Amanda Nasrallah, Fifth-year Medical Student at Al-Quds University, and Palestine National Delegate at IASSS (International Association of Student Surgical Societies), shared a brief summary of her recent article:
“I am pleased to share a summary of my recent work titled “Genetic Basis of Male Breast Cancer,” which investigates the distinct molecular and genetic features underlying this rare disease. My review highlights the pivotal role of BRCA2, CHEK2, PALB2, and emerging genes such as MAP2K4, ZNF217, THY1, and SPAG5 in shaping the oncogenic landscape of male breast cancer.
Male breast cancer (MaleBC) is a rare disease, accounting for <1% of all male tumors. Along with the rise in female breast cancer (FBC) over the past several years, there has also been an increase in the incidence of this disease. Though its pathophysiology has been linked to hormonal, environmental, and genetic variables, little is understood regarding the etiology of MaleBC.
Radiation exposure, hormone imbalance – causing clinical diseases, and, most importantly, a positive family history for BC – which indicates a genetic susceptibility – are major risk factors. High-penetrance gene mutations (BRCA1 and BRCA2) are rare and have a high risk of developing BC; low-penetrance gene mutations (CHEK -2) are more prevalent but carry a reduced risk. Subsequently, investigation of further studies may answer the question of “how does genetic factors correlate with male breast cancer?”.
Hence, in our comprehensive literature review focused on the genetic underpinnings of male breast cancer (MBC), exclusively considering studies on humans published in English. We assessed selected studies for their methodological integrity, sample size, statistical robustness, and relevance, revealing the pivotal role of genetics in MBC predisposition.
Specifically, BRCA2 mutations were identified as significant risk factors, while multi-gene panel testing has exposed other genes potentially increasing MBC risk. MBC research has classified two main subgroups, luminal M1 and luminal M2, through transcriptional and copy number profiling. Luminal M1 features chromosomal abnormalities and gene overexpression related to cellular processes and angiogenesis, whereas luminal M2 is characterized by upregulated genes in immune response and estrogen receptor signaling.
Additionally, unique somatic mutations in genes like MAP2K4, ZNF217, and novel genes THY1 and SPAG5 linked to cancer growth and metastasis have been noted (2). As a matter of fact, MBC is molecularly distinct from female breast cancer (FBC), lacking common genetic and epigenetic traits, indicating a unique pathogenesis. Inherited BRCA1 and BRCA2 mutations (1) account for a significant portion of MBC cases, suggesting a substantial genetic predisposition. Moreover, mutations in PALB2 and CHEK2, among others, also contribute to MBC risk, highlighting a complex genetic landscape (3).
Distinctions in genetic mutations within luminal subtypes and a gender-based variance in mutation hotspots further emphasize the intricate interaction between gender and genetic risk factors. Genome-wide association studies (GWAS) have identified specific single nucleotide polymorphisms (SNPs) increasing MBC susceptibility, underlining the genetic framework distinguishing MBC from FBC. This overview underscores the importance of genetic factors in understanding and managing MBC, pointing towards a nuanced and comprehensive approach to its study and treatment (4).
In conclusion, as we can follow up on the selected literature discovering the genetic basis of Male breast cancer, we can observe that the genetic component of the incidence of tumors arising in male breast is not as significant and clear as it is to their gender counterpart.
However, the rate of mutation in the studied genes mentioned, such as, MAP2K4, ZNF217 and the most famous BRCA1 and especially BRCA2, are directly related to more incidence of Male breast cancer suggesting that there is a solid relationship between the two. These somehow bombarding results strongly urges the need for further research and studies to better understand and navigate through the genetic basis of male breast cancer.”
References
- Bojesen SE , Pooley KA , Johnatty SE , et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013;45(4):371–384.
- Moelans, C. B., de Ligt, J., van der Groep, P., Prins, P., Besselink, N. J. M., Hoogstraat, M., ter Hoeve, N. D., Lacle, M. M., Kornegoor, R., van der Pol, C. C., de Leng, W. W. J., Barbé, E., van der Vegt, B., Martens, J., Bult, P., Smit, V. T. H. B. M., Koudijs, M. J., Nijman, I. J., Voest, E. E., Selenica, P., Weigelt, B., Reis-Filho, J. S., van der Wall, E., Cuppen, E., & van Diest, P. J. (2019).
The molecular genetic make-up of male breast cancer. Endocrine-Related Cancer, 26(10), 779-794. Retrieved Feb 20, 2024. - Sarah Maguire, Eleni Perraki, Katarzyna Tomczyk, Michael E Jones, Olivia Fletcher, Matthew Pugh, Timothy Winter, Kyle Thompson, Rosie Cooke, kConFab Consortium, Alison Trainer, Paul James, Stig Bojesen, Henrik Flyger, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines Zanna, Laura Ottini, Valentina Silvestri, Antoinette Hollestelle, Maartje J Hooning, Srdjan Novaković, Mateja Krajc, Manuela GagoDominguez, Jose Esteban Castelao, Hakan Olsson, Ingrid Hedenfalk, Emmanouil Saloustros, Vasilios Georgoulias, Douglas F Easton, Paul Pharoah, Alison M Dunning, D Timothy Bishop, Susan L Neuhausen, Linda Steele, Alan Ashworth, Montserrat Garcia Closas, Richard Houlston, Anthony Swerdlow, Nick Orr,
Common Susceptibility Loci for Male Breast Cancer, JNCI: Journal of the National Cancer Institute, Volume 113, Issue 4, April 2021, Pages 453–461, - Swerdlow AJ , Jones ME , Schoemaker MJ , et al. The Breakthrough Generations Study: design of a long-term UK cohort study to investigate breast cancer aetiology. Br J Cancer. 2011;105(7):911–917.
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