Abstract
Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM, commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2 and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p<0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p<0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results.
Highlights
Received December 13, 2018; received in revised form March 5, 2019; accepted April 11, 2019 ∗ Corresponding author at: City of Hope, Department of MedicalOncology and Therapeutics Research, Bldg. 173, Room #131, 1500E
The analysis examined the molecular characteristics of likelysomatic variants across the full testing population to identify trends that might provide further insight into their origins
Most individuals (75.0%; 9/12) who had a germline Pathogenic Variants (PV) and a somatic PV or Variants of Uncertain Significance (VUS) in ATM had a personal history of cancer. These analyses detail the frequency and characteristics of likely-somatic variants identified within the largest hereditary pan-cancer panel testing population described to date
Summary
Low-level mosaicism is seen frequently in normal tissues, and in those with higher turnover rates [1]. One such tissue is bone marrow, which produces the peripheral white blood cells that comprise a common source of genomic DNA used in next-generation sequencing (NGS) hereditary pan-cancer panel testing. NGS methods enable precise assessment of variant allele proportions and can reveal low-level mosaicism in an individual’s test sample [1,2]. Many likely-mosaic variants identified in this manner reflect amplification of mutations acquired somatically in blood via clonal hematopoiesis of indeterminate potential (CHIP), which involves the expansion of clonal blood cell subpopulations without other hematologic disease [3]. Putative CHIP-derived somatic variants hold potential as independent clinical biomarkers, following clinical validation of methods for CHIP confirmation and variant classification
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