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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients

Authors: Mónica Cappetta, María Berdasco, Jimena Hochmann, Carolina Bonilla, Mónica Sans, Pedro C Hidalgo, Nora Artagaveytia, Rick Kittles, Miguel Martínez, Manel Esteller, Bernardo Bertoni

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls.

Methods

We performed two case–control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants.

Results

We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005).

Conclusions

These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones.
Appendix
Available only for authorised users
Literature
1.
Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2011;28:1057–68.CrossRef
2.
Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010;19:698–711.CrossRefPubMed
3.
4.
Zhu ZZ, Sparrow D, Hou L, Tarantini L, Bollati V, Litonjua AA, et al. Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study. Cancer Causes Control. 2011;22:437–47.CrossRefPubMed
5.
6.
Terry MB, Ferris JS, Pilsner R, Flom JD, Tehranifar P, Santella RM, et al. Genomic DNA methylation among women in a multiethnic New York City birth cohort. Cancer Epidemiol Biomarkers Prev. 2008;17:2306–10.CrossRefPubMed
7.
Heyn H, Moran S, Hernando-Herraez I, Sayols S, Gomez A, Sandoval J, et al. DNA methylation contributes to natural human variation. Genome Res. 2013;23:1363–72.CrossRefPubMedPubMedCentral
8.
Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, et al. Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics. 2011;6:623–29.CrossRefPubMedPubMedCentral
9.
Das PM, Ramachandran K, Vanwert J, Ferdinand L, Gopisetty G, Reis IM, et al. Methylation mediated silencing of TMS1/ASC gene in prostate cancer. Mol Cancer. 2006;5:28.CrossRefPubMedPubMedCentral
10.
Wang S, Dorsey TH, Terunuma A, Kittles RA, Ambs S, Kwabi-Addo B. Relationship between tumor DNA methylation status and patient characteristics in African-American and European-American women with breast cancer. PLoS One. 2012;7:e37928.CrossRefPubMedPubMedCentral
11.
Adkins RM, Krushkal J, Tylavsky FA, Thomas F. Racial differences in gene-specific DNA methylation levels are present at birth. Birth Defects Res A Clin Mol Teratol. 2011;91:728–36.CrossRefPubMedPubMedCentral
12.
Fejerman L, Romieu I, John EM, Lazcano-Ponce E, Huntsman S, Beckman KB, et al. European ancestry is positively associated with breast cancer risk in Mexican women. Cancer Epidemiol Biomarkers Prev. 2010;19:1074–82.CrossRefPubMedPubMedCentral
13.
Fejerman L, Chen GK, Eng C, Huntsman S, Hu D, Williams A, et al. Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet. 2012;21:1907–17.CrossRefPubMedPubMedCentral
14.
15.
Luiz OC, Gianini RJ, Goncalves FT, Francisco G, Festa-Neto C, Sanches JA, et al. Ethnicity and cutaneous melanoma in the city of Sao Paulo, Brazil: a case–control study. PLoS One. 2012;7:e36348.CrossRefPubMedPubMedCentral
16.
Sans M, Salzano FM, Chakraborty R. Historical genetics in Uruguay: estimates of biological origins and their problems. Hum Biol. 1997;69:161–70.PubMed
17.
Hidalgo PC, Bengochea M, Abillera A, Cabrera A, Alvarez I. Genetic admixture estimate in the Uruguayan population based on the Loci LDLR, GYPA, HBGG, GC and D7S8. Int J Hum Genet. 2005;5:217–22.
18.
19.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
20.
Barrios E, Vasallo J, De Stéfani E. Patterns of cutaneous malignant melanoma incidence and mortality in Uruguay. Melanoma Res. 2001;11 Suppl 1:S138.
21.
Mohammed SI, Springfield S, Das R. Role of epigenetics in cancer health disparities. Methods Mol Biol. 2012;863:395–410.CrossRefPubMed
22.
Bonilla C, Bertoni B, Hidalgo PC, Artagaveytia A, Ackermann E, Barreto I, et al. Breast cancer risk and genetic ancestry: a case–control study in Uruguay. BMC Womens Health. 2015;15:11.CrossRefPubMedPubMedCentral
23.
Berdasco M, Fraga MF, Esteller M. Quantification of global DNA methylation by capillary electrophoresis and mass spectrometry. Methods Mol Biol. 2009;507:23–34.CrossRefPubMed
24.
Falush D, Stephens M, Pritchard JK. Inference of population structure using multilocus genotype data: dominant markers and null alleles. Mol Ecol Notes. 2007;7:574–78.CrossRefPubMedPubMedCentral
25.
Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and Regression Trees. Belmont, California: The Wadsworth Statistics/Probability Series, Wadsworth International Group; 1984.
26.
27.
28.
Li L, Choi JY, Lee KM, Sung H, Park SK, Oze I, et al. DNA methylation in peripheral blood: a potential biomarker for cancer molecular epidemiology. J Epidemiol. 2012;22:384–94.CrossRefPubMedPubMedCentral
29.
Hyland PL, Burke LS, Pfeiffer RM, Mirabello L, Tuker MA, Goldstein AM, et al. LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations. Melanoma Res. 2013;23:55–60.CrossRefPubMed
30.
Choi JY, James SR, Link PA, McCann SE, Hong CC, Davis W, et al. Association between global DNA hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis. 2009;30:1889–97.CrossRefPubMedPubMedCentral
31.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604–9.CrossRefPubMedPubMedCentral
32.
Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, et al. Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet. 2004;68:196–204.CrossRefPubMed
33.
Kok RM, Smith DE, Barto R, Spijkerman AM, Teerlink T, Gellekink HJ, et al. Global DNA methylation measured by liquid chromatography-tandem mass spectrometry: analytical technique, reference values and determinants in healthy subjects. Clin Chem Lab Med. 2007;45:903–11.CrossRefPubMed
34.
Ma H, Zhang W, Hu J, Yu Z, Chen Y, Luo Q, et al. Analysis of global DNA methylation levels in human blood using high-performance liquid chromatography/tandem electrospray ionization mass spectrometry. Eur J Mass Spectrom. 2009;15:555–61.CrossRef
35.
Moore LE, Pfeiffer RM, Poscablo C, Real FX, Kogevinas M, Silverman D, et al. Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case–control study. Lancet Oncol. 2008;9:359–66.CrossRefPubMedPubMedCentral
36.
Lim U, Flood A, Choi SW, Albanes D, Cross AJ, Schatzkin A, et al. Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology. 2008;134:47–55.CrossRefPubMed
37.
Terry MB, Delgado-Cruzata L, Vin-Raviv N, Wu HC, Santella RM. DNA methylation in white blood cells: association with risk factors in epidemiologic studies. Epigenetics. 2011;6:828–37.CrossRefPubMedPubMedCentral
38.
Zhu ZZ, Hou L, Bollati V, Tarantini L, Marinelli B, Cantone L, et al. Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol. 2010;41:126–39.CrossRefPubMedPubMedCentral
39.
Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6:e1000952.CrossRefPubMedPubMedCentral
40.
Zhang D, Cheng L, Badner JA, Chen C, Chen Q, Luo W, et al. Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet. 2010;86:411–9.CrossRefPubMedPubMedCentral
41.
Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, et al. Integrating common and rare genetic variation in diverse human populations. Nature. 2010;467:52–8.CrossRefPubMed
42.
43.
Winkler CA, Nelson GW, Smith MW. Admixture mapping comes of age. Annu Rev Genomics Hum Genet. 2010;11:65–89.CrossRefPubMed
44.
Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science. 2008;319:1100–4.CrossRefPubMed
Metadata
Title
Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients
Authors
Mónica Cappetta
María Berdasco
Jimena Hochmann
Carolina Bonilla
Mónica Sans
Pedro C Hidalgo
Nora Artagaveytia
Rick Kittles
Miguel Martínez
Manel Esteller
Bernardo Bertoni
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1461-0

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Prognostic significance of diabetes mellitus in locally advanced non-small cell lung cancer

Research article

BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer

Research article

Partial PTEN deletion is linked to poor prognosis in breast cancer

Research article

Combination of Iodine-125 brachytherapy and chemotherapy for locally recurrent stage III non-small cell lung cancer after concurrent chemoradiotherapy

Case report

Ewing sarcoma of the liver with multilocular cystic mass formation: a case report

Case report

The diagnostic challenge of pulmonary tumour thrombotic microangiopathy as a presentation for metastatic gastric cancer: a case report and review of the literature
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