Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Causes & Control
Published in: Cancer Causes & Control 4/2012

Open Access 01-04-2012 | Original paper

Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight

Authors: Cathrine Hoyo, Kimberly Fortner, Amy P. Murtha, Joellen M. Schildkraut, Adelheid Soubry, Wendy Demark-Wahnefried, Randy L. Jirtle, Joanne Kurtzberg, Michele R. Forman, Francine Overcash, Zhiqing Huang, Susan K. Murphy

Published in: Cancer Causes & Control | Issue 4/2012

Login to get access

Abstract

Purpose

Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.

Methods

Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.

Results

Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = −9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m2, β = −20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.

Conclusion

Our data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
Literature
1.
Bateson P, Barker D, Clutton-Brock T et al (2004) Developmental plasticity and human health. Nature 430:419–421PubMedCrossRef
2.
Cui H, Cruz-Correa M, Giardiello FM et al (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299:1753–1755 New York, NYPubMedCrossRef
3.
Nowakowska-Zajdel E, Mazurek U, Ziolko E et al (2011) Analysis of expression profile of gene encoding proteins of signal cascades activated by insulin-like growth factors in colorectal cancer. Int J Immunopathol Pharmacol 24:781–787PubMed
4.
Murphy SK, Huang Z, Wen Y et al (2006) Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res 4:283–292PubMedCrossRef
5.
Jarrard DF, Bussemakers MJ, Bova GS, Isaacs WB (1995) Regional loss of imprinting of the insulin-like growth factor II gene occurs in human prostate tissues. Clin Cancer Res 1:1471–1478PubMed
6.
Bhusari S, Yang B, Kueck J, Huang W, Jarrard DF (2011) Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer. Prostate 71:1621–1630PubMedCrossRef
7.
Zuo QS, Yan R, Feng DX et al (2011) Loss of imprinting and abnormal expression of the insulin-like growth factor 2 gene in gastric cancer. Mol Carcinog 50:390–396PubMedCrossRef
8.
Xu W, Fan H, He X, Zhang J, Xie W (2006) LOI of IGF2 is associated with esophageal cancer and linked to methylation status of IGF2 DMR. J Exp Clin Cancer Res 25:543–547PubMed
9.
Wu AH, McKean-Cowdin R, Tseng CC (2011) Birth weight and other prenatal factors and risk of breast cancer in Asian-Americans. Breast Cancer Res Treat 130:917–925PubMedCrossRef
10.
Forman MR, Cantwell MM, Ronckers C, Zhang Y (2005) Through the looking glass at early-life exposures and breast cancer risk. Cancer Invest 23:609–624PubMedCrossRef
11.
12.
Eriksson M, Wedel H, Wallander MA et al (2007) The impact of birth weight on prostate cancer incidence and mortality in a population-based study of men born in 1913 and followed up from 50 to 85 years of age. Prostate 67:1247–1254PubMedCrossRef
13.
Nilsen TI, Romundstad PR, Troisi R, Vatten LJ (2005) Birth size and subsequent risk for prostate cancer: a prospective population-based study in Norway. Int J Cancer 113:1002–1004PubMedCrossRef
14.
Akre O, Forssell L, Kaijser M et al (2006) Perinatal risk factors for cancer of the esophagus and gastric cardia: a nested case-control study. Cancer Epidemiol Biomarkers Prev 15:867–871PubMedCrossRef
15.
Kaijser M, Akre O, Cnattingius S, Ekbom A (2005) Preterm birth, low birth weight, and risk for esophageal adenocarcinoma. Gastroenterology 128:607–609PubMedCrossRef
16.
Strathdee G, Sim A, Brown R (2004) Control of gene expression by CpG island methylation in normal cells. Biochem Soc Trans 32:913–915PubMedCrossRef
17.
Waterland RA, Kellermayer R, Laritsky E et al (2010) Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet 6:e1001252PubMedCrossRef
18.
Woodfine K, Huddleston JE, Murrell A (2011) Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenetics Chromatin 4:1PubMedCrossRef
19.
Murphy SK, Jirtle RL (2003) Imprinting evolution and the price of silence. Bioassays 25:577–588CrossRef
20.
Murrell A, Ito Y, Verde G et al (2008) Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer LOI of IGF2 is associated with esophageal cancer and linked to methylation status of IGF2 DMR. PLoS ONE 3:e1849PubMedCrossRef
21.
Cui H, Niemitz EL, Ravenel JD et al (2001) Loss of imprinting of insulin-like growth factor-II in Wilms’ tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res 61:4947–4950PubMed
22.
Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP (2002) Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res 62:6442–6446PubMed
23.
Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A (2001) Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci U S A 98:591–596PubMedCrossRef
24.
Sullivan MJ, Taniguchi T, Jhee A, Kerr N, Reeve AE (1999) Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 18:7527–7534PubMedCrossRef
25.
Takai D, Gonzales FA, Tsai YC, Thayer MJ, Jones PA (2001) Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Hum Mol Genet 10:2619–2626PubMedCrossRef
26.
Heijmans BT, Tobi EW, Stein AD et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049PubMedCrossRef
27.
Hoyo C, Murphy SK, Jirtle RL (2009) Imprint regulatory elements as epigenetic biosensors of exposure in epidemiological studies. J Epidemiol Community Health 63:683–684PubMedCrossRef
28.
Heijmans BT, Tobi EW, Lumey LH, Slagboom PE (2009) The epigenome: archive of the prenatal environment. Epigenetics 4:526–531PubMedCrossRef
29.
Hoyo C, Murtha AP, Schildkraut JM et al (2011) Folic acid supplementation before and during pregnancy in the newborn epigenetics study (NEST). BMC Public Health 11:46PubMedCrossRef
30.
Hoyo C, Murtha AP, Schildkraut JM et al (2011) Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics 6:928–936PubMedCrossRef
31.
Huang Z, Wen Y, Shandilya R, Marks JR, Berchuck A, Murphy SK (2006) High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. Nucleic Acids Res 34:555–563PubMedCrossRef
32.
Umbers AJ, Boeuf P, Clapham C et al (2011) Placental malaria-associated inflammation disturbs the insulin-like growth factor axis of fetal growth regulation. J Infect Dis 203:561–569PubMedCrossRef
33.
Schlinzig T, Johansson S, Gunnar A, Ekstrom TJ, Norman M (2009) Epigenetic modulation at birth—altered DNA-methylation in white blood cells after caesarean section. Acta Paediatr 98:1096–1099PubMedCrossRef
34.
Steegers-Theunissen RP, Obermann-Borst SA, Kremer D et al (2009) Periconceptional maternal folic acid use of 400 microg per day Is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 4:e7845PubMedCrossRef
35.
Talens RP, Boomsma DI, Tobi EW et al (2010) Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24:3135–3144PubMedCrossRef
36.
Edwards CA, Rens W, Clarke O et al (2007) The evolution of imprinting: chromosomal mapping of orthologues of mammalian imprinted domains in monotreme and marsupial mammals. BMC Evol Biol 7:157PubMedCrossRef
37.
Varrault A, Gueydan C, Delalbre A et al (2006) Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell 11:711–722PubMedCrossRef
38.
Cruz-Correa M, Zhao R, Oviedo M et al. (2009) Temporal stability and age-related prevalence of loss of imprinting of the insulin-like growth factor-2 gene. Epigenetics 4:114–118
39.
Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev 8:253–262CrossRef
40.
41.
Cruz-Correa M, Cui H, Giardiello FM et al (2004) Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition. Gastroenterology 126:964–970PubMedCrossRef
42.
Dammann RH, Kirsch S, Schagdarsurengin U et al (2010) Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma. Int J Oncol 36:171–179PubMed
43.
Yang R, Wang Y, Zhu X, Gao X (2009) Study on genomic imprinting of IGF2 in breast cancer. Wei sheng yan jiu. J Hyg Res 38:423–425
44.
Zhao R, DeCoteau JF, Geyer CR, Gao M, Cui H, Casson AG (2009) Loss of imprinting of the insulin-like growth factor II (IGF2) gene in esophageal normal and adenocarcinoma tissues. Carcinogenesis 30:2117–2122PubMedCrossRef
45.
Paradowska A, Fenic I, Konrad L et al (2009) Aberrant epigenetic modifications in the CTCF binding domain of the IGF2/H19 gene in prostate cancer compared with benign prostate hyperplasia. Int J Oncol 35:87–96PubMedCrossRef
46.
Johnsen SP, Sorensen HT, Thomsen JL et al (2004) Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, -II and IGF binding protein 3 in adults. Eur J Epidemiol 19:41–47PubMedCrossRef
47.
Fowke JH, Matthews CE, Yu H et al (2010) Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3. Endocr Relat Cancer 17:51–60PubMedCrossRef
48.
Gronbaek H, Flyvbjerg A, Mellemkjaer L et al (2004) Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 13:1759–1764PubMed
49.
Shetty PJ, Movva S, Pasupuleti N et al (2011) Regulation of IGF2 transcript and protein expression by altered methylation in breast cancer. J Cancer Res Clin Oncol 137:339–345PubMedCrossRef
50.
Murphy SK, Wylie AA, Coveler KJ et al (2003) Epigenetic detection of human chromosome 14 uniparental disomy. Hum Mutat 22:92–97PubMedCrossRef
51.
Murrell A, Ito Y, Verde G et al (2008) Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS ONE 3:e1849PubMedCrossRef
52.
Turan N, Katari S, Gerson LF et al (2010) Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology. PLoS Genet 6:e1001033PubMedCrossRef
Metadata
Title
Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight
Authors
Cathrine Hoyo
Kimberly Fortner
Amy P. Murtha
Joellen M. Schildkraut
Adelheid Soubry
Wendy Demark-Wahnefried
Randy L. Jirtle
Joanne Kurtzberg
Michele R. Forman
Francine Overcash
Zhiqing Huang
Susan K. Murphy
Publication date
01-04-2012
Publisher
Springer Netherlands
Published in
Cancer Causes & Control / Issue 4/2012
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI
https://doi.org/10.1007/s10552-012-9932-y

Other articles of this Issue 4/2012

Cancer Causes & Control 4/2012 Go to the issue

Review article

Carbohydrates, glycemic index, glycemic load, and colorectal cancer risk: a systematic review and meta-analysis of cohort studies

Original paper

Asthma and risk of brain cancer in children

Original paper

Predictors of 25-hydroxyvitamin D and its association with risk factors for prostate cancer: evidence from the Prostate testing for cancer and Treatment study

Letter to the editor

Response to Grant, WB: “Ultraviolet exposure and non-Hodgkin’s lymphoma: beneficial and adverse effects?”

Original paper

Commentary: eight ways to prevent cancer: a framework for effective prevention messages for the public

Original paper

Factors associated with diagnostic and treatment intervals for prostate cancer in Queensland, Australia: a large cohort study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits