TY - JOUR
T1 - Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood
AU - Zhao, Naisi
AU - Ruan, Mengyuan
AU - Koestler, Devin C.
AU - Lu, Jiayun
AU - Marsit, Carmen J.
AU - Kelsey, Karl T.
AU - Platz, Elizabeth A.
AU - Michaud, Dominique S.
N1 - Funding Information:
This work was supported by 2018 American Association for Cancer Research (AACR)-Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-MICH). Note: The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that helped support the availability of the cancer registry data.
Funding Information:
Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that helped support the availability of the cancer registry data.
Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - Background: DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development. Methods: In a nested case–control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status. Results: We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95–4.59, P-value = 4.81 × 10–7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls. Conclusion: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.
AB - Background: DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development. Methods: In a nested case–control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status. Results: We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95–4.59, P-value = 4.81 × 10–7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls. Conclusion: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.
KW - DNA methylation
KW - Illumina MethylationEPIC array
KW - Lung cancer
KW - blood
KW - epigenome-wide association study (EWAS)
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U2 - 10.1080/15592294.2021.1923615
DO - 10.1080/15592294.2021.1923615
M3 - Article
C2 - 34008478
AN - SCOPUS:85106346340
VL - 17
SP - 460
EP - 472
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
IS - 4
ER -