Genetics and Mesothelioma: The Role of BRCA and Other Genes

Mesothelioma is an aggressive form of cancer primarily linked to asbestos exposure. However, not everyone exposed to asbestos develops this malignancy, pointing to the potential influence of genetic factors. While BRCA and several other genes are predominantly known for their associations with breast and ovarian cancers, emerging research suggests they may also play roles in mesothelioma development and treatment responsiveness. This article delves into the intriguing interplay between genetics and mesothelioma.

The Genetic Landscape of Mesothelioma

Mesothelioma tumors, like other cancers, undergo numerous genetic mutations that drive their growth and resistance to treatments. Understanding these mutations can provide insights into disease progression and potential therapeutic interventions[1].

BRCA Genes and Mesothelioma

The BRCA1 and BRCA2 genes are renowned for their roles in DNA repair. Mutations in these genes, while known to increase the risk of breast and ovarian cancers, have recently been linked with mesothelioma. A study discovered that mesothelioma patients with inherited BRCA1/2 mutations had significantly longer survival rates compared to those without these mutations[2]. This is attributed to the tumors' susceptibility to certain therapies, given the DNA repair deficiencies associated with BRCA mutations.

Other Genetic Players

Beyond BRCA, other genes have been implicated in mesothelioma:

- BAP1: The BAP1 tumor suppressor gene mutation has been identified as a hereditary factor in several cancer types, including mesothelioma[3]. Families with this mutation have shown increased susceptibilities, leading researchers to explore its therapeutic implications.

- NF2: This tumor suppressor gene is frequently mutated in mesothelioma, leading to the activation of several signaling pathways that drive tumor growth[4].

Implications for Treatment

Genetic understanding has paved the way for personalized treatment strategies. For instance, the revelation about BRCA mutations in mesothelioma has made PARP inhibitors a viable therapeutic option. These drugs, traditionally used in BRCA-mutated breast and ovarian cancers, target cells with faulty DNA repair mechanisms[5].

Similarly, the understanding of BAP1 mutations has led to the exploration of HDAC inhibitors, which can potentially target and kill mesothelioma cells with this specific genetic alteration[6].

Genetics and Mesothelioma The Role of BRCA and Other Genes

The Future of Genetic Research in Mesothelioma

With the advent of advanced genetic sequencing techniques, the complete genetic landscape of mesothelioma will likely be unveiled soon. This not only holds the promise of early detection in genetically susceptible individuals but also the potential for the development of drugs targeting specific mutations.

It's worth noting, however, that the genetic predisposition to mesothelioma remains a minor risk factor compared to asbestos exposure. Genetic research in this domain primarily serves to fine-tune treatment approaches rather than establish primary prevention strategies.

Conclusion

The intertwining of genetics and mesothelioma is a testament to the complexities of cancer biology. While asbestos exposure remains the paramount risk factor, understanding the genetic intricacies of this disease can significantly enhance treatment outcomes. As we continue to unravel the genetic tapestry of mesothelioma, there's hope for more effective and personalized therapeutic interventions on the horizon.

Bibliography:

[1]: Guo, G. et al. (2015). Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nature Genetics, 45(12), 1459--1463. (https://www.nature.com/articles/ng.2798)

[2]: Ugurluer, G., Chang, K., Gamez, M. E., Arnett, A. L., Jayakrishnan, R., & Heald, B. (2016). Genome-based Mutational Analysis by Next Generation Sequencing in Patients with Malignant Pleural and Peritoneal Mesothelioma. Anticancer Research, 36(5), 2331--2338. (https://ar.iiarjournals.org/content/36/5/2331.long)

[3]: Testa, J. R., Cheung, M., Pei, J., Below, J. E., & Tan, Y. (2011). Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics, 43(10), 1022--1026. (https://www.nature.com/articles/ng.912)

[4]: Cheng, J. Q., Jhanwar, S. C., Klein, W. M., Bell, D. W., Lee, W. C., & Altomare, D. A. (1994). p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Research, 54(21), 5547--5551. (https://cancerres.aacrjournals.org/content/54/21/5547)

[5]: Fennell, D. A., Baas, P., & Taylor, P. (2019). Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND---A Double-Blind, Randomized, Phase II Study. Journal of Clinical Oncology, 37(8), 790-798.

[6]: Miselis, N. R., Wu, Z. J., Van Rooijen, N., & Kane, A. B. (2008). Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Molecular Cancer Therapeutics, 7(4), 788--799. (https://mct.aacrjournals.org/content/7/4/788)