Editors' ChoiceCancer

Tumor mutations are not alone in the plasma

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Science Translational Medicine  11 Dec 2019:
Vol. 11, Issue 522, eaaz9767
DOI: 10.1126/scitranslmed.aaz9767


Most cell-free DNA mutations in cancer patients originate in hematopoietic clones.

Cell-free DNA (cfDNA) recovered from patient plasma has been the subject of intense research. Scientists and clinicians alike hope that detection of cancer-derived mutations in cfDNA can revolutionize early detection, alert physicians to recurrences, and help monitor therapy responses. However, analysis of cfDNA is challenging, as mutations occur at very low frequencies and can be difficult to interpret in the absence of matched tumor DNA. Now, a new study adds to these worries by showing that most cfDNA mutations detected in cancer patients originate in white blood cell clones and not in the tumor.

Razavi et al. performed ultra-deep sequencing of cfDNA and matched white blood cell genomic DNA in 124 cancer patients and 47 healthy people as controls. Matched tumor sequencing data were available for all cancer patients. Several encouraging insights emerged from the analysis: The fraction of tumor-derived cfDNA correlated with disease burden, and clinically relevant tumor characteristics, such as microsatellite instability, could be inferred from the cfDNA variants in some cases. However, the authors also found that in both controls and cancer patients, most variants found by the cfDNA assay were derived from clonal expansions of white blood cells (a largely benign phenomenon called clonal hematopoiesis). Since mutations in hematopoietic clones and solid tumors can be similar, sequencing of cfDNA alone may not be sufficient to distinguish between cancer and clonal hematopoiesis. Even in patients with metastatic disease, the number of clonal hematopoiesis–derived variants was on average higher than the number of tumor-derived variants.

Razavi et al.’s results suggest that many cfDNA mutations can only be unambiguously interpreted if matched data from white blood cells and tumor tissue are available. This could pose a problem for early detection where no tumor DNA exists. But even if DNA from matched white blood cells is sequenced, some level of uncertainty remains in the screening setting: In healthy controls, 18% of cfDNA variants cannot be attributed to clonal hematopoiesis, suggesting that somatic mosaicism or (benign) clonal expansions in other tissues may contribute cfDNA mutations that may at times be difficult to distinguish from cancer-derived variants.

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