AS673 - DNA methylation as a novel epigenetic biomarker that regulates metabolic and inflammatory cytokines in the development of obesity attributable cancers

 

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Investigator Names and Contact Information

Su Yon Jung (sjung@sonnet.ucla.edu)

Introduction/Intent

Postmenopausal women have an increased risk of developing breast cancer and colorectal cancer (CRC). The majority of new breast cancer and CRC cases (80% and 90%, respectively) occur in women age 50 years and older, 1-3 and obesity is a well-established risk factor. 4,5 Insulinlike growth factors (IGFs)/insulin resistance (IR) axis has been considered one of the major hormonal pathways mediating the biologic mechanism between obesity and postmenopausal breast cancer and CRC development. 5-8 IGFs/IR axis is central in developing many obesityrelevant cancers, including postmenopausal breast cancer and CRC,5-10 by overexpressing insulin and insulin-like growth factor receptors, leading to hyperactive and abnormal multiple cellular signaling downstream cascades, which are necessary in the tumor growth and development environment in particular cells. 5,11-13 IGFs/IR axis therefore may be associated with carcinogenesis. 

Chronic inflammation also plays an important role in the pathogenesis of colorectal cancer and as reported in more recent research, breast cancer, in postmenopausal women from tumor initiation to progression.14-16 The key inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) reflect different molecular pathways in the immune cascade in acute and chronic immune responses but may be interrelated in carcinogenesis.15 

The systemic development of metabolic (IGFs and IR) and inflammatory cytokines (CRP and IL-6) can be influenced by not only environmental4,17,18 but also genetic and epigenetic factors. 19 Despite advances in the understanding of genetic variances and gene–environment interactions in relation to those cytokines, common genetic variants explain a small proportion of the variation (IGFs/IR and CRP, < 5% each; IL-6, < 2%). 20-24 The analysis of epigenetics may, we hope, clarify some of the variation and provide insights into the mechanisms related to the biomarkers at the molecular level. DNA methylation (DNAm) is the well-characterized epigenetic modification. It involves mitotically heritable and reversible attachment of methyl groups at the 5´ carbon of cytosine in CpG dinucleotides, influencing DNA transcription without altering the primary DNA sequence. 25-27 DNAm is modifiable via lifestyle and environmental factors such as obesity, 25,28 nutrients, 29 smoking, 30 and environmental pollutants. 31 Finally, DNAm reflects a wide range of environmental exposures and genetic influences, regulating gene expression, and potentially affecting the risk for disease. 25,32,33 

Thus, the differential DNAm pattern in those metabolic and inflammatory cytokines may encompass interactions with lifestyles and serve as a useful biomarker for the susceptibility to breast cancer and CRC.34-36 Up to now, few studies17,37-42 have examined DNAm in relation to those cytokines at the epigenome-wide level and the results are inconclusive. Notably, those studies have neither determined the temporality of the cytokine and DNAm (i.e., which comes first) nor incorporated clinical consequences associated with the cytokine, such as cancer. Studying DNAm in relation to the metabolic and inflammatory cytokines that mediate risk for breast cancer and CRC reflects a largely untapped population-based genomic science resource and is important to understand the molecular underpinnings of those cytokines in cancer development. Further, integrating such epigenetic markers with genetic and lifestyle factors to construct risk profiles for breast cancer and CRC is important in developing a tool for cancer prevention and treatment efforts, but they are rare. 43 Without such studies, resolving the conflict over breast cancer and CRC causation and providing a plausible biologic basis for cancer therapies may be delayed. 

Our research goal is to understand how the pathways of obesity–metabolic and inflammatory cytokines (epigenetic/genetic)–breast cancer/CRC can be manipulated for the purpose of prevention. Our overall hypothesis is that epigenetic modification associated with those cytokines is a genomic pathway by which obesity factors influence the risk for breast cancer and AS673b 3/25/20 2 CRC. We propose an Ancillary Study with a nested case-control study design from the WHI Observational Studies and Clinical Trails. 

Specific Aims:  

• Aim1. Identify patterns of DNAm that are associated with IGFs/IR and inflammatory phenotypes.
• Aim2. Evaluate whether those patterns improve breast cancer and CRC risk prediction among postmenopausal women.