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DNA methylation may explain link between aspirin use, mortality after breast cancer diagnosis
DNA methylation could explain the apparent varying influence of aspirin use on mortality risk after breast cancer diagnosis, according to results of a retrospective study published in Cancer.
“Consideration of DNA methylation profiles as potential modifiers of the aspirin-mortality association may provide new insights on the underlying biological mechanisms on aspirin use in relation to mortality after breast cancer diagnosis,” Tengteng Wang, PhD, MBBS, MSPH, a doctoral candidate at Gillings School of Global Public Health at The University of North Carolina Chapel Hill during the formation of the study and now a postdoctoral research fellow in the department of epidemiology at Harvard University, said in a press release.
Previous studies have shown that aspirin reduces the risk for developing breast cancer because it inhibits cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis, which helps dictate inflammation and estrogen biosynthesis. However, only limited and inconclusive data exist on the underlying biological mechanisms linking aspirin use to breast cancer prognosis, according to the researchers, who hypothesized that epigenetic changes could help to clarify these mechanisms.
In this population-based study, Wang and colleagues assessed prediagnosis aspirin use within a cohort of 1,508 women aged 20 to 98 years (93% white) diagnosed with first primary breast cancer between 1996 and 1997. The researchers sought to determine whether aspirin used before diagnosis interacts with two global methylation markers in peripheral blood DNA and promoter methylation in 13 breast cancer-related genes in tumors to influence mortality after breast cancer.
Researchers assessed global methylation in peripheral blood by long interspersed elements-1 (LINE-1) and the luminometric methylation assay, and measured promoter methylation of the 13 breast cancer-related genes in tumors by methylation-specific polymerase chain reaction and the MethyLight assay.
The final analysis included 1,442 women with breast cancer who completed responses to questions on prediagnosis aspirin use (aspirin users, n = 301; nonusers, n = 1,141). Aspirin users appeared more likely than nonusers to be postmenopausal, have overweight or obesity at diagnosis, and consume more fruits and vegetables.
Median follow-up was 17.6 years (range, 0.2-18.4).
Among 1,266 women with available follow-up information, 476 died of any cause and 202 died of breast cancer by the end of 2014.
Results showed higher all-cause mortality among aspirin users who had methylated promoter of BRCA1 (HR = 1.67; 95% CI, 1.26-2.22) but not among those with unmethylated promoter of BRCA1 (HR = 0.99; 95% CI, 0.67-1.45).
Aspirin users with unmethylated tumor BRCA1 promoter had lower breast cancer mortality (HR = 0.6; 95% CI, 0.25-1.45) than women with methylated BRCA1 (HR = 1.16; 95% CI, 0.69-1.95). Women with a methylated PR promoter also demonstrated a higher risk for breast cancer-related mortality (HR = 1.63; 95% CI, 0.68-3.9) than women with unmethylated PR promoter (HR = 0.78; 95% CI, 0.46-1.33).
Among women with LINE-1 hypomethylation, aspirin use appeared associated with a higher risk for breast cancer mortality (HR = 1.45; 95% CI, 0.86-2.42), but this risk was lower among aspirin users with LINE-1 hypermethylation (HR = 0.63; 95% CI, 0.33-1.2).
Researchers did not observe any statistically significant association between aspirin use and PR promoter methylation on all-cause mortality.
Researchers could not obtain tumor tissue and blood specimens for all women and had to rely on self-reporting of aspirin use, which served as the study’s primary limitations.
“Future research designed to replicate our findings should include a larger sample size to allow examination of patterns of aspirin use, and an enlarged panel of genes to explore the role of genetic predisposition in driving overall genetic instability on survival after breast cancer diagnosis,” Wang and her mentor Marille Gammon, PhD, professor in the department of epidemiology at Gillings School of Global Public Health at The University of North Carolina at Chapel Hill, said in the press release.
The findings suggest that DNA methylation someday could help to identify people for whom treatment may or may not be successful, and that epigenetic biomarkers can be reliable across multiple tissue types, Kristen M. C. Malecki, PhD, MPH, associate professor in the department of population health sciences at University of Wisconsin, wrote in an accompanying editorial. Such studies are critical for translational research, Malecki noted.
“Studies like [this] suggest the time is right to advance cancer research using epigenetics as a promising tool to support novel discoveries and clinical advancement,” Malecki wrote. “The emergence of lower-cost assays and tools using clinically accessible biomarkers to determine the efficacy of treatment regimens is critically essential to advancing the field.” – by John DeRosier
Disclosures: Gammon and Wang report no relevant financial disclosures. Please see the study for all other relevant financial disclosures. Malecki reports research grants from the NIH.