A potential limitation of our study was the use

A potential limitation of our study was the use of hospital controls as proxies of healthy people. Controls were admitted for a wide variety of routine conditions unrelated to tobacco and it is implausible that a high proportion of the controls with a detectable damaging TP53 mutation developed a cancer in the short term. However, we cannot exclude this occurring in a small number of controls nor enriching for non-cancer diseases with unknown impact on the presence of circulating-tumor fragments. Nevertheless, as noted above, the prevalence of TP53 mutations in our study is approximately equal to that of GENAIR (when applying the same detection thresholds). Prospective cohorts may help to overcome the limitations of using hospital controls and also help to determine at what point in the development of the disease is ctDNA detectable in blood, and its correlation with a plausible diagnosis. The source of circulating-mutated fragments in the cfDNA of apparently healthy people is still unknown. There is, however, accumulating evidence that clonal expansions are more frequent than originally thought. Martincorena and colleagues estimated that there are 9.5 clones per cm2 of normal human skin carrying a driver mutation in TP53 in a selected population for high-sun exposure (Martincorena and Campbell, 2015). Such clonal expansions might act as a reservoir of circulating-mutated fragments in cfDNA. In addition, several studies have shown that a subset of normal individuals could undergo clonal hematopoiesis with mutations in driver Fmoc-Leu-OH (Genovese et al., 2014; Jacobs et al., 2012; Jaiswal et al., 2014; Laurie et al., 2012; Wong et al., 2015; Xie et al., 2014). Consistent with this, we observed 4 cfDNA TP53 mutations that appeared to be from clonal expansions in WBC. We also noted 2 TP53 mutations in one SCLC case, apparently from different organs; one originating from WBC, the second we assume from the SCLC tumor. Such ambiguity around the tissue of origin of the circulating-mutated fragments adds another layer of complexity when using ctDNA for early detection. The potential of ctDNA for early diagnosis of cancer is an area of much interest (The Lancet Oncology, 2016). While implementation in a screening setting will undoubtedly require more sensitive and specific tests as well as validation in pre-diagnostic blood samples, the unexpected presence of known cancer mutations in cfDNA among non-cancer controls represents an important challenge.
Funding Sources This work has been funded by IARC. TMD was supported by la Ligue Nationale (Française) Contre le Cancer. The work reported in Anticoding strand paper was undertaken during the tenure of PHA\'s Postdoctoral Fellowship from the International Agency for Research on Cancer, partially supported by the European Commission FP7 Marie Curie Actions – People – Co-funding of regional, national and international programmes (COFUND).
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Introduction 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) is the rate-limiting enzyme for cholesterol synthesis in the conversion of HMG-CoA to mevalonate. Statins are HMGR inhibitors decreasing serum cholesterol to reduce the incidence of cardiovascular and cerebrovascular disorders (Minder et al., 2012). In addition to cholesterol synthesis, activation of HMGR facilitated protein prenylation, such as farnesylation of Ras oncoproteins for cell growth and carcinogenesis (Thurnher et al., 2012). The mevalonate pathway was up-regulated by mutant p53 or activation of oncogenic signaling, such as HIF-1 or PI3K-Akt (Freed-Pastor et al., 2012; Semenza, 2003; Yuan and Cantley, 2008). Clinical studies also showed the promise of statins in cancer prevention (Simon et al., 2012; Poynter et al., 2005). Therefore, targeting HMGR-mevalonate pathway might be a strategy against cancer. However, the role of HMGR as an oncotarget remains to be elucidated.