Cancer Genomics: Germline, Somatic, and Liquid
Tumor mutation profiles, MRD by ctDNA, and the germline cases that change family screening.
What's covered
- T01Driver vs passenger mutations; mutational signatures (SBS, ID, DBS, CN)
- T02Targetable alterations: EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, NTRK, RET, FGFR, HER2
- T03Tumor-only vs tumor-normal sequencing; germline filtering
- T04ctDNA / liquid biopsy: tissue-agnostic profiling, MRD monitoring
- T05Hereditary cancer syndromes: HBOC, Lynch, Li-Fraumeni, Cowden, FAP
- T06Clonal hematopoiesis (CHIP) — incidental on liquid biopsy
By the end of this module you will be able to
- L01Distinguish driver from passenger mutations and explain mutational-signature interpretation (e.g. SBS3 for HRD).
- L02Order the appropriate germline workup for a patient meeting NCCN HBOC or Lynch criteria.
- L03Interpret a ctDNA report and recognize when an apparent tumor variant is actually CHIP.
What you should walk away believing
- Tumor-only panels routinely confound germline variants as somatic — paired tumor-normal is the gold standard for clinically actionable germline detection.
- ctDNA-based MRD (Signatera, Guardant Reveal, Natera) detects relapse months before imaging in colorectal, breast, and bladder cancer; clinical-utility trials (CIRCULATE, BESPOKE) are maturing.
- Mutational signatures are now actionable: SBS3 → HRD → PARP inhibitor; MMR loss/MSI-H → checkpoint inhibitor.
- CHIP variants (DNMT3A, TET2, ASXL1) appear in ctDNA in ~10% of adults >70; misclassifying them as tumor-derived causes harm.
What this means at your level
Cancer is a genetic disease of somatic cells, but ~5–10% of cancers arise on a hereditary background. Modern oncology routinely sequences tumors to find targetable alterations and increasingly uses blood-based ctDNA testing both to guide therapy and to monitor response.
For any new metastatic solid tumor, broad NGS tumor profiling is now standard. Pair with germline testing when family history, age, tumor type (e.g. ovarian, pancreatic, prostate), or tumor signature suggests hereditary risk. ctDNA MRD is reimbursed in CRC and increasingly in other indications; remember that absence of ctDNA does not exclude minimal disease, and presence in older patients may be CHIP.
Mutational signature decomposition (SigProfiler, SignatureAnalyzer) now resolves >70 SBS, 18 ID, 11 DBS, and 24 copy-number signatures. Methylation-based tumor classification (MNP/Heidelberg classifier for CNS tumors) outperforms histology in many cases. Whole-genome tumor sequencing (Genomics England 100k follow-on, Hartwig in NL) is becoming a research-grade default for advanced cancer.
If the tumor panel didn't find a BRCA mutation, the patient doesn't have hereditary breast cancer.
Tumor-only panels miss germline variants in regions with low coverage, large rearrangements, and BRCA1 promoter methylation. Negative tumor testing never replaces germline testing in a patient meeting clinical criteria.
What the data say
Test yourself
Key terms & abbreviations
- ctDNAcirculating tumor DNA
- Tumor-derived cell-free DNA in plasma. Used for therapy selection, MRD, and recurrence monitoring.
- MRDMinimal/Measurable Residual Disease
- Disease below imaging threshold, detectable by molecular methods (ctDNA, immunoglobulin/TCR rearrangement, flow MRD).
- HRDHomologous Recombination Deficiency
- Genomic phenotype (SBS3, large-scale state transitions, telomeric AI) marking PARP-inhibitor sensitivity.
- CHIPClonal Hematopoiesis of Indeterminate Potential
- Age-related expansion of hematopoietic clones carrying somatic driver mutations (DNMT3A, TET2, ASXL1) without overt malignancy. Confounder in liquid biopsy and an independent CV risk factor.
Anchor references
- The repertoire of mutational signatures in human cancer — Alexandrov et al., Nature 2020
- Circulating tumor DNA analysis in adjuvant colorectal cancer (DYNAMIC) — Tie et al., NEJM 2022