Tumor-derived cfDNA shows distinct fragmentation profiles versus cfDNA from healthy individuals.

  • Major Finding: Tumor-derived cfDNA shows distinct fragmentation profiles versus cfDNA from healthy individuals.

  • Concept: Genome-wide fragmentation profiles can be used to identify the tissue of origin of cancers.

  • Impact: Combined fragmentation and mutation-based cfDNA analyses may be useful for early cancer detection.


Analysis of circulating tumor cell–derived cell-free DNA (cfDNA) in a patient's blood has been developed as a noninvasive strategy for cancer detection. However, distinguishing tumor-derived DNA sequences from normal DNA using current analysis methods remains a challenge due to sensitivity thresholds. To overcome this limitation, Cristiano and colleagues developed an approach termed “DNA evaluation of fragments for early interception” (DELFI) that permits the detection of a large number of abnormalities by genome-wide analysis of fragmentation patterns in cfDNA using low-coverage whole-genome sequencing. This approach revealed that cfDNA fragmentation patterns from healthy individuals were consistent and highly correlated with lymphocyte nucleosomal DNA fragmentation profiles, whereas cfDNA from patients with cancer showed variable increases and decreases in fragment sizes at different genomic regions. These fragmentation differences were detectable even at 0.5X coverage, and the degree of detected fragmentation abnormality correlated with mutant allele fractions during therapy in patients with non–small cell lung cancer, suggesting that analysis of fragmentation patterns may be used to detect cfDNA from cancer cells and to monitor patients throughout the course of treatment. Application of a machine-learning model to cfDNA samples obtained from 208 patients across 7 different tumor types as well as 215 healthy individuals detected cancer-derived samples with 73% sensitivity and 98% specificity and identified the tissue-of-origin to one of two sites with 75% accuracy. Incorporating mutation detection with DELFI improved the sensitivity of cancer detection to 91%, while maintaining specificity. These results define differences in genome-wide cfDNA fragmentation profiles in patients with cancer compared with healthy people and suggest that DELFI may be a useful and highly sensitive tool for early cancer screening using cfDNA.

Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 2019 May 29 [ePub ahead of print].

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