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Breast Cancer Subtype-Specific Polygenic Risk Scores Identified

NEW YORK (GenomeWeb) – An international team has developed a new set of polygenic risk scores (PRS) for estimating women's lifetime risk of developing breast cancer, including estrogen receptor-positive or ER-negative forms of the disease.

By bringing together array-based genotyping data for nearly 94,100 breast cancer cases and more than 75,000 controls enrolled through dozens of Breast Cancer Association Consortium studies, the researchers came up with several potential PRS focused on overall breast cancer risk or the risk of developing specific breast cancer subtypes.

After testing the most promising PRS in tens of thousands more cases and controls, in individuals from 10 prospective studies, and in 190,040 female participants from the UK Biobank project, the team found that its top PRS — based on information at 313 SNPs — may help in classifying those at highest or lowest risk of breast cancer, particularly ER-positive breast cancer. The study appeared online today in the American Journal of Human Genetics.

"The PRS has the potential to improve stratification for screening, while ER-specific PRSs may be informative for prevention with endocrine therapies," first and corresponding author Nasim Mavaddat, a researcher with the University of Cambridge Centre for Cancer Genetic Epidemiology, and her colleagues wrote, noting that it will "be important to evaluate carefully the associations between the new PRS313 and other tumor characteristics."

Rare mutations in BRCA1/2 and a small handful of other genes can ramp up breast cancer risk significantly, the team noted. But even so, most cases of the disease occur in women who do not have mutations in these known high-risk genes, and instead carry common variants at many sites in the genome that are individually low risk but can be cumulatively informative.

In an effort to come up with approaches to refine risk estimates based on the latter, common variants — and to build on prior PRS from their group and others — the researchers began by splitting 94,075 individuals with breast cancer and 75,017 unaffected controls genotyped with iCOGS or OncoArray chips for 69 prior studies into training and validation groups.

From there, the team used several statistical methods to develop and assess several PRS based on varied sets of SNPs implicated in breast cancer overall or in certain disease subtypes. The best-performing PRS for breast cancer in general comprised 305 SNPs, the group reported.

By incorporating half a dozen more SNPs and a pair or rarer variants in the BRCA2 and CHEK2 genes, the researchers came up with the 313-SNP PRS for ER-positive or ER-negative breast cancer. In a series of validation and prospective cohort analyses, they found that women in the top 1 percent group on the PRS313 were 4.37 times as likely to develop ER-positive breast cancer and at almost threefold the risk of ER-negative breast cancer compared with women in the intermediate risk group.

On the other hand, their results suggested that those in the bottom 1 percent risk group based on the PRS313 score had 0.16-fold and 0.27-fold the lifetime risk of ER-positive or ER-negative breast cancers, respectively, compared to the individuals with midrange risk scores.

In the UK Biobank group, meanwhile, the team noted that overall breast cancer risk rose with each uptick in score on a PRS based on a subset of 306 SNPs from the PRS313. There, women in the highest risk group had an estimated 31 percent risk of developing breast cancer by the time they reached 80 years old, for example, compared to 2 percent risk in the lowest risk group.

"While the PRS provides powerful risk discrimination, better risk discrimination will be obtained by combining the PRS with family history and other risk factors," the authors wrote, adding that "further studies to validate risk models for individualized risk prediction based on the combined effects of genetic and lifestyle risk factors will be needed."