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      Relationship between Tumor DNA Methylation Status and Patient Characteristics in African-American and European-American Women with Breast Cancer

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          Abstract

          Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARβ2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes ( RASSF1A, RARβ2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naïve tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci ( RASSF1A, RARβ2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients.

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          Ethnicity and breast cancer: factors influencing differences in incidence and outcome.

          Rowan Chlebowski, Zhao Chen, Garnet Anderson … (2005)
          The lower breast cancer incidence in minority women and the higher breast cancer mortality in African American women than in white women are largely unexplained. The influence of breast cancer risk factors on these differences has received little attention. Racial/ethnic differences in breast cancer incidence and outcome were examined in 156,570 postmenopausal women participating in the Women's Health Initiative. Detailed information on breast cancer risk factors including mammography was collected, and participants were followed prospectively for breast cancer incidence, pathological breast cancer characteristics, and breast cancer mortality. Comparisons of breast cancer incidence and mortality across racial/ethnic groups were estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazard models. Tumor characteristics were compared as odds ratios (ORs) and 95% confidence intervals in logistic regression models. After median follow-up of 6.3 years, 3938 breast cancers were diagnosed. Age-adjusted incidences for all minority groups (i.e., African American, Hispanic, American Indian/Alaskan Native, and Asian/Pacific Islander) were lower than for white women, but adjustment for breast cancer risk factors accounted for the differences for all but African Americans (HR = 0.75, 95% CI = 0.61 to 0.92) corresponding to 29 cases and 44 cases per 10,000 person years for African American and white women, respectively. Breast cancers in African American women had unfavorable characteristics; 32% of those in African Americans but only 10% in whites were both high grade and estrogen receptor negative (adjusted OR = 4.70, 95% CI = 3.12 to 7.09). Moreover, after adjustment for prognostic factors, African American women had higher mortality after breast cancer than white women (HR = 1.79, 95% CI = 1.05 to 3.05) corresponding to nine and six deaths per 10 000 person-years from diagnosis in African American and white women, respectively. Differences in breast cancer incidence rates between most racial/ethnic groups were largely explained by risk factor distribution except in African Americans. However, breast cancers in African American women more commonly had characteristics of poor prognosis, which may contribute to their increased mortality after diagnosis.
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            Differences in breast cancer stage, treatment, and survival by race and ethnicity.

            Christopher Li, Kathleen E Malone, Janet R Daling (2003)
            In the United States, black and Hispanic white women with breast cancer present with more advanced stages and have poorer survival rates than non-Hispanic whites, whereas Asians and Pacific Islanders do not. However, Asians and Pacific Islanders and Hispanic whites are heterogeneous populations, and few studies have evaluated breast cancer stage, treatments, and mortality rates for subgroups of these populations. Using data from 11 population-based tumor registries that participate in the Surveillance, Epidemiology, and End Results Program, we conducted a retrospective cohort study to evaluate the relationship between race and ethnicity and breast cancer stage, treatments, and mortality rates. The cohort of 124,934 women diagnosed as having a first primary invasive breast carcinoma between January 1, 1992, and December 31, 1998, included 97,999 non-Hispanic whites, 10,560 blacks, 322 American Indians, 8834 Asians and Pacific Islanders, and 7219 Hispanic whites. Relative to non-Hispanic whites, blacks, American Indians, Hawaiians, Indians and Pakistanis, Mexicans, South and Central Americans, and Puerto Ricans had 1.4- to 3.6-fold greater risks of presenting with stage IV breast cancer. Blacks, Mexicans, and Puerto Ricans were 20% to 50% more likely to receive or elect a first course of surgical and radiation treatment not meeting the 2000 National Comprehensive Cancer Network standards. In addition, blacks, American Indians, Hawaiians, Vietnamese, Mexicans, South and Central Americans, and Puerto Ricans had 20% to 200% greater risks of mortality after a breast cancer diagnosis. Differences in breast cancer stage, treatments, and mortality rates are present by race and ethnicity. Breast cancer survival may be improved by targeting factors, particularly socioeconomic factors, that underlie these differences.
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              Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA.

              Trine L’Abée-Lund, Otis W Brawley, G O’Regan … (2008)
              Breast cancers with a triple negative tumor (TNT) subtype (as defined by lacking protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)) preclude the use of available targeted therapies and may contribute to poor outcome and to the historically poorest survival observed among African-American (AA) women. This study examines association of the ER/PR/HER2 subtypes with race and breast cancer survival. Breast tumors from a population-based cohort of 116 AA and 360 white Atlanta women aged 20-54, diagnosed from 1990 to 1992 were centrally reviewed and tested by immunohistochemistry. Multivariate survival analyses within subtypes (TNT, ER-PR-HER2+, ER+/PR+HER2+, ER+/PR+HER2-) were conducted using weighted Cox regression and included socio-demographic, prognostic, and treatment factors. TNTs were more prevalent among young women and particularly among AA women (Odds Ratio [OR] = 1.9, 95% Confidence Interval [CI] 1.2-2.9), adjusting for age, stage, grade, and poverty index. Overall mortality was higher for AA women (Hazard Ratio [HR] = 1.9, 95% CI, 1.5-2.5) and differed by subtypes (P < 0.001). Within the TNT subtype, racial differences in survival persisted, after additional adjustment for treatment and comorbidities (HR = 2.0, 95% CI 1.0-3.7). TNTs were uniquely associated with high expression of p16, p53, and Cyclin E; and low Bcl-2 and Cyclin D1 expression. The high prevalence of TNTs among younger women and particularly younger AA women, along with unique protein expression patterns and poorer survival, suggests varying gene-environment etiologies with respect to age and race/ethnicity and a need for effective therapies.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 31 May 2012
                Volume: 7
                Issue: 5
                Electronic Location Identifier: e37928
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, Howard University, Washington, D.C., United States of America
                [2 ]Laboratory of Human Carcinogenesis, Center of Cancer Research and Epidemiology and Genetics Research Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [3 ]Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America
                Geisel School of Medicine at Dartmouth, United States of America
                Author notes

                Conceived and designed the experiments: SA BKA. Performed the experiments: SW THD. Analyzed the data: AT RAK. Contributed reagents/materials/analysis tools: AT BKA. Wrote the paper: SA BKA.

                Article
                Publisher ID: PONE-D-12-03598
                DOI: 10.1371/journal.pone.0037928
                PMC ID: 3365111
                PubMed ID: 22701537
                SO-VID: fdb29875-c07c-4caf-982a-bc669f984a9f
                Copyright © Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 31 January 2012
                Date accepted : 30 April 2012
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Epigenetics
                Subject: DNA modification
                Subject: Gene Expression
                Subject: DNA modification
                Subject: Molecular Genetics
                Subject: Gene Regulation
                Subject: Cancer Genetics
                Subject: Molecular Cell Biology
                Subject: Gene Expression
                Subject: DNA modification
                Subject: Medicine
                Subject: Obstetrics and Gynecology
                Subject: Breast Cancer

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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