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Lam, W. K. Jacky; Jiang, Peiyong; Chan, K. C. Allen; Cheng, Suk H.; Zhang, Haiqiang; Peng, Wenlei; Tse, O. Y. Olivia; Tong, Yu K.; Gai, Wanxia; Zee, Benny C. Y.; Ma, Brigette B. Y.; Hui, Edwin P.; Chan, Anthony T. C.; Woo, John K. S.; Chiu, Rossa W. K.; Lo, Y. M. Dennis
Proceedings of the National Academy of Sciences - PNAS, 05/2018, Volume: 115, Issue: 22Journal Article
Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.
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