Variants with a low allele frequency detected in genomic DNA affect the accuracy of mutation detection in cell‐free DNA by next‐generation sequencing

Abstract

Because only a small fraction of total cfDNA might be derived from tumor cells, only mutations with the first allele frequency pattern may be regarded as tumor-specific mutations in cfDNA. Effective filtering of background mutations will be required to improve the accuracy of mutation calls in cfDNA. Cancer 2018;124:1061-9. © 2017 American Cancer Society.

Identification of driver genes and somatic mutations in cell‐free DNA of patients with pulmonary lymphangioleiomyomatosis

“…Nevertheless, important issues focusing on which subclones derived from LAM cells give rise to metastasis and the potential clinical benefits remain to be addressed. In our study, mutation levels in cfDNA from LAM patients were more than those from normal individuals, which was compatible with previous published studies that circulating cfDNA levels from nonapoptotic DNA fragments are drastically elevated in cancer patients . However, it should be noted that the displayed mutational burden was calculated based on predicted genetic mutations due to limited targeted genes in our study.…”

“…Fragments of circulating cfDNA were shown to be derived from apoptosis, necrosis or active secretion, which can be detected in the cell-free components of plasma and serum. 29 The mutant allele frequencies in cfDNA from apoptotic cells were almost identical with those in the blood cells. 29,30 Consistent with this, we observed that mutant allele frequencies in cfDNA were distinct from gDNA, and that had a significant correlation with gDNA in coexisting mutations.…”

“…29 The mutant allele frequencies in cfDNA from apoptotic cells were almost identical with those in the blood cells. 29,30 Consistent with this, we observed that mutant allele frequencies in cfDNA were distinct from gDNA, and that had a significant correlation with gDNA in coexisting mutations. Therefore, a significant fraction of alterations identified in cfDNA should be considered as the background mutations from apoptotic DNA fragments.…”

“…Fragments of circulating cfDNA were shown to be derived from apoptosis, necrosis or active secretion, which can be detected in the cell‐free components of plasma and serum . The mutant allele frequencies in cfDNA from apoptotic cells were almost identical with those in the blood cells .…”

“…Moreover, cfDNA from LAM patients harbored more than 70% unique mutations that were not detected in both gDNA and controls. The utilization of NGS for the detection of cancer‐associated mutations in the cfDNA opens up amazing possibilities . Thus, a potential prospective area for liquid biopsies to spread out a genetic landscape of LAM will be achieved from clinical studies in order to select novel molecular markers‐directed treatment for LAM development.…”