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Results of Two Large-Scale Studies of Putative Breast Cancer Genes

By Malorye Branca on April, 5 2021


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Primary Reference #1: Breast Cancer Association Consortium, N. Eng. J. Med., Feb. 4, 2021.

Genes: ATM, BARD1, BRCA1, BRCA2, CHEK2, MSH6, NF1, PALB2, PTEN, RAD51C, RAD51D, TP53, and more.

To better define the genes associated with breast cancer risk, the multinational Breast Cancer Association Consortium used a panel of 34 putative susceptibility genes and sequenced samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants, they estimated odds ratios for breast cancer overall and tumor subtypes, and they also evaluated missense variant associations according to domain and classification of pathogenicity.

Protein truncating variants in five genes were associated with a significant risk of breast cancer overall (P<0.0001). Those genes were: ATM, BRCA1, BRCA2, CHEK2, and PALB2. There was more modest evidence of an association with breast cancer overall for protein-truncating variants in seven other genes: BARD1, RAD51C, RAD51D, PTEN, NF1, TP53, and MSH6.

The authors write: “The results of this study 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.”


Primary Reference #2: Hu, C. et al. N. Eng. J. Med., Feb. 4, 2021.

Genes: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, RAD51D, and more.

These researchers performed sequencing using a custom multigene amplicon-based panel to study germline pathogenetic variants in 28 cancer-predisposition genes. Their study included 32,247 women with breast cancer and 32,544 unaffected women among subjects of the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium.  

They reported that pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, those in PALB2 were associated with a moderate risk, while variants in BARD1RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer. Variants in ATMCDH1, and CHEK2, meanwhile, were associated with an increased risk of estrogen receptor–positive breast cancer. However, variants in 16 candidate breast cancer–predisposition genes, were not associated with an increased risk of breast cancer.

These authors also aim to provide data that can “…inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.”


Additional resource:  

In an accompanying editorial, Steven A. Narod, MD, notes that “Variants in 8 genes — BRCA1BRCA2PALB2BARD1RAD51CRAD51DATM, and CHEK2 — had a significant association with breast cancer risk in both studies.”

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