Page 48 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
BRCA VUS in breast cancer in MENA region

the development of comprehensive models to enhance the of VUS to 2.1% through the accumulation of data. 54
accuracy of BRCA variant classification. Figure 4 provides
a visual representation of the distribution of distinct 4.2. Distribution of VUS in BRCA1 and BRCA2
BRCA1 and BRCA2 VUS from the MENA region based on Our analysis demonstrates a significant concentration of
their new reclassification. VUS in exons 10 and 11 of the BRCA1. These two exons
together account for 54.3% of all reported variants, with
4. Discussion exon 10 harboring 44 VUS (29.1%) and exon 11 containing
The comprehensive evaluation of VUS in BRCA1 and 38 VUS (25.2%). This clustering pattern is consistent with
BRCA2 among BC patients from the MENA region has previous studies, which have identified similar trends across
provided valuable insights into the genetic landscape diverse populations, reinforcing the notion that these exons
of this area. Our analysis encompassed 34 eligible represent major mutational hotspots within BRCA1. 55
studies from an initial pool of 480, involving a total of Our findings align with prior research highlighting
5984 patients and identifying 681 carriers with 385 distinct the prevalence of VUS in these exons across diverse
VUS. This extensive dataset offers a robust foundation populations. For example, exons 10 and 11 have been
for understanding the genetic distribution of BRCA1 shown to exhibit higher mutational frequencies in familial
and BRCA2 variants in the MENA region. The temporal BC and OC cases, potentially impacting the functionality
span of the included studies (2002 – 2021) allows for a of the BRCA1 protein. 56,57 Moreover, while exon 10 of
comprehensive view of how BRCA1 and BRCA2 testing BRCA1 exhibits a high mutation rate, exon 11 of BRCA2
and interpretation have evolved over time. also shows a remarkable frequency, containing 87 VUS

4.1. Prevalence and regional distribution of VUS in (37.2% of the total) in this analysis. This particular finding
BRCA1 and BRCA2 reinforces the critical role of both exons in gene function
and their contribution to BC susceptibility.
The observed regional variations in VUS distribution
between BRCA1 and BRCA2 are particularly noteworthy. Intriguingly, the distribution patterns of VUS also
Among all BRCA1 VUS in the MENA region, we found a highlight a decrease in frequency in subsequent exons, with
slight preponderance in North African populations (55%, exon 16 contributing only 4.6% of the total mutations. This
n = 158) compared to Middle Eastern populations (45%, notable drop-off after the major hotspots may reflect selective
n = 129). This finding aligns with previous studies that have pressures or functional constraints acting on different
reported varying frequencies of BRCA1 mutations across regions of the gene, corroborating insights from other
different ethnic groups. However, the distribution pattern studies that propose that certain regions are more prone to
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for BRCA2 VUS was markedly different, with a significantly mutations due to underlying biological mechanisms, such as
higher prevalence in Middle Eastern populations (76.14%, DNA repair processes and environmental interactions. The
n = 300) compared to North African populations (23.86%, data derived from the MENA region further emphasizes the
n = 94). This discrepancy in VUS distribution between unique mutational landscape of BRCA2, with exon 11 being
BRCA1 and BRCA2 across the MENA region may be the focal point, accounting for 37.2% of BRCA2 VUS. This
attributed to several factors, including the more frequent streamlined clustering, particularly in exon 11, underscores
use of NGS in Middle Eastern studies and larger sample its pivotal role in gene function and BC susceptibility, aligning
sizes. In addition, the higher preponderance of BRCA1 closely with other studies that emphasize the importance of
VUS in North Africa could be due to a methodological bias exon 11’s significance in genetic predisposition to cancer
toward BRCA1 testing in regional studies. across various ethnicities. 58
It is important to note that despite these regional Furthermore, the relatively low frequency of intronic
variations, the overall rates of BRCA1 and BRCA2 VUS in mutations, coupled with the few observed in the 3’ UTR
each subregion (8.91% in the Middle East and 21.5% in region, reflects a complex mutational paradigm. Studies
North Africa) appear to be consistent with global trends. investigating intronic variants have shown that they can
Previous research has reported an overall VUS rate of affect pre-messenger RNA (mRNA) splicing, adding
10–20% in women who have undergone BRCA testing, with complexity to genetic counseling for affected families. 59
frequencies varying worldwide based on testing prevalence
and population ancestry. Notably, studies have reported 4.3. Types of distinct VUS in BRCA1 and BRCA2
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VUS frequencies of 21% in African-Americans, 5 – 6% The predominant type of VUS observed in both BRCA1
in individuals of European ancestry in the United States, and BRCA2 was missense variants, accounting for 276 of
and 15% in European laboratories. Myriad Genetics Inc. the total variants (71.7%). This finding is consistent with
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(United States) has claimed to have reduced their proportion previous research, such as the one conducted by Caputo

Volume 9 Issue 1 (2025) 40 doi: 10.36922/ejmo.5800