Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Southey, Melissa C.; Dowty, James G.; Riaz, Moeen; Steen, Jason A.; Renault, Anne-Laure; Tucker, Katherine; Kirk, Judy; James, Paul; Winship, Ingrid; Pachter, Nicholas; Poplawski, Nicola; Scott, G. B. D.; Park, Daniel J.; Pope, Bernard J.; Mahmood, Khalid; Hammet, Fleur; Mahmoodi, Maryam; Tsimiklis, Helen; Theys, Derrick; Rewse, Amanda; Willis, Amanda; Morrow, April; Speechly, Catherine; Harris, Rebecca; Sebra, Robert; Schadt, Eric E.; Lacaze, Paul; McNeil, John J; Giles, Graham G.; Milne, Roger L.; Hopper, John L.; Nguyen-Dumont, Tú

doi:10.1038/s41523-021-00360-3

Cited by 13 publications

(7 citation statements)

References 44 publications

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“…In total, 88% of families were tested; see Southey et al. 26 for more details about the gene-panel testing and pathogenicity definition. In SEARCH, PVs were identified by gene-panel testing for 12,654 probands (86% of all probands).…”

Section: Methodsmentioning

confidence: 99%

Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction

MacInnis

Lee

et al. 2022

The American Journal of Human Genetics

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Section: Methodsmentioning

confidence: 99%

Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction

MacInnis

Lee

et al. 2022

The American Journal of Human Genetics

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“…It is generally estimated that around 5%–6% of breast cancer cases and 1%–2% of the general population, harbor PVs in established breast cancer susceptibility genes ( Dorling et al, 2021 ; Hu et al, 2021 ; Southey et al, 2021 ). Among breast cancer patients the most prevalent occur in BRCA2 , CHEK2, BRCA1 and ATM ( Dorling et al, 2021 ; Hu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls

Zanti,

Loizidou,

O’Mahony

et al. 2023

Front. Genet.

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Introduction: It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown.Methods: We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants.Results: Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For BRCA1 and PALB2, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in BRCA1, ATM, CHEK2 and PALB2 domains, were associated with increased risk of disease subtypes.Conclusion: This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus.

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“…In ABCFR, PVs were identified by gene-panel testing for 2,305 probands (85% of all probands) and 770 relatives, and by other tests conducted before gene-panel testing was widely available (Table S1) for 2,317 probands and 1,765 relatives; 2,244 probands and 611 relatives tested by both regimes. In total, 88% of families were tested; see Southey et al 26 for more details about the gene-panel testing and pathogenicity definition. In SEARCH, PVs were identified by gene-panel testing for 12,654 (86% of all probands) probands.…”

Section: Pvs In Breast Cancer Susceptibility Genesmentioning

confidence: 99%

Segregation analysis of 17,425 population-based breast cancer families: evidence for genetic susceptibility and risk prediction

MacInnis

Lee

et al. 2022

Preprint

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Rare pathogenic variants in known breast cancer susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM and TP53 using gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of pathogenic variants in known susceptibility genes and other unidentified major genes, and a normally distributed polygenic component. The proportion of familial variance explained by BRCA1, BRCA2, PALB2, CHEK2, ATM and TP53 was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessively inherited risk component with a combined genotype frequency of 1.7% (95% CI: 0.3-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38-95%) for homozygotes, and a polygenic variance of 1.27 (95% CI: 0.94-1.65) which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer susceptibility genes and improve breast cancer risk prediction, especially at a young age.

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Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Cited by 13 publications

References 44 publications

Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction

Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction

Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls

Segregation analysis of 17,425 population-based breast cancer families: evidence for genetic susceptibility and risk prediction

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