Cancer Genetics and Somatic Molecular Oncology
Concepts
Distinguish germline from somatic testing (specimen type, VAF interpretation, tumor purity). Know driver vs passenger alterations, oncogenes (gain-of-function, often activating hotspots) vs tumor suppressors (loss-of-function, often two-hit). Understand variant allele fraction and how tumor cellularity, copy number, and clonal hematopoiesis of indeterminate potential (CHIP) distort interpretation. Know the clinical significance of key biomarkers: EGFR, KRAS, BRAF, BRCA1/2, MSI/dMMR, TMB, NTRK and other fusions, and HER2 amplification.
Assay and interpretation issues
Be able to reason about tissue vs liquid biopsy (ctDNA shedding, low VAF, CHIP confounding), the limits of amplicon panels (allele dropout, primer-site variants), and the need for orthogonal confirmation. Understand the difference between a pathogenic variant and a variant of unknown significance in a somatic report, and how tumor heterogeneity affects sensitivity.
Traps
Questions conflate VAF with tumor fraction, ignore CHIP in plasma testing, or assume a negative panel excludes a fusion. Watch for items about resistance mutations (e.g., EGFR T790M, ESR1) and about the difference between predictive, prognostic, and diagnostic biomarkers.
Rule of thumb
Interpret somatic VAF in the context of estimated tumor purity: a VAF of 5% in a 20%-pure tumor may represent a clonal heterozygous alteration, whereas the same VAF in a 90%-pure tumor suggests subclonality or a different copy state. Confirm low-VAF or unexpected findings orthogonally.
Worked example
A plasma EGFR result shows a low-VAF variant also seen at low level in an age-matched control without cancer. Consider CHIP; correlate with tissue or a matched white-cell control before calling it tumor-derived.