Cancer Biology, Carcinogenesis and Molecular Genetics
Core framework
Carcinogenesis is a multistep process in which a cell accumulates genetic and epigenetic alterations that progressively deregulate proliferation, death and genomic maintenance. The hallmarks of cancer, plus the later additions (genome instability, immune evasion, metabolic reprogramming, tumour-promoting inflammation), give you the framework for almost any question in this domain.
Oncogenes versus tumour suppressors
Proto-oncogenes become oncogenes by gain-of-function: point mutation (KRAS), amplification (HER2, MYCN) or translocation (BCR-ABL, MYC). One altered allele is enough. Tumour suppressors need loss of function of both alleles (Knudson's two-hit hypothesis); RB in retinoblastoma is the classic. Because loss is the mechanism, the usual findings are deletion, truncating mutation or promoter hypermethylation.
Pathways to recognise
Cell-cycle control (CDKN2A-cyclin D-CDK4/6-RB-E2F), p53 as the 'guardian of the genome' arresting the G1/S checkpoint after DNA damage, apoptosis (BCL-2, BAX), DNA repair (mismatch repair, homologous recombination, NHEJ), telomere maintenance (hTERT), angiogenesis (VEGF) and the invasion-metastasis cascade.
Traps
Questions test direction: amplification implies oncogene, deletion or methylation usually implies tumour suppressor. Do not confuse the colorectal adenoma-carcinoma sequence (APC, then KRAS, then SMAD4/TP53) with the GIST model (KIT) or with HPV biology, where viral E6 degrades p53 and E7 inactivates RB, so the virus behaves like a double suppressor-loss event rather than an amplified oncogene.
Rule of thumb
Two hits equals recessive equals tumour suppressor; one hit equals dominant equals oncogene. Worked example: a lung adenocarcinoma with EGFR amplification is oncogene-driven, whereas a pancreatic cancer with a truncating APC mutation has lost a gatekeeper.