Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) is traditionally associated with mutations in the BRCA1 and BRCA2 genes, predominantly impacting breast, ovarian, pancreatic, and prostate cancers. However, recent research suggests that these mutations may also predispose carriers to a broader spectrum of malignancies, including biliary tract, cervical, colorectal, endometrial, esophageal, and gastric cancers. This review presents findings from extensive datasets, including a significant study from a nationwide Japanese biobank that examined cancer risks in 63,828 patients and 37,086 controls. Our review highlights notable associations, such as an increased risk of uterine and cervical cancers in BRCA1 mutation carriers and increased risk of esophageal and gastric cancers in BRCA2 mutation carriers. These emerging associations underscore the necessity of revisiting and potentially expanding current clinical guidelines to incorporate these additional risks. These findings advocate a comprehensive approach to genetic counseling and underscore the importance of tailored cancer surveillance strategies in populations carrying BRCA mutations. This expanded understanding could significantly influence preventive, diagnostic, and therapeutic strategies, promoting personalized approaches to manage and potentially prevent these malignancies in genetically susceptible populations.
Introduction
Hereditary breast and ovarian cancer syndrome (HBOC) is primarily associated with mutations in the BRCA1 and BRCA2 genes and is well documented for its significant impact on breast, ovarian, pancreatic, and prostate cancers. However, emerging evidence suggests that the spectrum of malignancies linked to these mutations may extend beyond traditional confines. Recent familial and case-control studies have revealed the potential risks of a variety of other cancers, including those of the biliary tract, cervix, colorectal region, endometrium, esophagus, and stomach. Despite the intriguing nature of these findings,1,2,3,4,5,6 these associations have not been sufficiently substantiated for integration into clinical management guidelines, often owing to limitations such as small cohort sizes, modest statistical support, and analyses predominantly confined to affected family members carrying pathogenic variants.
To address these gaps, studies employing extensive datasets, such as those from a nationwide Japanese biobank that includes 63,828 patients and 37,086 controls across 14 common cancer types, have provided valuable insights.7 These and similar studies are distinguished by their significant scale and diversity of their cohorts, offering unique perspectives within the genetic cancer risk study landscape. Such large-scale sequencing efforts are critical to refine our understanding of the broader cancer risks associated with BRCA mutations. By examining the clinical characteristics prevalent among carriers of these pathogenic variants, these studies collectively provide a comprehensive overview that may guide future research directions. The findings from these diverse sources have the potential to inform the design and implementation of clinical trials, specifically to evaluate the efficacy of treatments, such as poly ADP ribose polymerase (PARP) inhibitors, across a wider spectrum of BRCA-related cancers. Such contributions are vital for advancing our approach to managing and potentially preventing diverse malignancies in genetically susceptible populations.
Methods
A comprehensive literature search was conducted across databases such as PubMed, focusing on studies related to BRCA mutations and associated risks for various cancers. Keywords included “BRCA1,” “BRCA2,” and specific cancer types such as “biliary tract cancer,” “cervical cancer,” and “colorectal cancer.” The inclusion criteria targeted peer-reviewed articles and clinical studies, excluding case reports, to compile empirical data on cancer risks associated with BRCA mutations. Quality assessment was tailored to each study type, focusing on the clarity of genetic testing methods and result specificity for smaller studies, while emphasizing the comprehensiveness of data and robustness of statistical methods for larger datasets. Because of the varied nature of the studies and the impracticality of a statistical meta-analysis, the findings were synthesized qualitatively. This approach aimed to identify common patterns and discrepancies across studies, emphasizing significant contributions or unusual results, particularly from an extensive dataset from the Japanese biobank.
Results
Our review separated the findings into categories specific to BRCA1 and BRCA2 mutations, focusing on cancer risks beyond the established associations with breast, ovarian, pancreatic, and prostate cancers. This approach provides a detailed exploration of less commonly recognized risks.
BRCA1 mutation carriers
Uterine and Cervical Cancers: Increased incidence of cancers of the uterine body (relative risk; RR =2.65) and cervix (RR =3.72) was noted in BRCA1 mutation carriers.3 These findings suggest a broader role of BRCA1 in gynecological malignancies than in ovarian cancers.
Gastric and Biliary Tract Cancers: Studies from the Japanese biobank revealed particularly strong association between BRCA1 mutation and gastric cancer (odds ratio; OR =5.2) and between BRCA1 mutation and biliary tract cancers (OR =17.4).7 These findings are significant and suggest that these cancer types require more attention during the clinical screening and management of BRCA1 mutation carriers.
BRCA2 mutation carriers
Esophageal Cancer: The association between BRCA2 mutation and esophageal cancer was significant in a Chinese cohort (OR =15.89).4 This elevated risk suggests that esophageal cancer could be a critical type of cancer in populations with a high prevalence of these mutations.
Gastric Cancer: BRCA2 mutations are associated with an increased risk of gastric cancer.6,7 The risk was quantified with an OR of 4.7 in the Japanese study,7 confirming the need for a broader cancer surveillance strategy in BRCA2 mutation carriers.
Gallbladder and Biliary Tract Cancers: An increased risk of gallbladder and bile duct cancers (RR =4.97) has been reported among BRCA2 mutation carriers.1 This finding was echoed by the significant associations reported in a Japanese study, indicating a possible trend that warrants further investigation.7
These results emphasize the importance of considering a wider range of associated cancer risks in BRCA1 and BRCA2 mutation carriers. Evidence suggests that certain cancers, such as those of the uterine body, cervix, gastric tract, esophagus, and biliary tract, should be subjected to more rigorous surveillance and early intervention strategies in populations known to carry these mutations. The variability in risk profiles across studies and populations also indicates the need for tailored approaches to cancer screening and management that reflect both genetic and environmental factors.
In addition to the narrative synthesis provided, we compiled a summary table detailing the findings from the reviewed studies regarding the cancer risks associated with BRCA1 and BRCA2 mutations, as shown in Table 1. This table highlights the elevated cancer risks identified for each gene mutation across different populations and studies. This tabular summary facilitates a clear comparison and understanding of the global impact of BRCA mutations beyond that of commonly associated cancers.
Table 1.Summary of elevated cancer risks associated with
BRCA1 and
BRCA2 mutations
| Authors | Country | Gene | Elevated cancer risk |
|---|
| BRCA1 mutation carriers | BRCA2 mutation carriers |
|---|
Breast Cancer
Linkage Consortium | Western Europe, USA, Canada | BRCA2 | N/A | Buccal cavity and pharynx, gastric, gallbladder and bile ducts, malignant melanoma |
| Johannsson et al. | Sweden | BRCA1/2 | Gastric, skin | N/A |
| Thompson et al. | Europe, North America | BRCA1 | Uterus, cervix | N/A |
| Ko et al. | China | BRCA2 | N/A | Esophagus |
| Moran et al. | United Kingdom | BRCA1/2 | Esophagus, gastric | Esophagus, gastric, cutaneous melanoma, uveal melanoma |
| Jakubowska et al. | N/A | BRCA2 | N/A | Gastric |
| Momozawa et al. | Japan | BRCA1/2 | Biliary tract, gastric | Esophagus, gastric |
Discussion
Our review highlights the potential extension of cancer risks associated with BRCA1 and BRCA2 mutations beyond the well-known associations with breast, ovarian, pancreatic, and prostate cancers. While emerging evidence on additional cancer types, such as gastric, esophageal, and biliary tract cancers, is intriguing, it is important to note that these associations are still under investigation and have been reported inconsistently across studies. These findings prompt cautious consideration of their integration into current clinical management strategies.
Given the preliminary nature of these findings, genetic counseling should be adapted to include discussions about these potential risks, impacting the decision-making processes for carriers and their families. This would involve discussions about preventive surgeries, pharmacological interventions, such as PARP inhibitors, and lifestyle changes. Furthermore, robust data from large-scale multicenter cohort studies and randomized controlled trials are crucial for corroborating these findings and guiding clinical practice.
Integrating advanced genetic testing into standard care, ensuring comprehensive cancer screening coverage, and facilitating access to specialized care are essential policy measures. These should embrace a global perspective, acknowledging the variations in genetic risk and the prevalence of BRCA mutations across different populations. Ultimately, embracing a nuanced understanding of BRCA mutations will enhance personalized medicine and cancer prevention strategies, aiding in the support of individuals with a high genetic predisposition to cancer.
In conclusion, a comprehensive review of the cancer risks associated with BRCA1 and BRCA2 mutations suggests the need for a broader and more nuanced approach in oncology practice and genetic counseling. Our findings underscore the importance of including a diverse array of associated cancers in the screening and management protocols for individuals with these mutations. As the landscape of genetic research has evolved, the adoption of more sophisticated genetic screening, customized preventive strategies, and personalized treatment plans has become critical. This approach not only promises to improve outcomes for individuals with a genetic predisposition to cancer but also lays the groundwork for the effective use of emerging therapeutic options, such as PARP inhibitors. By emphasizing a multidisciplinary, global perspective, advancements in understanding can be translated into better care and prevention measures, paving the way for personalized medicine in the field of hereditary cancers.
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japanese Society for the Promotion of Science (Grant number 23K08829).
Conflicts of Interest
The authors have declared that no conflict of interest exists.
References
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