Genome Wide DNA Methylation In Pre Diagnostic Blood And Bladder Cancer Risk In The Women's Health Initiative.

In this study we found higher Alu methylation among participants who were younger and had lower BMI. For cancer incidence, time-dependent LINE-1 methylation was positively associated with risk of prostate cancer only. For cancer mortality, Alu methylation at the first blood draw as well as time-dependent LINE-1 methylation were associated with increased risk of all-cancer mortality. We identified associations between Alu methylation, and respiratory and digestive cancers, however, because of the small number of cases in these analyses our results should be interpreted cautiously. Interestingly, LINE-1 methylation was significantly lower in participants who ultimately developed cancer >10 years prior to conventional diagnosis, whereas a more rapid rate of increase in Alu methylation was significantly associated with risk of developing cancer. The updated results are different from our previous report (Zhu et al, 2011), which might be owing to the much larger number of incident cancer cases in our analysis (138 in our analysis vs 30 in the previous report), as well as our exclusion of prevalent cancers from the mortality analysis (leaving us with 37 deaths due to an incident cancer vs 11 in the previous report).

Although most studies of cancer, and Alu and LINE-1 methylation have found inverse relationships between these methylation measures and cancer, the vast majority of these findings have used tumour tissue, or blood leucocytes collected after cancer diagnosis (Brennan and Flanagan, 2012). Furthermore, two recent meta-analyses found that different measures of global DNA methylation in blood produce different associations with cancer risk, and that the methodological heterogeneity of studies makes drawing conclusions as to its use as a cancer biomarker difficult (Brennan and Flanagan, 2012; Woo and Kim, 2012). The findings of the handful of prospective studies of blood leucocyte Alu or LINE-1 methylation have thus far been less consistent. Three studies of gastric, liver, and breast cancer found no prospective associations between cancer risk and LINE-1 methylation (Balassiano et al, 2011; Brennan et al, 2012; Wu et al, 2012). In another prospective study, LINE-1 hypomethylation was associated with breast cancer risk (Deroo et al, 2014), whereas two others found marginally significant associations between LINE-1 hypermethylation, and kidney (Karami et al, 2015) and bladder cancer (Andreotti et al, 2014). A prospective study of Alu methylation found an inverse association between Alu methylation and gastric cancer risk, but only with latencies of >1 year (Gao et al, 2012). These discrepant results are likely owing to high variation in study designs and populations (Brennan and Flanagan, 2012), such as the intervals between blood sample collection and cancer diagnosis, which ranged from 1 to 16 years in those cited above. A recent prospective analysis of prostate cancer patients found that the relationship between Alu methylation and prostate cancer risk varied by length of this interval, with associations between Alu hypermethylation and increased risk appearing only among subjects diagnosed 4 or more years after their blood draw (Barry et al, 2015). Although the effects of various intervals between blood sample collection and cancer diagnosis have not been studied in LINE-1 hypermethylation specifically, this effect may also explain our findings of increased prostate cancer risk with time-dependent LINE-1 methylation.Sponsored: Gambar Koala

To our knowledge, few studies have examined associations between global DNA methylation of blood leucocytes collected pre-diagnostically and cancer mortality. Two studies found associations between serum LINE-1 hypomethylation and all-cause mortality in populations composed largely of cancer patients (Tangkijvanich et al, 2007; Ramzy et al, 2011), and our prior analysis of NAS data found associations between both LINE-1 and Alu hypomethylation and all-cancer mortality (Zhu et al, 2011). That our results represent a marked shift from the prior publication is cause for concern. We feel that this is primarily because of the fact that approximately half (59%) of cancer deaths in the previous study were due to cancers diagnosed prior to the first blood draw, potentially obscuring the temporal (and thus causal) relationship. The fact that our mortality analysis was conducted solely on participants who were free of cancer at the first blood draw may explain the discrepancy between our findings and those reported elsewhere in the literature examining cancer mortality among methylation measures obtained pre- and post-diagnosis. Future studies should further examine Alu and LINE-1 methylation as potential prognostic biomarkers for cancer mortality, and the differences in these relationships between methylation measures pre and post diagnosis.

Recent research suggests a dynamic role of Alu methylation during normal development and aging (Luo et al, 2014). Our analysis found a significant association between faster Alu methylation and higher cancer incidence, coupled with what is already known about the involvement of Alu methylation in tumourigenesis, this raises the possibility that Alu may have a dynamic role in cancer development as well. Similarly, we found that on average participants who would ultimately develop cancer had much lower LINE-1 methylation compared with cancer-free participants, but only at 10 years before diagnosis. Although both these findings are not unprecedented in this data set (Joyce et al, 2015), the low sample size of the NAS means that these results should be interpreted with caution. Further validation of these longitudinal biomarkers of cancer is required, but, if successful, could yield potent new tools for cancer early detection.

Although methylation of LINE-1 and Alu elements have both been widely used as surrogates for global DNA methylation, growing evidence shows that they each have a distinct functional role potentially affecting cancer development and progression via different mechanisms in methylation regulation, responses to cellular stressors and environmental exposures, and methylation levels (Li and Schmid, 2001; Jones and Baylin, 2002; Biemont and Vieira, 2006; Rusiecki et al, 2008). Even specific LINE-1 loci may exert different effects on disease risk (Nusgen et al, 2015; though there was no evidence for this in our particular data set). Thus, our finding different relationships between Alu and LINE-1 methylation and cancer is unsurprising, despite both being surrogates for global DNA methylation.

Our use of samples collected and stored before cancer diagnosis is a particular strength of this study as it avoids a number of biases inherent in case-control designs, particularly disease- or treatment-induced epigenetic changes. Nonetheless, this study has several limitations. The trade-off to collecting a large quantity of data across multiple follow-up measurements is a relatively low sample size. These factors limited our ability to examine specific subtypes of cancer beyond prostate cancer. In addition, as noted above, our sample was not representative of the general population. Being older, male, white, educated, and/or having a history of military service may all influence both global DNA methylation and cancer. Therefore, our results will need to be confirmed in other, more representative populations. Finally, it should be noted (as it has in both recent meta-analyses (Brennan and Flanagan, 2012; Barchitta et al, 2014) on the subject) that publication bias is a serious and unresolved concern for studies of Alu and LINE-1 methylation, and that care should be taken in the future to report null results.

In conclusion, this prospective study of global DNA methylation and cancer found a series of complex relationships underlying Alu and LINE-1 methylation, cancer incidence and mortality, and time. Alu and LINE-1 hypermethylation of blood leucocytes may be a predictor of cancer incidence, in particular prostate cancer. Furthermore, Alu and LINE-1 methylation may serve as useful prognostic indicators of cancer mortality. The possible use of these two measures as cancer early-detection and prognostic biomarkers, and whether such relationships are consistent with other measures of global DNA methylation, should be validated in larger prospective studies. In addition, the rate of change of Alu methylation and average LINE-1 methylation 10 years pre-diagnostically are interesting (if speculative) findings that need to be confirmed in future research. Taken together, these findings suggest that global DNA methylation has a dynamic role in tumourigenesis and cancer progression, and identify several new avenues of research for the study of Alu and LINE-1 as biomarkers of cancer.

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