Polygenic Risk Score Modifies Breast Cancer Risk in Pathogenic Variant Carriers - GenomeWeb

NEW YORK – A polygenic risk score for breast cancer can modify risk assessments for individuals who are carriers of pathogenic breast cancer variants, a new analysis has found.

Pathogenic alterations in BRCA1 and BRCA2 are associated with an increased risk of breast cancer, as are variants in genes like PALB2, CHEK2, and ATM, though to a more moderate degree. At the same time, common variants in a range of genes can slightly influence disease risk. Combined into a polygenic risk score, those common variants may explain about another 18 percent of familial risk of breast cancer, nearly as much as pathogenic variants in BRCA1 and BRCA2 do.

Researchers led by Memorial Sloan Kettering Cancer Center's Mark Robson conducted a retrospective case-control study to ascertain whether a polygenic risk score based on 86 single nucleotide variants could further stratify disease risk among women who are carriers of pathogenic variants in one of five breast cancer risk genes. 

Myriad Genetics developed its 86-SNP-based riskScore test for use in women of European ancestry who tested negative on its myRisk next-generation sequencing panel and found that combined with traditional risk factor analysis, it could better predict breast cancer risk than the traditional risk factors alone. In December, the firm announced early results from this analysis during the San Antonio Breast Cancer Symposium that indicated the PRS score could modify risk among women with mutations in high and moderate penetrance risk genes.

In JAMA Network Open on Wednesday, Robson and his colleagues, who included Myriad Genetics employees, reported that polygenic risk scores could modify risk in carriers of pathogenic variants in BRCA1, BRCA2, CHEK2, ATM, or PALB2. They suggested a combined approach could better determine "personalized risks for women and could enhance the quality of clinical care offered." 

The researchers analyzed a cohort of women who underwent hereditary cancer testing at Myriad Genetics, which funded the study. At the time of testing, 32,812 of the women had been diagnosed with breast cancer.

Of the more than 152,000 women tested, 10,852 had a germline pathogenic variant in one of the 11 genes analyzed. In particular, 2,249 women had a pathogenic variant in BRCA1; 2,638 in BRCA2; 2,564 in CHEK2; 1,445 in ATM; and 906 in PALB2. Other women had pathogenic variants in BARD1, CDH1, NBN, PTEN, STK11, and TP53 but were excluded from the rest of the analysis due to low numbers.

The researchers additionally genotyped the cohort using next-generation sequencing to derive the 86-SNV polygenic risk score. In all carrier groups, the polygenic risk score was associated with modified risk for breast cancer, the researchers reported.

The effect sizes, however, varied. It was lower among BRCA1 and BRCA2 variant carriers, as compared to non-carrier women or women who were CHEK2 variant carriers. The effect size among ATM and PALB variant carriers, meanwhile, fell between the BRCA1 and BRCA2 groups and CHEK2 groups.

The researchers additionally estimated breast cancer risk by 80 years of age for the carrier groups based on their polygenic risk scores. Women in the lowest polygenic risk score percentile with a pathogenic variant in ATM or CHEK2 had a lifetime risk of breast cancer similar to that of the population average. However, women who were carriers of variants in moderate-risk genes but were in the highest polygenic risk scores percentiles had risk estimates that approached those of BRCA1 and BRCA2 pathogenic variant carriers. 

This risk stratification among CHEK2, ATM, and PALB2 variant carriers by polygenic risk score highlights the need for integrative testing, the researchers wrote. A high polygenic risk score in those carriers could push them past the risk threshold to be recommended to undergo, for instance, MRI screening, they added.

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Polygenic Risk Score Modifies Breast Cancer Risk in Pathogenic Variant Carriers - GenomeWeb
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