Polygenic risk in familial breast cancer: Changing the dynamics of communicating genetic risk

2021 ◽  
Author(s):  
Gillian Gregory ◽  
Kuheli Das Gupta ◽  
Bettina Meiser ◽  
Kristine Barlow‐Stewart ◽  
Peter Geelan‐Small ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Risk ◽  
Familial Breast Cancer ◽  
Polygenic Risk

scholarly journals A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer

2012 ◽  
Vol 30 (35) ◽  
pp. 4330-4336 ◽  
Author(s):  
Sarah Sawyer ◽  
Gillian Mitchell ◽  
Joanne McKinley ◽  
Georgia Chenevix-Trench ◽  
Jonathan Beesley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Familial Breast Cancer ◽  
Brca2 Mutation ◽  
Mutation Screening ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genomic Variants ◽  
Risk Distribution

Purpose Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear. Patients and Methods We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer–associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared. Results Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10−16). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10−6). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk. Conclusion Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.

scholarly journals Genetic assessments of breast cancer risk that do not account for polygenic background are incomplete and lead to incorrect preventative strategies

2021 ◽  
Author(s):  
George B Busby ◽  
Paul Craig ◽  
Nesrine Yousfi ◽  
Saurabh Hebbalker ◽  
Paolo Di Domenico ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Genetic Risk ◽  
Disease Risk ◽  
Population Level ◽  
Polygenic Risk ◽  
Cancer Susceptibility Genes ◽  
Pathogenic Mutations ◽  
Genome Wide

Breast cancer is the most common cancer among women and is a leading cause of cancer mortality worldwide. There is a significant genetic component to breast cancer risk which is the result of both rare pathogenic mutations and common genome-wide variation. However, the penetrance of pathogenic mutations varies widely and their frequency is low, both at a population level and amongst breast cancer cases. Polygenic risk scores, which aggregate the effect of hundreds to millions of common genome-wide variants offer a way to further understand the contribution of genetics to disease risk. Here we analyse genome-wide data from 221,479 women and 90,307 high coverage exomes to understand how rare and common variation affect lifetime breast cancer risk. We show that PRS strongly modulates the penetrance of mutations in 8 breast cancer susceptibility genes. For example, lifetime risk in BRCA1 carriers with low polygenic risk is almost one third that of carriers with high PRS (26% v 69% in the bottom and top PRS deciles, respectively). Adding family history of breast cancer provides additional stratification on the potential outcome of disease in carriers of rare mutations. PRS also identifies a significant fraction of the population at equivalent risk to carriers of moderate impact pathogenic variants and who are an order of magnitude more common at a population level. These results have important implications for breast cancer risk mitigation strategies, indicating that the genetic risk of breast cancer is determined by both monogenic mutation and polygenic background, and that assessments of genetic risk for breast cancer risk that do not consider the polygenic background are imprecise and unreliable.

scholarly journals Genetic risk transmission in a family affected by familial breast cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 51-53 ◽  
Author(s):  
Brunella Pilato ◽  
Simona De Summa ◽  
Katia Danza ◽  
Rosanna Lacalamita ◽  
Rossana Lambo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Risk ◽  
Familial Breast Cancer

Communicating polygenic risk scores in the familial breast cancer clinic

2021 ◽  
Author(s):  
Kuheli Das Gupta ◽  
Gillian Gregory ◽  
Bettina Meiser ◽  
Rajneesh Kaur ◽  
Maatje Scheepers-Joynt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Familial Breast Cancer ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Cancer Clinic
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