Exploring the role of non-BRCA mutations in breast cancer susceptibility within the unique genetic landscape of Saudi Arabia
For decades, the conversation around hereditary breast cancer has largely revolved around two key players: BRCA1 and BRCA2. These genes have dominated genetic testing and public awareness, creating the impression that they hold most answers about inherited breast cancer risk. But what happens when patients with strong family histories test negative for BRCA mutations? This question has driven scientists to look deeper, exploring a wider genetic landscape that extends far beyond BRCA—particularly in unique populations like Saudi Arabia.
In the western region of Saudi Arabia, scientists have made a startling discovery: approximately 24.4% of breast cancer patients carry identifiable genetic mutations, with a substantial portion occurring in genes other than BRCA1/2 1 . These findings are reshaping our understanding of hereditary breast cancer in the region and opening new avenues for prevention, early detection, and personalized treatment strategies tailored to the specific genetic profile of the Saudi population.
of Saudi breast cancer patients carry identifiable genetic mutations
of mutations found in non-BRCA genes
pathogenic variants identified in non-BRCA genes
The human genome contains numerous genes that act as guardians against uncontrolled cell growth. When functioning properly, these tumor suppressor genes and DNA repair genes maintain our cellular integrity. However, when mutated, they can significantly increase cancer risk. While BRCA1 and BRCA2 remain the most prominent, scientists have identified multiple other genes that contribute to breast cancer susceptibility.
BRCA1 and BRCA2 - High-penetrance genes responsible for DNA repair
CHEK2, ATM, PALB2 - Moderate to high-penetrance genes with varying cancer risks
These non-BRCA genes generally fall into two categories: high-penetrance genes that dramatically increase risk (like TP53, PTEN, and PALB2) and moderate-penetrance genes that confer a more modest elevation in risk (including CHEK2, ATM, and BRIP1) 6 . Each of these genes plays a distinct role in cellular function, and understanding their specific contributions helps paint a more complete picture of breast cancer genetics.
In Saudi Arabia, where consanguineous marriages are relatively common and the population has a distinct genetic background, the spectrum of non-BRCA mutations may differ significantly from other regions 5 . This genetic uniqueness makes comprehensive local research essential for developing effective, population-specific healthcare approaches.
The Saudi population presents a particularly interesting case for genetic research due to its homogeneous genetic makeup and high rates of consanguinity 1 5 . These factors can influence how genetic disorders, including hereditary cancer syndromes, manifest across the population.
Recent studies from different regions of Saudi Arabia have revealed intriguing patterns. In the Eastern province, research showed that only 12.2% of familial breast cancer cases had BRCA1/2 mutations, with BRCA2 mutations being more prevalent than BRCA1 5 . This contrasts with Western region findings, where BRCA1 mutations were more dominant 1 . These regional variations highlight the importance of local genetic studies rather than relying solely on data from other populations.
A landmark 2025 study conducted at King Abdullah Medical City (KAMC) in Makkah exemplifies the sophisticated approach scientists are taking to unravel the genetic architecture of breast cancer in Saudi Arabia 1 . The research team employed next-generation sequencing (NGS)—a cutting-edge technology that allows simultaneous examination of multiple genes—to analyze blood samples from 209 Saudi breast and/or ovarian cancer patients.
The genetic analysis covered a panel of cancer predisposition genes beyond BRCA, including ATM, CHEK2, PALB2, TP53, RAD51C, and several others 1 . This comprehensive approach enabled researchers to cast a wide net, capturing both common and rare genetic variants that might contribute to cancer development. The use of NGS technology represents a significant advancement over earlier methods that could only examine one or two genes at a time, potentially missing important mutations in less-familiar genes.
The Western Saudi Arabia study yielded several important discoveries that enhance our understanding of non-BRCA mutations in the local population. Among the 209 patients analyzed, 51 (24.4%) carried identifiable pathogenic mutations in breast/ovarian cancer predisposition genes 1 . While the majority occurred in BRCA1 and BRCA2, a significant number—seven pathogenic/likely pathogenic variants—were found in non-BRCA genes 1 .
| Gene Category | Examples | Primary Function |
|---|---|---|
| High-Penetrance Genes | TP53, PTEN, CDH1 | Tumor suppression, cell growth regulation |
| Moderate-Penetrance Genes | CHEK2, ATM, PALB2 | DNA damage repair, cell cycle control |
| Other Cancer-Associated Genes | BRIP1, RAD51C, NBN | DNA repair, genomic stability |
These findings align with international research showing that non-BRCA mutations contribute substantially to hereditary breast cancer. For instance, a study of 139 bilateral breast cancer patients found that 14.4% would have been missed with BRCA-only testing 2 . Similarly, research from India reported that 15.1% of detectable mutations in breast/ovarian cancer patients occurred in non-BRCA genes 3 .
The revolution in our understanding of non-BRCA mutations has been powered by advances in genetic technologies and research methods. Central to this progress is next-generation sequencing (NGS), which allows scientists to examine dozens of genes simultaneously from a small blood or tissue sample 1 6 . This technology has made comprehensive genetic testing more accessible and cost-effective, enabling the broad gene panels necessary to detect non-BRCA mutations.
Blood samples from patients with breast/ovarian cancer
Using commercial kits to obtain high-quality genetic material
NGS technology to examine multiple genes simultaneously
Bioinformatics tools to identify meaningful genetic variants
The integration of these technologies has created a powerful platform for discovering previously overlooked genetic contributors to breast cancer, particularly in understudied populations like Saudi Arabia.
The identification of non-BRCA mutations carries significant implications for breast cancer management in Saudi Arabia. From a clinical perspective, comprehensive genetic testing that includes non-BRCA genes can provide explanations for previously mysterious family cancer clusters, guiding enhanced screening and prevention strategies for mutation carriers 2 7 .
Enhanced screening and prevention strategies for mutation carriers
PARP inhibitors and other targeted therapies for specific mutations
Development of cost-effective, population-specific testing strategies
On a public health level, understanding the unique spectrum of mutations in the Saudi population enables development of cost-effective genetic testing strategies appropriate for the local context 3 . As research continues, scientists hope to identify region-specific mutations that could be incorporated into targeted screening panels, making genetic testing more accessible and informative for Saudi patients and their families.
Perhaps most importantly, this research brings personal significance to individuals and families affected by hereditary breast cancer. For those who previously tested negative for BRCA mutations, expanded genetic testing can provide long-sought answers about their cancer risk, ending diagnostic odysseys and enabling informed decisions about risk management.
The exploration of non-BRCA mutations in Saudi breast cancer patients represents a significant shift in our approach to hereditary cancer genetics. Moving beyond the narrow focus on BRCA1/2, scientists are now uncovering a more complex genetic landscape that reflects the unique characteristics of the Saudi population.
This research not only advances scientific knowledge but also holds tangible promise for improving patient care through more personalized prevention, screening, and treatment strategies.
As genetic research continues to evolve in Saudi Arabia, the integration of comprehensive genetic testing into routine clinical practice will be essential for translating these discoveries into better health outcomes. With ongoing studies and advancing technologies, the future of breast cancer management in the Kingdom looks increasingly precise, personalized, and powerful—ensuring that no genetic clue goes unnoticed in the fight against this devastating disease.