Deep sequencing reveals that low level TP53 mutations are ubiquitous in ovarian cancer patients and controls: successes and challenges for early detection

Solid tumor cancers can have good prognosis if detected early, which has driven the search for screening techniques that are minimally invasive, inexpensive, and sensitive. Circulating tumor DNA (ctDNA) can be detected in the blood, even for localized tumors, as a result of tumor cell death. ctDNA can also be used to monitor response to therapy and relapse. Detection of low-level ctDNA in bodily fluids has been limited by artifactual mutations induced by the sequencing technologies or sample preparation protocols. Krimmel and colleagues (1) applied deep duplex sequencing (DS) to detect low levels of ctDNA in the peritoneal fluid (PF) of women with and without ovarian cancer. DS reduces many artifactual mutations by sequencing independently multiple copies of each strand of the same double-stranded molecule. This group not only found diagnostic mutations in nearly all ovarian cancer samples, but also low-level background TP53 mutations in all control samples. While the first finding may drive interest in duplex sequencing of liquid biopsies, the later findings shows that additional strategies will be needed to deal with the background mutations if deep-sequencing for mutations is to become an early detection biomarker.