C. Downstream mutation making the pathway constitutively active independent of the target
- KRAS mutation causing anti-EGFR antibody failure in colorectal cancer - the receptor is blocked but the signal is generated below it
Also: lineage plasticity (small cell transformation of EGFR-mutant lung cancer, neuroendocrine transformation of prostate cancer), drug efflux pumps, target loss
*Re-biopsy at progression* - the resistance mechanism changes the next drug

BCR-ABL - CML; PML-RARA - APL; EML4-ALK - NSCLC; EWSR1-FLI1 - Ewing sarcoma; IGH-MYC - Burkitt
VHL - clear cell RCC, von Hippel-Lindau syndrome (haemangioblastoma, phaeochromocytoma, retinal angioma)
RB1 - retinoblastoma, osteosarcoma, small cell lung cancer
TP53 - Li-Fraumeni; APC - FAP; BRCA1/2 - breast/ovarian; MMR genes - Lynch
RET - MEN2, medullary thyroid carcinoma, papillary thyroid carcinoma fusion
MYCN amplification - neuroblastoma prognosis
Oncogenic viruses: HPV (E6->p53, E7->Rb), EBV, HBV/HCV, HTLV-1, HHV-8, H. pylori

Clonal evolution under selection pressure - treatment selects resistant subclones that were already present
Branched rather than linear evolution - metastases can be genetically divergent from the primary and from each other
Field cancerisation (aerodigestive, urothelial) -> synchronous and metachronous primaries
Clonal haematopoiesis of indeterminate potential (CHIP) - age-related somatic mutations (DNMT3A, TET2, ASXL1) predisposing to MDS/AML and cardiovascular disease
Therapy-related malignancy: alkylators (-5/-7, latency 5-7 yr), topoisomerase-II inhibitors (11q23/MLL, latency 1-3 yr)

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