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Blogger's Note: see tables for additional detailed information
JAMA Oncology - open access
Conclusions and Relevance Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.
.....In some patients, a cancer-predisposing variant is present in the “normal” DNA, either inherited or as an early postzygotic event. The burden of germline variants differs by tumor type, although it can be substantial (eg, mutations of the Fanconi pathway genes can be seen in 20% of patients with ovarian cancer).6 Most germline susceptibility variants are not targetable, although there are exceptions (eg, PARP inhibitors in patients with BRCA1 and BRCA2 mutation-associated cancers). Efforts to characterize germline susceptibility are therefore usually ancillary to the primary purpose of clinical tumor mutation profiling. However, knowledge of these variants could guide the preventive care of the patient or the patient’s family, even if the knowledge does not influence the treatment of the patient’s cancer.7....
- Targeted tumor sequencing with a panel of 341 genes and matched normal DNA in 1566 individuals with advanced malignant neoplasms revealed presumed pathogenic germline variants (PPGVs) in about 16% of individuals.
- Most PPGVs (80.5%; 95% CI, 75.1%-85.0%) were in genes related to cancer susceptibility.
- The PPGVs in genes previously designated as clinically actionable were seen in 5.0% (95% CI, 4.1%-6.2%) of individuals.
- Most cancer-susceptibility PPGVs were retained in the tumor (91.9%; 95% CI, 87.3%-95.0%).
- Almost all individuals carried germline variants of uncertain significance that will require significant curation to determine clinical significance.
Supplement.eTable 1. Distribution and demographics of cases across 68 cancer types (n=1566)eTable 2. Genes on MSK-IMPACT (n=341)eTable 3. Summary of OMIM annotated genes on MSK-IMPACT compared by modes of inheritanceeTable 4. OMIM genes and associated syndromes on MSK-IMPACT paneleTable 5. Presumed pathogenic germline variant classifications in OMIM genes (including Cancer and ACMG gene subsets) included on MSK-IMPACTeTable 6. Genes with variant totals for single nucleotide variants, insertion or deletions, and copy number variants (SNV, Indels, CNVs) grouped by potential phenotype in the patienteTable 7. Presumed pathogenic germline variants in OMIM genes (including Cancer and ACMG gene subsets) included on MSK-IMPACT per subjecteTable 8. Presumed pathogenic germline variants in OMIM genes and status of PPGV in tumoreTable 9. Aggregate presumed pathogenic germline variant totals by disease site and gene
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