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Alan Stolier and Pat Whitworth/


Study builds on data predicting risk in non-carriers


Several moderate risk breast cancer genes have been identified and are commonly reported. However, risk estimates for these moderate penetrance genes have wide confidence intervals and appear to be influenced by family history (so-called “familial polygenic background”). Evidence presented at the 2019 San Antonio Breast Cancer Symposium suggests an established, commercially available polygenic risk score (PRS) can provide more accurate risk assessment for patients with these moderate penetrance single gene variants.

At least three of the major genetic testing laboratories (Myriad, Ambry, Color) now offer validated polygenic risk scores to refine lifetime risk estimates for patients suspected to be at elevated breast cancer risk, but who have tested negative for any known single gene pathogenic variant. In general the PRS is generated by combining a broad polygenic assay with a validated clinical risk assessment model such as Tyrer-Cuzick (TC) to yield a more accurate estimate of personal risk for an individual patient. This is useful since only 10% of cancers appear to be related to identifiable single gene variants. Myriad Genetics currently has a PRS tool called riskScore® which uses a weighted analysis with a modified version of TC to yield 5-year and lifetime risk. Ambry Genetics has developed a similar tool called AmbryScore® which uses 100 SNPs combined with the TC score yielding a lifetime risk score. 

Currently, the commercially available risk assessment tools apply only to those women unaffected by a major genetic mutation. However, at the 2019 San Antonio Breast Cancer Symposium (SABCS), scientists from Myriad Genetics presented data from a validation study that used an 86 SNP PRS as well as integration with TC to develop a riskScore for women with mutations in 5 hereditary breast cancer genes: BRCA1, BRCA2, PALB2, ATM, and CHEK2. This data may now give us more precise risk information for germline gene-positive patients. 

At the SABCS, investigators at Myriad analyzed results from 152,000 women of European ancestry who received a myRisk Hereditary Cancer panel. Testing was negative for pathogenic variants in 141,000. The remaining 11,000 carried mutations in the high and moderate penetrance breast, ovarian and prostate risk genes: BRCA1, BRCA2, CHEK2, ATM, and PALB2. Again, Myriad incorporated 86 SNPs with the TC model to estimate 5 year and lifetime risk of developing breast cancer. It was noted that coupled with PRS, the lower penetrance CHEK2, ATM, and PALB2 showed the greatest risk modification. On their own, these genes confer a substantially lower risk than other genes such as BRCA1,2. But coupled with a high polygenic risk, some carriers of these genes appear to have cancer risks approaching those of BRCA1 and BRCA2. This may have important implications in clinical care. 

Jerry Lanchbury, Myriad Chief Scientific Officer suggests, "The [big achievement] here is that we've done this PRS modification now for all CHEK2  mutation carriers in a very large sample and these are also the first data showing modification of ATM risk and PALB2 associated risk by PRS." Elisha Hughes, the lead investigator on this study and Myriad’s director of bioinformatics, said in a statement that the findings suggest a potential to “ significantly improve the precision of hereditary cancer risk assessment for women who test positive for mutations in the high and intermediate breast cancer genes.”

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