Posted: Friday, April 8, 2022
An international case-control study involving about 90,000 women between the ages of 18 and 79 reveals that variants in nine genes linked with higher breast cancer risk are generally associated with triple-negative and/or high-grade disease. However, the subtype pathologies that are expressed differ substantially, according to work by the Breast Cancer Association Consortium published in JAMA Oncology.
“Knowing the age and tumor subtype distributions associated with individual breast cancer genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification, and [this information can] guide targeted screening strategies,” the consortium members wrote. They examined protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.
Specifically, RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease, with odds ratios of 6.19, 6.19, and 10.05, respectively. CHEK2 variants were associated with all subtypes, with odds ratios ranging from 2.21 to 3.17, except for triple-negative disease.
For ATM variants, the association was strongest for the hormone receptor–positive, ERBB2-negative, high-grade subtype (odds ratio = 4.99). TP53 variants were most strongly associated with hormone receptor–positive/ERBB2-positive and hormone receptor–negative/ERBB2-positive subtypes.
BRCA1 was associated with an increased risk of all subtypes, but with odds ratios varying widely; the highest, 55.32, was for triple-negative disease. BRCA2 and PALB2 variants were associated with triple-negative disease as well.
Overall, tumors occurring in pathogenic variant carriers were of higher grade, the authors noted. Also, for most genes and subtypes, a decline in odds ratios was observed with increasing age.
“Together, the nine genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger,” wrote the consortium members. “The combined prevalence of pathogenic variants in any of the nine genes reached 10% for triple-negative cases in those who received a diagnosis when younger than 60 years.”
Disclosure: The study authors’ disclosure information can be found at JAMAnetwork.com.