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

Permanent lenke
https://hdl.handle.net/10037/20759
DOI
https://doi.org/10.1158/1055-9965.EPI-20-0451
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Dato
2020-08-11
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Forfatter
Gagliardi, Amedeo; Dugué, Pierre-Antoine; Nøst, Therese Haugdahl; Southey, Melissa C.; Buchanan, Daniel D.; Schmidt, Daniel F; Makalic, Enes; Hodge, Allison M; English, Dallas R.; Wong Doo, Nicole; Hopper, John L.; Severi, Gianluca; Baglietto, Laura; Naccarati, Alessio; Krogh, Vittorio; Palli, Domenico; Panico, Salvatore; Sacerdote, Carlotta; Tumino, Rosario; Lund, Eiliv; Giles, Graham; Pardini, Barbara; Sandanger, Torkjel M; Milne, Roger L.; Paolo, Vineis; Polidoro, Silvia; Fiorito, Giovanni
Sammendrag

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.

Forlag
American Association for Cancer Research
Sitering
Gagliardi, Dugué, Nøst, Southey, Buchanan, Schmidt, Makalic, Hodge, English, Wong Doo, Hopper, Severi, Baglietto, Naccarati, Krogh, Palli, Panico, Sacerdote, Tumino, Lund, Giles, Pardini, Sandanger, Milne, Paolo, Polidoro, Fiorito. Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms. Cancer Epidemiology, Biomarkers and Prevention. 2020
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Copyright 2020 The Author(s)

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