Abstract
BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.
Highlights
In the latest global cancer data released by the International Agency for Research on Cancer (IARC), breast cancer has been confirmed as the most commonly diagnosed cancer in women
485 single-nucleotide polymorphisms (SNPs) were obtained for 436 CpG sites (Supplementary Table S1), with F statistics ranging from 19 to 952, reflecting a strong instrument strength for smoking-related DNA methylation
For ER+ breast cancer, we observed four CpG-cancer effect estimates that survived in multiple comparisons test (q-value after false discovery rate < 0.05): using rs8035987 as an instrument, we found that the smoking-related DNA methylation level of cg2583948 was associated with the risk of ER+ breast cancer [OR = 0.94, 95% CI (0.91–0.97)]
Summary
In the latest global cancer data released by the International Agency for Research on Cancer (IARC), breast cancer has been confirmed as the most commonly diagnosed cancer in women (https://www. iarc.who.int/). In the latest global cancer data released by the International Agency for Research on Cancer (IARC), breast cancer has been confirmed as the most commonly diagnosed cancer in women It has been confirmed that cigarette smoking, one of the most important environmental risk factors, represents a significant effect on breast cancer risk [1,2,3,4]. In contrast to previous studies with the above limitations, Mendelian randomization (MR) offers an opportunity to efficiently and reliably assess the causal effects between smoking-related DNA methylation patterns and breast cancer risk. Whether smoking promotes breast cancer through DNA methylation remains unknown
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