Background Epigenetic changes contribute to colorectal cancer (CRC) pathogenesis. We investigated whether methylation quantitative trait loci (mQTLs) are associated with CRC risk, survival and recurrence. Methods Using a well-characterised Scottish case-control study (6821 CRC cases, 14,692 controls), we derived 118,982 mQTLs based on the Genetics of DNA Methylation Consortium (GoDMC). Association analysis between mQTLs and CRC risk, survival and recurrence was performed using logistic regression or Cox models respectively. Additionally, colocalisation analysis was performed. Results 19 mQTLs within 10 distinct genomic regions were associated with CRC risk. Two novel regions were mapped to MDGA2 (p value = <InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="41416_2025_3064_Article_IEq1.gif" Format="GIF" Height="18" Rendition="HTML" Resolution="72" Type="Linedraw" Width="71" /> </InlineMediaObject> <EquationSource Format="TEX">$3.0 \times\!{10}^{-6}$</EquationSource> <EquationSource Format="MATHML"><math> <mn>3.0</mn> <mo>×</mo> <mspace width="0.3em" /> <msup> <mrow> <mn>10</mn> </mrow> <mrow> <mo>−</mo> <mn>6</mn> </mrow> </msup> </math></EquationSource> </InlineEquation>) and STARD3 (p value = <InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="41416_2025_3064_Article_IEq2.gif" Format="GIF" Height="18" Rendition="HTML" Resolution="72" Type="Linedraw" Width="71" /> </InlineMediaObject> <EquationSource Format="TEX">$5.6 \times\!{10}^{-6}$</EquationSource> <EquationSource Format="MATHML"><math> <mn>5.6</mn> <mo>×</mo> <mspace width="0.3em" /> <msup> <mrow> <mn>10</mn> </mrow> <mrow> <mo>−</mo> <mn>6</mn> </mrow> </msup> </math></EquationSource> </InlineEquation>). Four regions mapped to POU5F1B, POU2AF2 (c11orf53)/POU2AF3 (COLCA2), GREM1 and CABLES2 were previously identified. Four regions mapped to PPA2, PANDAR/LAP3P2, POU6F1 and CTIF contained SNPs previously identified by CRC GWAS but with SNPs annotated to different genes. We found no evidence that any of the 19 mQTLs associated with CRC risk influenced survival or recurrence after FDR correction. Colocalisation analysis suggested that in three of the ten regions the causal variants were shared for methylation and CRC risk. Conclusion This study adds to the repertoire of CRC genes. However, we found no associations between methylation and CRC survival or recurrence.

Association between methylation quantitative trait loci and colorectal cancer risk, survival and cancer recurrence

期刊论文
出版模式：

开放获取
发表日期：

2025年6月12日

查看全文

Ines Mesa-Eguiagaray,
Andrii Iakovliev,
Xue Li,
Maria Timofeeva,
Yazhou He,
Xiaomeng Zhang,
Farhat V. N. Din,
Susan M. Farrington,
Athina Spiliopoulou,
Malcolm G. Dunlop,
Evropi Theodoratou

摘要

Background

Epigenetic changes contribute to colorectal cancer (CRC) pathogenesis. We investigated whether methylation quantitative trait loci (mQTLs) are associated with CRC risk, survival and recurrence.

Methods

Using a well-characterised Scottish case-control study (6821 CRC cases, 14,692 controls), we derived 118,982 mQTLs based on the Genetics of DNA Methylation Consortium (GoDMC). Association analysis between mQTLs and CRC risk, survival and recurrence was performed using logistic regression or Cox models respectively. Additionally, colocalisation analysis was performed.

Results

19 mQTLs within 10 distinct genomic regions were associated with CRC risk. Two novel regions were mapped to MDGA2 (p value = $3.0 \times\!{10}^{-6}$ $3.0 \times 10^{- 6}$ ) and STARD3 (p value = $5.6 \times\!{10}^{-6}$ $5.6 \times 10^{- 6}$ ). Four regions mapped to POU5F1B, POU2AF2 (c11orf53)/POU2AF3 (COLCA2), GREM1 and CABLES2 were previously identified. Four regions mapped to PPA2, PANDAR/LAP3P2, POU6F1 and CTIF contained SNPs previously identified by CRC GWAS but with SNPs annotated to different genes. We found no evidence that any of the 19 mQTLs associated with CRC risk influenced survival or recurrence after FDR correction. Colocalisation analysis suggested that in three of the ten regions the causal variants were shared for methylation and CRC risk.

Conclusion

This study adds to the repertoire of CRC genes. However, we found no associations between methylation and CRC survival or recurrence.