Analysis of Key Breast Cancer Genes Reveals Distinct Profiles for African-American, European-American Women
BUFFALO, N.Y. — Researchers have uncovered new information that may begin to explain why many African-American women are more likely to be diagnosed with aggressive, often deadly forms of breast cancer, which strengthens the evidence that increased dietary folate intake may prove to be an effective strategy for reducing risk for the disease in African-American women. In the first large study of its kind, the team, led by Roswell Park Cancer Institute(RPCI) epidemiologists Zhihong Gong, PhD, and Christine Ambrosone, PhD, identified patterns in gene variations associated with breast cancer risk that diverged significantly between African-American women and women of European descent.
The researchers, who included collaborators from the Rutgers Cancer Institute of New Jersey and the Icahn School of Medicine at Mount Sinai School of Medicine, honed in on differences in folate-regulated one-carbon metabolism, a complex network of interdependent processes that enable key cell processes such as DNA methylation, nucleotide synthesis and DNA replication and repair.
In a case-control study involving 1,275 European-American and 1,299 African-American women who participated in the Women’s Circle of Health Study, a multisite study designed to evaluate risk factors for early and aggressive forms of breast cancer, they conducted a comprehensive analysis of single-nucleotide polymorphisms (SNPs) in 11 genes involved in one-carbon metabolism and risk of breast cancer.
They found distinct patterns in these genetic variations between the two groups of women and identified associations between several of those SNPs — particularly in genes such as MTR, MTRR, SHMT1, TYMS, and SLC19A1 — with overall breast cancer risk and with breast cancer risk by estrogen-receptor (ER) status. While the single-SNP associations they uncovered were not statistically significant after adjustment for key factors, their polygenetic risk-score analyses revealed significant associations between the variations and breast cancer risk.
Importantly, the findings also indicate that SNP associations may be modified by level of dietary intake of folate, a B vitamin found in leafy green vegetables and fruits. And the team’s investigations of genes that have not previously been well studied in breast cancer led to new findings about the metabolism of key enzymes.
“These findings are provocative because they provide new evidence that, by disrupting key processes and ultimately contributing to gene instability, certain genetic variants and interactions in these key metabolic pathways may contribute to risk of breast cancer in both African-American and European-American women,” says Dr. Gong, Assistant Professor of Oncology and Assistant Member of the Department of Cancer Prevention and Control at RPCI.
Additional large-scale studies and functional evaluations will be needed, the authors note, to confirm these findings and explore the molecular mechanisms responsible for these dynamics.
The researchers plan to further investigate associations of blood folate levels, dietary folate intake and genotypes of these key SNPs to shed additional light on differences in association by race and uncover potential associations with breast cancer outcomes.
The study, “Genetic variants in one-carbon metabolism genes and breast cancer risk in European American (EA) and African American (AA) women,” has been published online ahead of print in the International Journal of Cancer.
This work was supported by grants from the U.S. Army Medical Research and Material Command (project number DAMD17-01-1-0334), National Cancer Institute (project numbers K07CA178293,R01CA100598, P01CA151135, K22CA138563, P30CA016056 and P30CA072720) and Breast Cancer Research Foundation, and by a gift from the Philip L. Hubbell family.