Journal: European journal of human genetics : EJHG
This review focuses on how tumor genomic features can be leveraged to better diagnose, classify, and treat hereditary cancers.
Key points:
- Hereditary cancers arise from germline pathogenic variants, mainly in tumor suppressors and DNA repair/replication genes, occasionally in oncogenes.
- Most follow Knudson’s two-hit model: a germline pathogenic variant plus a second somatic hit in the same gene drives tumorigenesis.
Tumor mutational features:
- Genome-wide sequencing now allows systematic assessment of:
- Microsatellite instability (MSI)
- Tumor mutational burden (TMB)
- Mutational signatures
- High or ultra-high TMB often signals underlying DNA repair deficiency.
- Distinct mutational signatures can point to the specific defective pathway (e.g., mismatch repair, homologous recombination, base excision repair, nucleotide excision repair, polymerase proofreading).
Clinical utility for hereditary cancer:
- Tumor sequencing helps:
- Distinguish hereditary from sporadic tumors.
- Interpret germline variants (e.g., supporting pathogenicity vs VUS).
- Detect somatic mosaicism that may underlie atypical presentations.
- Tumor profiling refines syndrome diagnosis and risk assessment by linking germline findings to tumor molecular phenotypes.
Therapeutic implications:
- DNA repair–deficient tumors can be matched to targeted therapies:
- PARP inhibitors for tumors with BRCA1/2 and other homologous recombination defects.
- Immune checkpoint inhibitors for tumors with mismatch repair deficiency or polymerase proofreading defects, often characterized by very high TMB.
- Tumor sequencing can also identify targetable oncogenic drivers in hereditary settings (e.g., RET, VHL), enabling the use of specific inhibitors.
Overall, the article emphasizes integrating tumor molecular profiling with germline genetics to improve diagnostic accuracy, guide surveillance and risk management, and individualize systemic therapy for patients with hereditary cancer syndromes.