Comprehensive Guide to Breast Cancer Risk Genes: What 113,000 Women Taught Us

Table of Contents

• Background: Why This Research Matters
• Study Methods: How This Massive Research Was Conducted
• Key Findings: Detailed Results with All Numbers
• Clinical Implications: What This Means for Patients
• Limitations: What the Study Couldn't Prove
• Recommendations: Actionable Advice for Patients
• Source Information

Background: Why This Research Matters

Genetic testing for cancer susceptibility has become a standard part of medical care, especially for patients with strong family histories of cancer. Until recently, testing focused on a limited number of genes known to carry high cancer risks. However, with advances in DNA sequencing technology, testing larger panels of genes has become more affordable and accessible.

The problem is that for many genes included on these commercial testing panels, the evidence linking them to breast cancer risk is weak. Accurate risk estimates are often unavailable, and reliable information about how these risks might differ for various breast cancer subtypes is lacking. This creates challenges for both doctors and patients when interpreting genetic test results and making decisions about prevention and screening.

This study aimed to solve this problem by conducting the most comprehensive analysis to date of 34 potential breast cancer susceptibility genes. By analyzing genetic data from over 113,000 women, researchers sought to determine which genes truly increase breast cancer risk and by how much, providing much-needed clarity for patients and healthcare providers.

Study Methods: How This Massive Research Was Conducted

Researchers analyzed data from 44 different studies participating in the Breast Cancer Association Consortium (BCAC). The study included genetic information from 60,466 women with breast cancer and 53,461 unaffected controls, making it one of the largest genetic studies of breast cancer ever conducted.

The research team examined a panel of 34 genes that are either known or suspected to be associated with breast cancer risk, including genes commonly included on commercial genetic testing panels. They performed sophisticated DNA sequencing on all samples and implemented rigorous quality control measures to ensure accurate results.

Thirty studies were population-based, meaning they didn't select participants based on family history, while 14 studies specifically oversampled patients with family histories of breast cancer. This approach allowed researchers to both detect associations and obtain accurate risk estimates that apply to the general population.

The statistical analysis focused on two main types of genetic variants: protein-truncating variants (which typically completely disrupt gene function) and rare missense variants (which alter but don't necessarily completely disrupt gene function). Researchers calculated odds ratios, confidence intervals, and statistical significance values for each gene's association with breast cancer risk overall and with specific tumor subtypes.

Key Findings: Detailed Results with All Numbers

The study produced extensive findings about which genes actually increase breast cancer risk and by how much. The results provide crucial information for patients considering genetic testing or interpreting existing test results.

Definitive High-Risk Genes

Researchers found overwhelming evidence that protein-truncating variants in five genes significantly increase breast cancer risk:

• BRCA1: 10.57 times higher risk (95% CI: 8.02-13.93, P = 1.1×10⁻⁶²)
• BRCA2: 5.85 times higher risk (95% CI: 4.85-7.06, P = 2.2×10⁻⁷⁵)
• PALB2: 5.02 times higher risk (95% CI: 3.73-6.76, P = 1.6×10⁻²⁶)
• CHEK2: 2.54 times higher risk (95% CI: 2.21-2.91, P = 3.1×10⁻³⁹)
• ATM: 2.10 times higher risk (95% CI: 1.71-2.57, P = 9.2×10⁻¹³)

Additional Risk Genes

Four other genes showed significant evidence of increased risk with Bayesian false-discovery probabilities below 0.05:

• BARD1: 2.09 times higher risk (95% CI: 1.35-3.23, P = 0.00098)
• RAD51C: 1.93 times higher risk (95% CI: 1.20-3.11, P = 0.0070)
• RAD51D: 1.80 times higher risk (95% CI: 1.11-2.93, P = 0.018)
• TP53: 3.06 times higher risk (95% CI: 0.63-14.91, P = 0.17)

Genes Without Significant Risk Association

For 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio was less than 2.0, meaning they don't appear to confer moderate or high risk. These include genes like ABRAXAS1, AKT1, BRIP1, CDH1, and others that sometimes appear on commercial panels despite lacking strong evidence for breast cancer risk association.

Subtype-Specific Risks

The study revealed important differences in risk patterns for different breast cancer subtypes:

For ATM and CHEK2, risks were significantly higher for estrogen receptor (ER)-positive breast cancer than for ER-negative disease. ATM variants showed a 2.33 times higher risk for ER-positive cancer versus 1.01 times for ER-negative cancer. CHEK2 variants showed a 2.67 times higher risk for ER-positive cancer versus 1.64 times for ER-negative cancer.

In contrast, BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D variants conferred higher risks for ER-negative breast cancer. Three of these genes (BARD1, BRCA1, and BRCA2) showed particularly strong associations with triple-negative breast cancer, the most aggressive subtype.

Age-Related Risk Changes

The research found that risks decreased significantly with increasing age for six genes: BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53. This important finding suggests that the risk conferred by these genes is highest at younger ages and decreases as women get older.

Absolute Risk Calculations

By combining the study's odds ratios with population incidence data, researchers calculated absolute lifetime risks:

• BRCA1, BRCA2, and PALB2 carriers exceeded 30% lifetime risk (high risk threshold)
• ATM, BARD1, CHEK2, RAD51C, and RAD51D carriers had 17-30% lifetime risk (moderate risk range)

Missense Variant Risks

The study also examined rare missense variants and found evidence of increased risk for six genes: CHEK2 (1.42 times), ATM (1.06 times), TP53 (1.10 times), BRCA1 (1.11 times), CDH1 (1.10 times), and RECQL (1.12 times). Importantly, when researchers specifically looked at missense variants classified as pathogenic according to clinical guidelines, they found risks similar to protein-truncating variants for BRCA1, BRCA2, and TP53.

Clinical Implications: What This Means for Patients

This research provides crucial guidance for which genes should be included on clinical genetic testing panels for breast cancer risk assessment. The findings help distinguish between genes with strong evidence of risk association and those without convincing evidence.

For patients with variants in the nine genes with strong evidence (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53), these results provide more precise risk estimates that can guide screening recommendations and preventive decisions. The subtype-specific risk information is particularly valuable, as it helps patients understand what type of breast cancer they might be at risk for developing.

The decreasing risk with age for several genes has important implications for screening schedules. Women with variants in these genes might benefit from more intensive screening at younger ages, with possible adjustment of screening intensity as they get older.

For patients who have undergone genetic testing and received results for genes that this study found not to be associated with significant breast cancer risk, these findings may provide reassurance and prevent unnecessary anxiety or invasive preventive measures.

Limitations: What the Study Couldn't Prove

While this is an exceptionally large and comprehensive study, it does have some limitations. The research focused primarily on protein-truncating variants and rare missense variants, but didn't comprehensively evaluate all possible types of genetic variations that might influence breast cancer risk.

The study population was predominantly of European and Asian ancestry, so the results may not apply equally to women of other ancestral backgrounds. Additional research is needed to understand how these genetic risks might vary across different racial and ethnic groups.

Although the study included over 113,000 women, for some of the rarer genes and variants, the numbers of carriers were still relatively small, leading to wider confidence intervals in the risk estimates. This is particularly true for the TP53 gene, where the confidence interval was quite wide (0.63-14.91).

The research also couldn't account for all possible gene-gene interactions or how these genetic risks might interact with environmental factors, lifestyle choices, or other genetic variations not included in the analysis.

Recommendations: Actionable Advice for Patients

Based on these findings, here's what patients should know about genetic testing and breast cancer risk:

1. If considering genetic testing, ensure the panel includes the nine genes with strong evidence (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) and be cautious about putting too much weight on results for other genes without strong evidence of risk association.
2. If you have a variant in a high-risk gene (BRCA1, BRCA2, or PALB2), discuss with your doctor about enhanced screening starting at earlier ages, and consider consultation with a genetic counselor to discuss preventive options.
3. If you have a variant in a moderate-risk gene (ATM, BARD1, CHEK2, RAD51C, or RAD51D), discuss appropriate screening strategies with your healthcare provider, which may include earlier or more frequent mammograms or breast MRIs.
4. Understand your subtype-specific risks - variants in different genes predispose to different types of breast cancer, which may affect screening approaches and treatment considerations if cancer develops.
5. Remember that risk decreases with age for several genes, which may affect decisions about the duration and intensity of screening regimens.
6. If you have variants in genes without strong evidence of breast cancer risk association, be cautious about making major medical decisions based solely on these results, and discuss them with a genetics professional.

Source Information

Original Article Title: Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Authors: Breast Cancer Association Consortium

Publication: The New England Journal of Medicine, January 20, 2021

DOI: 10.1056/NEJMoa1913948

This patient-friendly article is based on peer-reviewed research originally published in The New England Journal of Medicine. The information has been comprehensively translated to make complex genetic concepts accessible while preserving all scientific details, numerical data, and research findings.