NIEHS scientists in the Biostatistics and Computational Biology Branch, led by Clarice Weinberg, Ph.D., have identified three genetic variants, or single-nucleotide polymorphisms (SNPs), associated with the risk of young-onset breast cancer. Their family-based, genome-wide association study (GWAS), published Feb. 17 in the European Journal of Human Genetics, is the first to examine the prenatal influence of a mother’s genome on the disease risk of adult daughters.
Genetic tests using Sister Study participants
The study, funded in part by Susan G. Komen for the Cure, involved analyzing data using three sets of genetic association tests. Researchers first examined the influence of inherited genetic variants carried by the affected daughters. They also looked for the possible prenatal influence of the mother’s genome on their adult daughter’s disease risk, and they analyzed risk in relation to inherited mitochondrial DNA.
“The methodology of this family-based GWAS makes use of a case-parent triad design,” said staff scientist Min Shi, M.D., Ph.D., who is co-lead author along with Katie O'Brien, Ph.D., a postdoctoral fellow on the Weinberg team. This type of design includes the case, or affected sister, and family members, usually one or both parents. Cases, drawn from participants in The Sister Study or The Two Sister Study, were diagnosed younger than the age of 50 years with either ductal carcinoma in situ or invasive breast cancer.
Identifying novel SNPs
The first set of tests, a GWAS analysis of inherited genetic effects, found three SNPs associated with increased risk of young-onset breast cancer. These three variants have not previously been linked to breast cancer or any other diseases. “Their functional roles and gene associations are unknown, and therefore, are worthy of further investigation,” O’Brien said.
After analyzing results of the other two tests, the team was surprised to find neither maternal influence nor mitochondrial DNA were associated with disease risk. “We haven’t ruled it out, because it’s possible we didn’t have the power [enough participants] to find it, but it’s evidence against maternal influence,” O’Brien said.
“This is the first study that’s been able to look at maternally-mediated genetic effects on a large scale,” added Weinberg. “Our findings clarify the interpretations of previous GWAS literature, and should be somewhat reassuring.” Maternally-mediated refers to the possible influence of the mother’s genome on her daughter’s prenatal environment, including the molecular pathways involved in the mother’s metabolism of environmental chemicals.
Publicly available data
The scientists emphasized that the genetic data from this study are publicly available through The database of Genotypes and Phenotypes. This database enables other researchers to use additional analytical methods with these data and possibly identify sets of SNPs that may have joint effects on breast cancer susceptibility.
“This will allow crowd-sourcing, so people who are interested can explore these high-dimensional data in creative ways,” Weinberg emphasized. “It is possible that making the data available in this way will lead to new insights about young-onset breast cancer.”
Next, Weinberg and her team plan to analyze toenail samples from sister pairs for trace elements and heavy metals. Published experimental evidence strongly suggests that cadmium may be related to breast cancer risk, according to Weinberg. They also hope to use the large panel of genetic SNP data to examine associations with various pathways of metal metabolism.
Citation: O'Brien KM, Shi M, Sandler DP, Taylor JA, Zaykin DV, Keller J, Wise AS, Weinberg CR.. 2016. A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects. Eur J Hum Genet; doi:10.1038/ejhg.2016.11 [Online 17 February 2016].
(Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group).