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27-01-2021 | Oncology | News | Article

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Population-based risk estimates for breast cancer genes reported

Shreeya Nanda

medwireNews: Two analyses have provided population-level estimates of the risk for breast cancer associated with known or suspected susceptibility genes.

These studies “are useful in that they help to establish the genes that confer a predisposition to breast cancer and those that do not,” says Steven Narod (Women’s College Research Institute, Toronto, Ontario, Canada) in an editorial accompanying the research published in The New England Journal of Medicine.

He adds, however, that “[t]hese studies are less helpful in refining the lifetime cancer risks for women with mutations” than prospective cohort studies, and cautions against revising previously established risk estimates “downward on the basis of the new results.”

The authors of the first study evaluated a panel of 34 putative susceptibility genes using samples from 48,826 patients with breast cancer and 50,703 controls from 30 population-based studies included in the Breast Cancer Association Consortium (BCAC).

The presence of protein-truncating variants in five genes – ATM, BRCA1, BRCA2, CHEK2, and PALB2 – was significantly associated with increased breast cancer risk (p<0.0001), with odds ratios (ORs) ranging from 2.10 for ATM to 10.57 for BRCA1.

There was “more modest evidence” for the association between protein-truncating variants in four other genes – BARD1, RAD51C, RAD51D, and TP53 – and the risk for breast cancer (p<0.05), with ORs ranging from 1.80 for RAD51D to 3.06 for TP53, report the researchers.

Of note, variants in ATM and CHEK2 were significantly more likely to occur in patients with estrogen receptor (ER)-positive rather than negative disease, while the converse was true for variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D.

The absolute breast cancer risks, derived by combining age-specific estimated ORs with population incidences in the UK, ranged from around 20% for RAD51C and RAD51D to around 55% for BRCA1, report Douglas Easton, from the University of Cambridge in the UK, and fellow BCAC investigators.

They believe that the study findings “define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling.”

But the team adds that “because breast cancer risk is influenced by other genetic and lifestyle factors, in addition to family history, the incorporation of this information into risk models would be required to give appropriate estimates.”

For the second study, Fergus Couch (Mayo Clinic, Rochester, Minnesota, USA) and co-authors analyzed samples from 32,247 women with breast cancer and 32,544 unaffected women enrolled in the 12 population-based studies included in the US CARRIERS (Cancer Risk Estimates Related to Susceptibility) consortium to identify pathogenic variants in 28 cancer predisposition and 16 candidate cancer predisposition genes.

The key breast cancer risk genes identified in this study overlapped with those revealed in the BCAC analysis.

Specifically, pathogenic variants in BRCA1 and BRCA2 were significantly associated with a high risk for breast cancer, at ORs of 7.62 and 5.23, respectively, while the risk was more moderate but still significant for PALB2 and CHEK2, with respective ORs of 3.83 and 2.47. Pathogenic variants in ATM also conferred a significantly increased risk for breast cancer, at an OR of 1.82.

Once again, ATM and CHEK2 variants, as well as those in CDH1, had a significant association with ER-positive disease, whereas variants in BARD1, RAD51C, and RAD51D were significantly associated with ER-negative and triple-negative breast cancer.

The lifetime absolute risks – based on age-specific ORs and population incidences from SEER – ranged from approximately 25–35% for ATM, CHEK2, and PALB2 to around 50% for BRCA1 and BRCA2.

Couch and colleagues conclude: “To date, the management recommendations for women with pathogenic variants in these genes have been based on risk estimates from studies involving women at high risk.

“We anticipate that the estimates from the population-based CARRIERS analysis will inform cancer screening and other risk-management strategies for women with pathogenic variants in cancer-predisposition genes in the general population.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2021; doi:10.1056/NEJMoa1913948
N Engl J Med 2021; doi:10.1056/NEJMoa2005936 
N Engl J Med 2021; doi:10.1056/NEJMe2035083

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