Background
Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based Comprehensive Genomic Profiling (CGP). However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.
Methods
We assessed the landscape of 11,914 liquid profiles across 48 cancer types using the Caris Assure assay, a whole exome and whole transcriptome NGS workflow that independently sequences both plasma-derived cell-free total nucleic acids (cfTNA) as well as the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.
Results
39.5% of 11,914 patients presented at least one pathogenic or likely pathogenic CH variant among reportable clinical genes. We found 79.9% of all BRCA2 variants to be of CH origin, as well as 79.4% of CHEK2, 68.5% of BRCA1, 41.9% of ATM, 6.3% NRAS, 6.2% BRAF, 2.4% KIT, 2.3% KRAS, and 1.8% EGFR. For patients aged 65-69, the median rate of CH variant classification was 17%, whereas it was 29% for patients aged 70-74, 33% for ages 75-79, and 50% for ages 80+. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.