U.S./U.K. Researchers Agree On 8 Genes/Variants That Increase Breast Cancer Risks

Pathogenic variants in the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes are associated with an increased risk of breast cancer, according to results from an analysis of data from the 17 studies that comprised the population-based Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. CARRIERS researchers also found that pathogenic variants in three additional genes—BARD1, RAD51C, and RAD51D—were associated with increased risks of estrogen receptor (ER)-negative breast cancer in the general population.

Results from a European trial by the Breast Cancer Association Consortium supported these results with findings of an association between protein-truncating variants in the same five genes—ATM, BRCA1, BRCA2, CHEK2, and PALB2—and significantly higher risks of breast cancer. Further, they found that pathogenic variants in four other genes—BARD1, RAD51C, RAD51D, and TP53 — were also associated with high breast cancer risks.

“[L]arge-scale population-based studies that provide estimates of the prevalence of pathogenic variants in predisposition genes in the general population are lacking,” according to the CARRIERS’ analysis senior author Fergus Couch, PhD, of the Mayo Clinic, Rochester, MN, and fellow researchers, who published their results in The New England Journal of Medicine.

For this analysis, they conducted gene sequencing with a multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes. From the CARRIERS studies, they included 32,247 women with breast cancer and 32,544 women without breast cancer who served as the control group.

In 12 previously established breast cancer predisposition genes, Couch and colleagues found pathogenic variants in 5.03% of case patients and 1.63% of controls. The risks of breast cancer were highest in patients with pathogenic variant in the BRCA1 (OR: 7.62; 95% CI: 5.33-11.27) and BRCA2 (OR: 5.23; 95% CI: 4.09-6.77) genes, followed by moderate risks in those with pathogenic variants in PALB2 (OR: 3.83; 95% CI: 2.68-5.63).

In addition, Couch et al found that pathogenic variants in BARD1, RAD51C, and RAD51D were associated with an increased risk of ER-negative breast cancer and triple-negative breast cancer. Pathogenic variants in ATM, CHD1, and CHEK2 were associated with increased risks of ER-positive breast cancer.

“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,” concluded Couch and colleagues.

In the study conducted by the Breast Cancer Association Consortium, also published in The New England Journal of Medicine, researchers led by Douglas F. Easton, PhD, of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, Cambridge, England, conducted genetic sequencing in a panel of 34 known susceptibility genes from 60,466 women with breast cancer and 53,641 controls to assess the missense-variant association by domain and classification of pathogenicity.

In this cohort, about 6.8% of women with cancer had protein-truncating variants in any of the nine genes associated with breast cancer risk, compared with 2.0% of controls, while 2.2% of breast cancer patients had missense variants in the CHEK2 gene, compared with only 1.4% of controls.

They found that protein-truncating variants in the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were associated with an overall risk of breast cancer (P ˂0.0001), and in the BARD1, RAD51C, RAD51D, and TP53 genes (P ˂ 0.05; Bayesian false-discovery probability: ˂0.05).

In 19 of the 25 remaining genes, protein-truncating variants had an upper limit of the 95% CI of the odds ratio (OR) for breast cancer was less than 2.0. Higher ORs for estrogen receptor (ER)-positive disease compared with ER-negative disease were seen with protein-truncating variants in the ATM and CHEK2 genes, and higher ORs for ER-negative disease compared with ER-positive disease for protein-truncating variants in the BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D genes.

In addition, they found that rare missense variants in the ATM, CHEK2, and TP53 genes were associated with an overall risk of breast cancer (P ˂ 0.001). Pathogenic missense variants in the BRCA1, BRCA2, and TP53 genes were associated with an overall risk of breast cancer that was similar to that seen with protein-truncating gene variants.

Limitations in the CARRIERS analysis included restricted enrollment to women ≥50 years old, penetrance estimation based on population-based rates, and that the genetic sequencing was conducted in research laboratory sequencing instead of in commercial genetic-testing facilities.

Limitations of the study from the Breast Cancer Association Consortium include that analyses of associations in rare variants are susceptible to bias, as is testing for cancer susceptibility genes in genetics clinics.

In his accompanying editorial comment, Steven A. Narod, MD, of the Women’s College Research Institute, Toronto, Canada, wrote:

“These two studies pose important clinical questions. Should we start discussing with our patients each gene shown to have an association with breast cancer risk in these two studies before offering a panel test? Should the 28 extraneous genes be removed from the panels?”

Ultimately, he conceded the value of both studies.

“The studies… are useful in that they help to establish the genes that confer a predisposition to breast cancer and those that do not,” he noted.

Narod concluded, however, with a cautionary note: “These studies are less helpful in refining the lifetime cancer risks for women with mutations. I do not think it is prudent at this time to revise these risk estimates downward on the basis of new results.”

1. According to results from two studies from the United States and the UK, pathogenic variants in the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes are associated with an increased risk of breast cancer.

2. Both studies show that variants in eight genes—BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2—are significantly associated with breast cancer risk.

E.C. Meszaros, Contributing Writer, BreakingMED™

Cat ID: 22

Topic ID: 78,22,497,730,22,691,192,925