Study links new genetic anomalies to breast cancer in African-American families
The “Jewels in our Genes” study, led by University at Buffalo researcher Heather Ochs-Balcom, has uncovered previously unknown segments of DNA shared by African American family members who have breast cancer.
“The discovery of these regions supports our hypothesis that there are still undiscovered breast cancer genes that may be unique to African Americans,” says Ochs-Balcom, PhD, a genetic epidemiologist in the UB Department of Epidemiology and Environmental Health. “We can now focus on these specific chromosomes to learn if they house genetic mutations linked to breast cancer.
“We also need to determine whether those mutations are found in other racial groups or if they are unique to African Americans. If they are unique, it could explain why young African American women have a higher risk of pre-menopausal breast cancer compared to other groups,” she says.
“Our study used linkage analysis, a powerful tool that helps to detect the chromosomal location of disease genes by examining genetic markers across the entire human genome. Our family-based gene hunt is similar to the groundbreaking study among women with European ancestry done in the early 1990s that led to the discovery of BRCA1 and BRCA2 gene mutations, which greatly increase susceptibility to breast and ovarian cancer.”
African American women can also carry the BRCA mutations, but Ochs-Balcom suspects there may be additional, undiscovered mutations linked to breast cancer in this population.
“Family studies like this one have been difficult to conduct in the past,” Ochs-Balcom says, “in part because it’s difficult to get multiple family members to commit the time needed to participate. We found here that approaching the recruitment of African Americans by using a multi-pronged approach that included collaboration from our community partnerships greatly facilitated success.”
Breast cancer incidence is lower in African-American than in Caucasian-American women, yet breast cancer mortality rates are paradoxically higher for African-American women. These poorly understood disparities have been consistently documented in population-based data from the Surveillance, Epidemiology, and End Results (SEER) program since its inception in 1976. Another notable feature regarding ethnicity-related variation in the epidemiology of breast cancer is that African-American women face a greater risk for being diagnosed with early-onset disease. This review summarizes the information available on the epidemiology of breast cancer in African-American women, as well the possible socioeconomic, genetic, and primary tumor biologic factors that account for these variations.
The prevalence and strength of the established breast cancer risk factors among African-American women are not well documented, but some differences in the significance of various factors have been reported in analyses of the Contraceptives and Steroid Hormone (CASH) study. Mayberry and Stoddard-Wright analyzed standard familial and gynecologic risk factors among breast cancer cases (3,934 Caucasian Americans, 490 African Americans) and controls (3,901 Caucasian Americans, 485 African Americans) from the CASH study and found that age at first live birth, parity, and surgical menopause had similar associations with breast cancer risk, but family history and age at menarche behaved differently as risk factors. For African Americans, first-degree and second-degree family history of breast cancer had comparable strengths as risk factors (odds ratios, 1.61 and 1.71, respectively), whereas the association in Caucasian Americans was notably stronger in relation to the pattern of family history (odds ratio, 2.16 for first-degree relatives, and 1.44 for second-degree relatives). Relatively younger ages at menarche have also been reported for African-American women, but the impact of this finding on breast cancer incidence has not been defined.
An intriguing pattern of breast cancer in African-American women is seen in the age-incidence curves for the disease, as demonstrated in Figure 2. Although breast cancer risk clearly increases as a function of age, African-American women under the age of 45 years have a greater incidence of breast cancer than Caucasian-American women in this young age range. These rates equalize during the fifth decade of life, and for women over the age of 50 years, incidence rates for Caucasian Americans surpass those for African Americans, resulting in an overall higher lifetime risk for the Caucasian Americans. Although the absolute values of these population-based incidence rates may not appear very large in magnitude, this ethnicity-related variation in age distribution is far more striking in clinical practice, where 20% of Caucasian-American breast cancer patients are younger than 50 years of age, compared with 30%-40% of African-American breast cancer patients.
She points out that African American women have a higher incidence of pre-menopausal breast cancer and a higher breast cancer mortality rate than European Americans. They also more likely to develop early-onset cancers that are aggressive and difficult to treat. Some of these may be caused by unknown genetic anomalies that if found, could lead to early screening, detection and treatment.
The study was funded by a grant from the Susan G. Komen for the Cure Foundation and is the subject of two recent papers published by the team in the journal Cancer, Epidemiology, Biomarkers and Prevention and the Journal of Community Genetics.
It was conducted between 2009 and 2014 by researchers in the UB School of Public Health and Health Professions, Case Western Reserve School of Medicine, Roswell Park Cancer Institute and the Icahn School of Medicine at Mount Sinai Hospital, New York.
The study examined the DNA of 106 African American families not known to carry BRCA mutations tied to hereditary breast-ovarian cancer syndrome. Participants included 179 women who had been diagnosed with breast cancer and 76 of their sisters who never had the disease.
It has been reported that the crossover in breast cancer age incidence between African-American and Caucasian-American women is a relatively recent phenomenon that evolved over the 1960s. A sudden shift in age distribution is difficult to explain, making the accuracy of this observation dubious. The SEER program is the most well-established and comprehensive registry of population-based cancer data in the U.S., and case ascertainment for SEER began in 1974. One could easily speculate that research regarding the cancer burden among African Americans was inadequately documented during the first half of the twentieth century.
A plausible and interesting explanation for the younger age distribution of African-American breast cancer patients has been proposed by Pathak et al.. Those investigators correlated the short-term increase in breast cancer risk that occurs in the postpartum period with premenopausal breast cancer risk. They hypothesized that the higher prevalence of early childbearing that is observed among African-American compared with Caucasian-American women thereby accounts for the higher incidence of early-onset breast cancer. Palmer et al. reported supporting data for this concept in an analysis of The Black Women’s Health Study. Those investigators demonstrated a dual effect of pregnancy on breast cancer risk: multiparity increased breast cancer risk prior to the age of 45 years but was protective against breast cancer risk after age 45.
Postmenopausal obesity is an established risk factor for breast cancer because of the higher circulating estrogen levels that result from fatty tissue metabolism of adrenal gland steroids in the absence of ovarian function. Flegal et al. analyzed the Third National Health and Nutrition Examination Survey (NHANES III) and found that more than half the African-American women over the age of 40 years were obese (body mass index ?30), and more than 80% were overweight (body mass index ?25). However, as noted previously, breast cancer incidence rates are significantly lower for African-American women in the postmenopausal age range. The extent to which dietary fat contributes to breast cancer incidence among African-American women is unclear at present. Other NHANES findings have implicated physical inactivity and inadequate intake of micronutrients, as well as other dietary components, as factors contributing to pre- and postmenopausal breast cancer risk among African-American women.
“Perhaps the most important motivating factor in their decision to participate in our study,” says Ochs-Balcom, “was the potential to prevent suffering in their daughters and granddaughters.”
She says the investigation itself was spurred by Veronica Meadows-Ray of Buffalo, an African American woman involved in Roswell Park’s breast cancer survivor programs. Ray asked if a study could be undertaken to look into why her mother, aunt and several cousins developed breast cancer although they do not carry the BRCA mutations. She suspected that their cancer was hereditary and provoked by genetic mutations unique to African Americans.
“Our exciting results suggest that family-based studies are a great strategy to use when searching for new breast cancer genes,” Ochs-Balcom says, “and these findings may pave the way for further family-based research in this understudied population.”
Ochs-Balcom’s co-authors are Xiangqing Sun and Yanwen Chen, Jill Barnholtz-Sloan and Robert Elston of Case Western Reserve University School of Medicine; Deborah Erwin and Lara Sucheston-Campbell of Roswell Park Cancer Institute, and Lina Jandorf of the Icahn School of Medicine at Mount Sinai Hospital.
University at Buffalo
Cancer Epidemiology, Biomarkers, and Prevention