Epigenome-based cancer risk prediction: rationale, opportunities and challenges

Abstract

The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.

New perspectives on screening and early detection of endometrial cancer

“…Around 57 and 43% of endometrial cancers in the United States and the European Union, respectively, are thought to be attributable to overweight and obesity . Obesity can increase risk of endometrial cancer by a variety of mechanisms, including the conversion of androgens to estrogens via aromatase activity enhancing concentrations of endogenous sex hormones, and chronic inflammation mediated by proinflammatory adipokines and hyperinsulinemia, and epigenetic changes among others . Both Types I and II endometrial cancers have been linked to BMI, although the endometrioid subtype seems to be the histology predominantly associated to BMI.…”

“…Epigenetic markers have the advantage of being modifiable and they can also be used to monitor response to preventive actions, besides indicating risk of developing cancer. 43 MLH1 and HAND2 methylation are also early events in endometrial carcinogenesis, and occur in AH/EIN and/or endometrial cancer. [43][44][45][46] Furthermore, HAND2 methylation in premalignant endometrial lesions have shown to be less likely to respond to hormonal treatment.…”

“…43 MLH1 and HAND2 methylation are also early events in endometrial carcinogenesis, and occur in AH/EIN and/or endometrial cancer. [43][44][45][46] Furthermore, HAND2 methylation in premalignant endometrial lesions have shown to be less likely to respond to hormonal treatment. 44,46 Other frequently hypermethylated genes include CDKN2A, PTEN and ADCYAP1; while CTCF and CTCFL are commonly demethylated in endometrial cancer and precursors.…”

“…87 Obesity can increase risk of endometrial cancer by a variety of mechanisms, including the conversion of androgens to estrogens via aromatase activity enhancing concentrations of endogenous sex hormones, and chronic inflammation mediated by proinflammatory adipokines and hyperinsulinemia, and epigenetic changes among others. 43,82 Both Types I and II endometrial cancers have been linked to BMI, although the endometrioid subtype seems to be the histology predominantly associated to BMI. Pooled analyses from the Epidemiology of Endometrial Cancer Consortium showed that the odds ratio per 2 kg/m 2 increase was 1.20 for Type I and 1.12 for Type II tumors.…”

Early detection and prevention

“…For other cancer forms, longitudinally followed cohorts with blood samples may be particularly useful. There are indications that even cervical smear biobanks may be useful for the discovery of biomarkers for screening for other cancer forms because epigenetic modifications of DNA occur early in life, affect the risk for multiple cancer forms and can be measured in the DNA of cervical cells (Widschwendter et al, 2018). The concept to systematically link biobanks with cancer registries aiming to establish a study base with blood samples that can be used for longitudinal research on screening has been known for decades (Pukkala et al, 2007) and there are very large cohorts with blood samples established for cancer research broadly, such as the Janus cohort in Norway (Langseth et al, 2017) and the Finnish Maternity Cohort (Lehtinen et al, 2017), or more specifically for breast cancer screening, such as the Karma cohort in Sweden (Gabrielson et al, 2017).…”