Which Inherited Gene Mutation Is Associated with Which Breast Cancer Subtype?

A comprehensive case-control study involving more than 80 thousand people shows that breast cancer risk genes are generally associated with triple-negative and high-grade disease, but vary considerably across breast cancer subtypes. What does this mean?

The authors noted that the findings have potential implications for genetic testing, risk prediction, variant (genetic alteration) classification and cancer screening for early diagnosis.

In this study, researchers compared data from 42,680 women with breast cancer and 42,387 women without breast cancer enrolled in another study to assess links between pathogenic germline (inherited) variants in nine major breast cancer susceptibility genes and the pathological characteristics of nonmetastatic breast tumors.

The study examined features related to the cancer’s course and different treatment-related options, including tumor subtype, morphology (structure), size, stage and lymph-node involvement, and found significant differences in tumor-subtype distribution associated with inherited cancer genes.

Pathogenic mutations (genetic alterations that cause faulty protein production) were associated with more aggressive breast cancer, particularly among younger women. These mutations were seen in 27% of women diagnosed with triple-negative breast cancer (mainly driven by a BRCA1 mutation) at age 40 or younger, and in about 16% of those diagnosed with hormone receptor (HR)-positive, HER2-negative high-grade disease.

Together, the nine genes were associated with 14.4% of tumors in women aged 40 or younger, but less than 4% in women over 60; among younger women, these genetic alterations were more frequent in those with triple-negative breast cancer.

These findings were published online on 27 January 2022 in JAMA Oncology.

Nine Breast Cancer Genes Associated with Aggressive Biology

Study participants were women aged 18-79 from 38 international population- or hospital-based studies conducted between 1991 and 2016.

The genes evaluated included ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D and TP53 (see All inherited cancer mutations)

The distribution of breast cancer subtypes affected by these genes was quite mixed. For example,

• RAD51C, RAD51D and BARD1 gene variants were mainly associated with the risk of triple-negative breast cancer (with odds ratios of 6.2, 6.2 and 10-fold, respectively), while
• CHEK2 gene variants were associated with all subtypes other than triple-negative breast cancer (with odds ratios ranging from 2.2 - 3.2 ).
• ATM variants had a 5-fold odds ratio for the hormone-positive, HER2-negative high-grade subtype.
• BRCA1 was associated with an increased risk of all subtypes, but the odds ratio was highest for triple-negative breast cancer: 55-fold.
• BRCA2 and PALB2 variants were also associated with triple-negative disease.
• TP53 variants were most strongly associated with hormone-positive HER2-negative and hormone-negative HER2-positive subtypes, and tumors occurring in carriers of pathogenic variants were higher grade. The odds ratio also decreased with increasing age.
• All genes other than CHEK2 were more strongly associated with high-grade disease.,

Making Predictions about Genetic Alterations of Uncertain Significance

Sometimes a genetic test finds an alteration in inherited cancer genes that has not previously been associated with cancer and is rare in the general population. This type of test result is called a “variant of uncertain significance” or VUS (Variant of Uncertain Significance), because it is not clearly known whether this specific genetic alteration is pathogenic/harmful. However, a genetic alteration described as a VUS today may be identified as pathogenic in the future as genetic data accumulate.

The authors noted that these and other findings from the study could inform gene-panel sequencing and breast cancer guidelines in the general population, adding that tumor characteristics such as subtype could also be used to determine whether variants of uncertain significance are pathological.

The researchers therefore said, “the data should improve the precision of variant-classification algorithms and extend them to a larger set of genes”.

In conclusion, this case-control study reveals marked heterogeneity by tumor subtype in rare variants in genes that increase breast cancer risk. The study provides a detailed description of subtype-specific breast cancer risks, which could potentially improve risk-prediction models and breast cancer prevention strategies.

Women found to carry variants in these genes may be offered enhanced screening, including MRI (magnetic resonance imaging), risk-reducing surgery, chemoprevention and genetic counseling.

Such studies of inherited cancer genes are highly valuable because they improve our understanding of breast cancer biology and support efforts to classify whether genetic variants of uncertain significance are pathogenic.