SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence.
Genetic testing for cancer susceptibility with multigene testing panels is now becoming widely available and affordable. Identification of pathogenic variants in predisposition genes such as BRCA1 and BRCA2 among carriers has provided benefit through early intervention. However, the evidence of an association with cancer is often weak for many other genes on multigene testing panels, and estimates of the cancer risks associated with such variants are often not available. Further, estimates of the prevalence of pathogenic variants in predisposition genes in the general population are lacking.
Two large breast cancer case-control studies analyzed the associations between a number of commonly accepted cancer susceptibility genes and breast cancer risk.
The multinational study by Dorling et al. used a panel of 34 commonly accepted cancer susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls (unaffected woman) from 25 countries participating in the Breast Cancer Association Consortium. The authors estimated odds ratios for breast cancer overall and tumor subtypes and evaluated missense-variant associations and classification of pathogenicity. The researchers found strong evidence of an association with breast cancer risk for Protein-Truncating Variants (genetic variants) caused by frameshift mutations in 9 genes, with a significant risk for breast cancer and P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2 – Odds Ratios ranging from 2.1 for ATM to 10.6 for BRCA1), and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53 – Odds Ratio ranging from 1.8 for RAD51D to 3.06 for TP53). Further, it was noted that for the genetic variants in most of these genes, the Odds Ratio differed according to breast cancer subtype. Protein-Truncating Variants in ATM and CHEK2 were more strongly associated with ER-positive disease than with ER-negative disease, whereas genetic variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D were more strongly associated with ER-negative disease than with ER-positive disease. It was also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, were associated with moderate breast cancer risk. The researchers also noted that none of the other 25 genes in the panel were informative for the prediction of breast cancer risk. This study places Protein-Truncating Variants in BRCA1, BRCA2, and PALB2 in the high-risk category and Protein-Truncating Variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in the moderate-risk category.
The US study by Hu et al. used a panel of 28 cancer predisposition genes to perform sequencing on samples from 32,247 women with breast cancer and 32,544 controls (unaffected women) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. The researchers assessed the associations between pathogenic variants in each gene and the risk of breast cancer.
The researchers noted that pathogenic variants in 12 established breast cancer predisposition genes were detected in 5% of breast cancer patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with Odds Ratios of 7.62 and 5.23 respectively and pathogenic variants in PALB2 were associated with a moderate risk (Odds Ratio 3.83). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of ER-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of ER-positive breast cancer. Pathogenic variants in the other 16 candidate breast cancer predisposition genes were not associated with an increased risk of breast cancer.
Taken together, the results from these two large case-control studies suggested that variants in 8 genes – BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2, had a significant association with breast cancer risk and majority of the other genes tested did not have a significant association with disease. Further, the distribution of mutations among women with breast cancer was different from the distribution among controls (unaffected women). Among breast cancer patients, the majority of mutations were in BRCA1, BRCA2, and PALB2, and among controls, the majority of mutations were in CHEK2 and ATM.
It can be concluded that, these two studies define the genes that are of utmost clinical value for inclusion on sequencing panels, for the prediction of breast cancer risk, and provides estimates of the prevalence of the pathogenic variants in the unaffected population. The authors added that these estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.
Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al. N Engl J Med 2021;384:428-439.
A Population-Based Study of Genes Previously Implicated in Breast Cancer. Hu C, Hart SN, Gnanaolivu R, et al. N Engl J Med 2021;384:440-451.
