Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms

Amedeo Gagliardi, Pierre-Antoine Dugué, Therese H Nøst, Melissa C Southey, Daniel D Buchanan, Daniel F Schmidt, Enes Makalic, Allison M Hodge, Dallas R English, Nicole W Doo, John L Hopper, Gianluca Severi, Laura Baglietto, Alessio Naccarati, Sonia Tarallo, Luigia Pace, Vittorio Krogh, Domenico Palli, Salvatore Panico, Carlotta SacerdoteRosario Tumino, Eiliv Lund, Graham G Giles, Barbara Pardini, Torkjel M Sandanger, Roger L Milne, Paolo Vineis, Silvia Polidoro, Giovanni Fiorito

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated.

METHODS: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case-control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions.

RESULTS: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11-1.41 for breast cancer, and 1.23; 95% CI, 1.07-1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25-1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome.

CONCLUSIONS: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples.

IMPACT: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.

Original languageEnglish
Pages (from-to)2026-2037
Number of pages12
JournalCancer Epidemiology Biomarkers and Prevention
Volume29
Issue number10
DOIs
Publication statusPublished - Oct 2020

Fingerprint Dive into the research topics of 'Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms'. Together they form a unique fingerprint.

Cite this