INVESTIGATION OF THE RELATIONSHIP OF TNFRSF11A
GENE POLYMORPHISMS WITH BREAST CANCER
DEVELOPMENT AND METASTASIS RISK IN PATIENTS
WITH BRCA1 OR BRCA2 PATHOGENIC VARIANTS
LIVING IN THE TRAKYA REGION OF TURKEY
Özdemir K, Gürkan H, Demir S, Atli E, Özen Y, Sezer A, Tunçbilek N, Çicin İ
*Corresponding Author: Hakan Gürkan, MD, PhD, Department of Medical Genetics, Genetic Diseases
Diagnosis Center, Trakya University Faculty of Medicine, Balkan Campus, 22030 Edirne, Turkey. Tel:
+90-533-218-8005. Fax: +90-284-235-7641. Email: dr_hakangurkan@yahoo.de, hgurkan@trakya.edu.tr
page: 49
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DISCUSSION
It is now thought that the results of genetic studies
will provide insight into new approaches for the treatment
of breast cancer, which is a very important health problem
with significant mortality rates, especially among women.
For this purpose, extensive studies with genes, proteins and
enzymes have been performed to examine the molecular
mechanisms that play a role in the pathogenesis of breast
cancer [1,19]. However, it is thought that there are still
many mechanisms that are yet to be discovered. In recent
years, the rising number of reports about the newly discovered
genes and proteins have not only been focused on
the molecular mechanisms of cancer, but also on the basis
for developing approaches to both detect and treatment of
cancer [20]. TNFRSF11A and RANKL are genes that are
functionally linked, and they are often considered together
in terms of their role in determining various traits. RANKL
and receptor activator of nuclear κ B (RANK) genes are
essential for osteoclast activation and development [13].
In addition, it has been reported that the RANK gene contributes
to breast tumorigenesis because it is expressed in
mammary gland cells and controls lactation development
during pregnancy [21,22].
Although many genes that influence breast cancer
have been investigated to date, there have been a limited
number of studies on the effect of the TNFRSF11A gene
on breast cancer. The results of genome-wide association
studies conducted by the Cancer and Genetics Markers
of Susceptibility (CGEMS) initiative have suggested that
the common genetic variation (rs7226991) near the 5’
terminal of TNFRSF11A was associated with breast cancer
risk [8,23]. Several common breast cancer susceptibility
alleles, identified by genome-wide association studies and
in different populations, have also been associated with
breast cancer risk among BRCA1 and/or BRCA2 mutation
carriers [24].
Regarding these developments, rs7226991 genotypes
have been detected in two Spanish case-control studies.
Bonifaci et al. [8] revealed that rs7226991 was associated
with a risk of breast cancer among the general Spanish
population (BRCA1 or BRCA2) along with BRCA2 mutation
carriers from different populations, which is consistent
with the above observations. In addition, the results of
the study exhibited effects parallel to those shown in the
CGEMS results [8,25,26].
In their study, Sigl et al. [17]. indicated that a total
of 19 SNPs genotyped in or near the TNFRSF11A gene.
In this particular study, it was reported that TNFRSF11A
possibly contributes to both menarche and the natural onset
of menopause, and early menarche and natural menopause
age have been shown to increase the risk of breast cancer.
Similar to our results, no statistically significant difference
was found for rs17069904, rs9646629 and rs884205
SNPs. Sigl et al. [17] also identified the role of the loci
responsible for encoding TNFRSF11A as a genetic regulator
of breast cancer risk in women with hereditary BRCA1
mutations, as RANK/RANKL significantly affected breast
car-cinogenesis in mice with BRCA1 mutation carriers.
Six SNPs (rs9646629, rs4485469, rs34739845, rs4941129,
rs17069904 and rs884205) have been reported to be significantly
associated with the risk of breast cancer in ERnegative
or triple-negative BRCA1 mutation carriers; such
a determination was made based on the consideration of
15,200 BRCA1 and 8200 BRCA2 mutation carriers using
Collaborative Oncological Gene-environment Study
(iCOGS) data in which 51 TNFRSF11A SNPs were genotyped.
In addition, Sigl et al. [17] suggested that two SNPs
in the TNFRSF11A gene (rs884205 and rs4485469) were
significantly associated with breast cancer risk (p <0.05)
in BRCA1 and BRCA2 mutation carriers.
In our study, we found that TNFRSF11A rs4485469
SNP has a borderline significance between the patient
group with and without BRCA1 or BRCA2 mutation (p =
0.059), compatible with the results of the study performed
by Sigl et al. [17]. We anticipate that statistically significant
results can be obtained if the study is repeated with
an increased number of patients.
A limited number of studies in the literature have
reported on the TNFRSF11A gene and its effect on the
risk of developing breast cancer. Rao et al. [27] aimed to
determine the effect of RANK signaling in breast cancer
formation based on previous findings, showing that RANK
plays an important role in mammary gland development
and progestin-induced breast carcinogenesis. In their studies,
in which they performed a multi-faceted analysis of
the RANK/RANKL system, Rao et al. [27] reported that
the SNPs in the TNFRSF11A gene that increased RANK
expression levels, were associated with an increased risk
of breast cancer development in women with BRCA1 or
BRCA2 mutations. They also suggested that developing
breast cancer against the background of BRCA1 or BRCA2
mutations can be prevented by blocking RANK/RANKL
signaling. These findings may pave the way for a new era
of breast cancer prophylaxis by changing the lives of millions
of women worldwide [27]. With respect to our own
findings, we predict that the investigation of the effects of
the TNFRSF11A gene variations on breast cancer development
risk in BRCA1 and/or BRCA2 mutation carrier breast
cancer patients in different populations will contribute to
refining the proper treatment protocols.
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