Cancer genetics
Hereditary cancer predispositions
Watch scope
Weekly selection of publications on pathogenic and likely pathogenic constitutional variants in major cancer predisposition genes (BRCA1/2, TP53, PALB2, ATM, CHEK2, CDH1, Lynch syndrome — MLH1, MSH2, MSH6, PMS2). Covers penetrance and expressivity studies, surveillance and prophylactic surgery in carriers, targeted therapies for constitutional carriers (PARP inhibitors, immunotherapy), and mainstreaming of germline testing in clinical oncology.
Inclusion / exclusion criteria
Included
- ✓Pathogenic/LP constitutional variants in cancer predisposition genes
- ✓Penetrance and expressivity studies
- ✓Clinical trials involving germline carriers
- ✓Institutional guidelines (ESMO, NCCN, INCa, ACMG)
- ✓New genotype-phenotype correlations
Excluded
- ✕Purely somatic oncology (without germline component)
- ✕Acquired somatic variants
- ✕Studies without direct implications for constitutional carriers
- ✕Reviews without original data if deemed low added value
Scoring methodology
Each article is evaluated out of 10 points. Inclusion threshold: score ≥ 5.
- Clinical impact (0–3)Primary criterion. +3: changes practice immediately (CPIC A dose recommendation, prophylactic surgery, deployable tool). +2: likely impact in the short term. +1: indirect contribution to counselling or understanding. 0: fundamental interest only.
- Strength of evidence (0–3)+3: robust causality — functional + multi-family segregation, large prospective cohort, or RCT. +2: good evidence — quality functional alone, cohort ≥10 families or ≥100 patients. +1: partial evidence. 0: preliminary data or single case report.
- Novelty (0–2)+2: unprecedented element (new gene, new CPIC A/B interaction, breakthrough tool). +1: significant extension (phenotypic expansion, VUS→P/LP reclassification, major replication). 0: minor replication or narrative review.
- Cohort size / robustness (0–1)+1 if ≥5 independent cases, ≥100 genotyped patients, cohort ≥1000, open-source code (bioinformatics), or meta-analysis ≥5 studies. 0 otherwise.
- Journal quality (0–1)+1 for a peer-reviewed journal recognised in the specialty (Nat Genet, AJHG, Genet Med, JCO, Pharmacogenomics J, Nat Methods…). 0 otherwise.
- Preprint penalty (−1)−1 for bioRxiv/medRxiv preprints not yet peer-reviewed. The preprint is still included if it carries major information.
Domain-specific note: In cancer genetics, clinical impact is the primary criterion (0–3 pts). Maximum score goes to studies modifying surveillance recommendations, opening access to PARP inhibitors, or supporting prophylactic surgery. Strength of evidence (0–3 pts) rewards large carrier cohorts and prospective penetrance studies.
Sources consulted
- —PubMed — BRCA1/2, TP53, PALB2, Lynch, hereditary predisposition query
- —Genetics in Medicine, Journal of Medical Genetics, EJHG
- —Journal of Clinical Oncology, Annals of Oncology
- —Nature Genetics, NEJM (exceptional high-impact cases)
Author
Informational document — does not constitute medical advice.