Abstract
Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.
Highlights
Circulating tumor DNA provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information
DNA isolated from plasma and matched white blood cell (WBC) underwent hybridization capture and targeted deep sequencing to detect somatic single-nucleotide variants (SNVs), small fragment of insertions and deletions (Indels), copy number variants, and chromosomal rearrangements
Discussion we report a study of noninvasive Circulating tumor DNA (ctDNA) detection for pan-cancer Chinese patients
Summary
Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Despite many ctDNA-related studies published in recent years, large-scale analysis of ctDNA across diverse cancer types is still lacking To fill this gap and understand the Chinese-specific cancer genome, we employed a targeted deep sequencing assay that utilizes extensive error correction methods and provides the depth and breadth necessary to optimally investigate tumorderived genomic alterations in plasma cfDNA, even at low allelic fractions (AFs)[16,17]. To eliminate the interference of clonal hematopoiesis (CH)-related variants, we performed parallel sequencing for white blood cell (WBC) DNA and performed comparisons with cfDNA to identify tumor-specific genomic alterations, which we benchmarked against a tissue-based genomic database. The results of this study provide a foundation for further exploration and application of ctDNA and identify limitations in need of additional strategic and technological improvements
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