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The Potential Contribution of 
BRCA Mutations to Early Onset 
and Familial Breast Cancer in 
Uzbekistan 

 
Abdulla Abdikhakimov1,  
Mukaddas Tukhtaboeva1, 
Bakhtiyar Adilov2,  
Shahlo Turdikulova2 
 
1Tashkent Institute of Postgraduate 
Education, Tashkent Regional 
Oncological Dispensary;  
2Center for High Technologies Academy 
of Sciences Republic of Uzbekistan 

 
Vol. 5, No. 1 (2016)   |   ISSN 2166-7403 (online)  
DOI 10.5195/cajgh.2016.228 |   http://cajgh.pitt.edu 

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ABDIKHAKIMOV 
 

 
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Abstract 

Introuduction: Breast cancer is the most common malignancy in women and affects approximately 1 out of 8 females in the US. 
Risk of developing breast cancer is strongly influenced by genetic factors. Germ-line mutations in BRCA1 and BRCA2 genes are 
associated with 5–10% of breast cancer incidence. To reduce the risk of developing cancer and to increase the likelihood of early 
detection, carriers of BRCA1 or BRCA2 mutations are offered surveillance programs and effective preventive medical 
interventions. Identification of founder mutations of BRCA1/2 in high risk communities can have a significant impact on the 
management of hereditary cancer at the level of the national healthcare systems, making genetic testing more affordable and cost-
effective. BRCA1 and BRCA2 mutations in breast cancer patients have not been characterized in the Uzbek population. This 
pilot study aimed to investigate the contribution of BRCA1 and BRCA2 mutation to early onset and familial cases of breast 
cancer in Uzbekistan.  
Methods: A total of 67 patients with breast cancer and 103 age-matched disease free controls were included in this study. 
Utilizing SYBR Green based real-time allele-specific PCR, we have analyzed DNA samples of  patients with breast cancer and 
disease free controls to identify the following BRCA1 and BRCA2 mutations: BRCA1 5382insC, BRCA1 4153delA, BRCA1 
185delAG, BRCA1 300T>G, BRCA2 6174delT.  
Results: Three unrelated samples (4.5%) were found to be positive for the heterozygous 5382insCBRCA1 mutation, representing 
a possible founder mutation in the Uzbek population, supporting the need for larger studies examining the contribution of this 
mutation to breast cancer incidence in Uzbekistan.We did not findBRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, and 
BRCA2 6174delT mutations.  
Conclusion: This preliminary evidence suggests a potential contribution of BRCA1 5382insC mutation to breast cancer 
development in Uzbek population. Taking into account a high disease penetrance in carriers of BRCA1 mutation, it seems 
reasonable to recommend inclusion of the 5382insC mutation test in future research on the development of screening programs 
for breast cancer prevention in Uzbekistan. 

Keywords: BRCA1, BRCA2, Founder mutation, Real-time PCR, Breast cancer, Uzbek population 

 

The Potential Contribution of BRCA 
Mutations to Early Onset and Familial 
Breast Cancer in Uzbekistan 

Abdulla Abdikhakimov1, Mukaddas 
Tukhtaboeva1, Bakhtiyar Adilov2, 
Shahlo Turdikulova2 
 
1Tashkent Institute of Postgraduate 
Education, Tashkent Regional Oncological 
Dispensary;  
2Center for High Technologies Academy of 
Sciences Republic of Uzbekistan 

Research 

Breast cancer is one of the most commonly 
diagnosed malignancies around the world with the 
incidence potentially rising in Asia due to an 
increasingly westernized lifestyle.1 The average lifetime 
risk of breast cancer in women living in the US is 12.3% 
(1/8)2, and it is the most prevalent cancer in women 
other than skin cancer.3 While lifestyle factors such as 
obesity and reproductive factors play an important role 
in breast cancer development, in a small percentage of 
families the risk of developing breast cancer is strongly 
influenced by hereditary factors. The most significant 
and well-characterized genetic risk factors for breast 

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cancer published to date are germline mutations of the 
BRCA1and BRCA2 genes.4 In the general population, 
about 5–10% of all breast cancer cases are linked to the 
mutations in these genes, which can explain around half 
of the cases of breast cancer aggregation in some 
families.5,6 It is estimated that the total frequency of 
BRCA1 and BRCA2 mutation carriers in Europe is 
around 0.2% (1/500), while the prevalence of BRCA1 
mutation carriers is approximately 0.13% (1/800)7; 
however, it can vary widely among different countries 
and ethnic groups due to  the founder effect.8 

 According to the data from the Republican 
Oncology Research Center of the Ministry of Health of 
the Republic of Uzbekistan, 2273 new cases of breast 
cancer were diagnosed in Uzbekistan in 2010, which is 
784 cases higher than in 2001 (data not published). 
These numbers demonstrate that the number of reported 
cases of breast cancer in Uzbekistan is potentially 
increasing. It is possible to approximate that the number 
of patients with breast cancer diagnosis increased by an 
average of 87 people per year in this time period. The 
rate of increase of breast cancer within a 10–year period 
was 37.3%.9 Inherited BRCA mutations are associated 
with high disease penetrance. Women carrying a 
BRCA1 mutation have a lifetime risk of 65–80% of 
developing breast cancer, while BRCA2 mutation 
carriers have a lifetime risk of 45–85%.10 BRCA1and 
BRCA2 are tumor suppressor genes that encode large 
proteins of 1,863 and 3,418 amino acids, respectively.11 
Previous research demonstrated that BRCA proteins are 
key regulators of important cellular processes such as 
DNA repair, transcription, as well as cell cycle and 
apoptosis in response to DNA damage.12  

The identification of BRCA1 and BRCA2 mutation 
carriers is of great clinical significance, since 
management protocols for mutation carriers are 
becoming well established13-15 and effective preventive 
medical interventions exist.16,17 Once a mutation is 
identified in a given family, oncogenetic tests can be 
applied to all members of the affected family to identify 

carriers.18 Moreover, molecular genetic testing is 
becoming an important tool in predicting drug response, 
as new targeted therapeutic agents, such as poly(ADP-
ribose) inhibitors19,20, emerge and chemosensitivity to 
platinum-based therapy has been reported.21 Improved 
knowledge of the genetic make-up of populations where 
breast cancer is increasing is very important for the 
development of an effective screening strategy. 

Previous research demonstrated that there is a wide 
spectrum of mutations in the affected population.5 This 
fact makes identification of BRCA carriers difficult. A 
full analysis of the BRCA1 and BRCA2 genes includes 
not only the complete sequencing of all the coding 
regions of the genes, but also the detection of mutations 
by the multiple ligation dependent probe amplification 
method. In the mid-1990s, it was discovered that some 
populations are characterized by a pronounced “founder 
effect” - the predominance of the so-called recurring 
mutations in BRCA1 and BRCA2. For example, in 
Ashkenazi Jews, virtually all the mutations in BRCA1 
and BRCA2 genes are related to 185delAG, 5382insC, 
and 6174delT.22 Elucidation of founder mutations of 
BRCA1/2 genes can have a significant impact on the 
management of families with hereditary cancer at the 
level of the national healthcare system, ultimately 
making genetic testing more affordable and cost-
effective. To date, BRCA1 and BRCA2 mutations in 
breast cancer patients have not been characterized in the 
Uzbek population. The purpose of this pilot study is to 
investigate the contribution of common BRCA1 and 
BRCA2 mutations to early onset and familial cases of 
breast cancer in Uzbekistan. 

 

Methods 

Participants 

This study included 67 Uzbek women who (1) 
had at least one first- or second-degree relative with 
breast and/or ovarian cancer, regardless of age; (2) were 
less than 35 years of age at diagnosis; (3) had bilateral 

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breast cancer; (4) had triple negative (TN) or medullary 
type pathology; (5) had at least one relative with cancers 
other than breast and ovarian cancer such as stomach 
and prostate that are known to be related to BRCA 
mutations. A standard epidemiological questionnaire, 
including a detailed family history, was administered to 
all patients after obtaining informed consent. Medical 
information, including pathology records, was retrieved 
from the patients’ medical records. Information 
collectected from the epidemiological questionnaires 
included age at breast cancer diagnosis, history of other 
primary cancers, and a family history of breast, ovarian, 
and other cancers in first, second, and third degree 
relatives. In addition, the questionnaire included 
information about the usage of alcohol, tobacco, 
contraceptives (pills, patches, or injections), hormone 
replacement therapy, and prior use of infertility 
medications. Reproductive history (including history of 
breastfeeding), as well as menopausal status, was 
recorded for each patient. Age of patients ranged from 
27 to 77 years. The median age was 43 years. Eighty-six 
percent of the patients were living in the Tashkent 
district (rural area located in the northeastern part of 
Uzbekistan, between the Syr Darya River and the Tien 
Shan Mountains) and the remaining 16% of the patients 
were residents of the Tashkent city. All women 
underwent cancer treatment in the Tashkent Regional 
Oncological Dispensary, Tashkent, Uzbekistan. 
Pathological diagnosis of breast cancer was made 
according to the World Health Organization (WHO) 
classification and the tumor–node–metastases (TNM) 
staging system.  

Age-matched disease free control group (n=103) 
was identified through the clinical specialists 
participating in the study and included women 
undergoing regular prophylactic breast examinations in 
the Tashkent Regional Oncological Dispensary, 
Tashkent, Uzbekistan. They were defined as “disease 
free” based on the results of their last breast 
examinations conducted by clinicians with expertise in 
breast cancer. Controls were also screened for family 

history of breast and ovarian cancer and were 
determined to be free of family history of these 
conditions. Women in the control group were age-
matched to cases and resided in Tashkent city and 
Tashkent Region. 

All study participants signed informed 
consents before participating in this research. The study 
was conducted according to the standards of the 
National Ethic Committee of Uzbekistan, developed in 
accordance with the World Medical Association’s 
Declaration of Helsinki "Ethical Principles For Medical 
Research Involving Human Subjects" with 
amendments.23 

Laboratory methods 

Blood samples (2 ml) were drawn from an 
antecubital vein using vacutainers containing sodium 
citrate, and stored at −20°C for further analysis. 

Genomic DNA was extracted from peripheral blood 
leucocytes using DNA extraction kit Diatom™ DNA 
Prep 200 (“IsoGen Laboratory”, Moscow, Russia). 
Detection of 5 common mutations (BRCA1 5382insC, 
BRCA14153delA, BRCA1 185delAG, BRCA1 
300T>G, BRCA2 6174delT) was performed by SYBR 
Green based real-time allele-specific PCR.24,25 

These five common mutations were chosen 
based on their widespread pattern of occurrence in the 
world.25-29 The PCR with allele-specific primers (Table 
1) was performed in a 25 µl reaction mixture containing 
9.3 µl of ddH2O, 1,5 µl 10xPCR buffer containing the 
intercalating dye SYBR Green I, 1,5 µl 25 mM MgCl2, 
0.3 µl 2.5 mM dNTP Mix, 0,25 µl (10pkmol/µl) of each 
oligonucleotide primer, 0.1 ul (0.5 units.) "hot-start" 
Taq-polymerase and 1.8 µl of DNA.PCR amplification 
was carried out in Applied Biosystems 7500 Real-Time 
PCR System. 

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Table 1.Oligonucleotide primers used in the study 

The PCR conditions were optimized for each 
mutation and were as follows: BRCA1 5382insC  (95 
°C for 5 min, and then 45 cycles of 95 °C for 20 s, 55 
°C for 45 sec, and 72 °C for 45 sec), BRCA1 4153delA 
(95 °C for 5 min, followed by 42 cycles of 95 °C for 15 
sec, 63°C for 30 sec, and 72 °C for 40sec), BRCA1 
185delAG (95 °C for 5 min, and then 40 cycles of 95 °C 
for 20 sec, 67°C for 30 sec, and 72 °C for 40 sec), 
BRCA1 300T>G (95 °C for 5 min, and then 45 cycles 
of 95 °C for 20 s, 50°C for 30 sec, and 72 °C for 40 sec) 
and BRCA2 6174delT (95 °C for 5 min, followed by 45 
cycles of 95 °C for 10 sec, 65°C for 30 sec, and 72 °C 
for 45 sec). 

Negative control DNA was extracted from a patient 
who was confirmed not to have BRCA mutations. 
Positive control DNA was extracted from blood 
obtained from a confirmed BRCA 5382insC mutation 
carrier. Both control DNAs were confirmed by direct 
DNA sequencing. Negative control, positive control, 
and blank tube without DNA (reagent contamination 
control) were included in each run. 

Statistical analysis 

Descriptive statistics were done as the first step of 
the statistical analysis. Associations of mutations with 
breast cancer were evaluated by Pearson’s χ2 test under 
dominant model of inheritance, followed by risk 
assessment using odds ratio and 95% confidence 
interval (CI) computation. All statistical analyses were 
performed using STATA software version 12.0 for 
Windows (Stata Corporation, USA). A p-value <0.05 
(two-sided) was considered statistically significant. 

 

Results 

Among 67 patients, we detected 3 cases (4.5%) 
with the 5382insC BRCA1mutation (Fig.1). Among 
these three patients, 1 patient had multiple primary 
breast cancers (multiple lesions in one breast) and 2 

patients had a family history of breast cancer. In the 
investigated group of patients, 4 other mutations 
(BRCA1 4153delA, BRCA1 185delAG, BRCA1 
300T>G and BRCA2 6174delT) were not found. None 
of the mutations were found in the control group. 
Comparative analysis of resulting genotypes between 
patients and controls showed a significant association 
between 5382insc mutation and breast cancer (p=0.03, 
Pearson’s χ2 test, dominant model of inheritance). 

  

Figure.1 Allele-specific PCR detection of 
BRCA15382insC mutation.  

A) Negative control DNA(wild type) DNA samples 
show clear difference between cycle thresholds (delta 
Ct) of amplification of wild-type(1) and mutated 
alleles(2) upon real-time PCR analysis  

B) Positive control DNA 5382insC heterozygote 
mutation is characterized by simultaneous amplification 
of both wild-type and mutated alleles. 

C) 5382insC heterozygote mutation in patient №22 

 

Table 2. The frequency of BRCA1 and BRCA2 
mutations in patients with breast cancer and control 
group 

 

Table 3. Association between 5382insC mutation and 
breast cancer (χ2 test, df = 1, dominant model of 
inheritance). 

 

Discussion 

To our knowledge, this is one of the first pilot 
studies to explore the prevalence of BRCA mutations in 
women affected by breast cancer in Uzbekistan in 
comparison with disease free controls. The occurrence 
of the same 5382insC BRCA1 mutation in the 3 
unrelated patients in Tashkent, Uzbekistan, may imply 

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that this recurrent mutation originated from a common 
ancestor (founder mutation) and may need to be further 
investigated in Uzbekistan, and possibly Central Asia. 
The BRCA1 mutation 5382insC was originally 
described as a founder mutation in the Ashkenazi 
Jewish population. This mutation has also been detected 
in 13 different population groups: Russian, Latvian, 
Ukrainian, Czech, Slovak, Polish, Danish, Dutch, 
French, German, Italian, Greek, Brazilian, Turkish, and 
Iranian.30,31 Previously published microsatellite marker 
study by Hamel indicated that the 5382insC mutation of 
BRCA1 gene originated about 1,800 years in northern 
Europe and later spread to the many different 
populations.30 The presence of BRCA1 5382insC 
mutations in Uzbekistan is consistent with the historical, 
archaeological, and genetic evidence of the “hybrid 
zone” ethnic scenario, which postulate several waves of 
migration of western Caucasoid peoples followed by 
their integration and hybridization with East Asian 
people.32,33 Haplotype analysis would help to determine 
if 5382insC mutation found in our cohort was 
ancestrally related to the corresponding mutation found 
in other populations.22,34 It should be noted that it is 
quite possible that BRCA1 5382insC mutations found in 
Uzbek women may have its origins in a Jewish founder.  

The exact number of women in Uzbekistan with 
Ashkenazi Jewish background is difficult to calculate. 
The first Ashkenazim who came to Central Asia were 
merchants of the ancient Silk Road and there is 
evidence that the historical exchange between 
Ashkenazim and the Far East was not confined to 
cultural alone, but also extended to the sharing of 
genes.35 Large numbers of Jewish migrants moved to 
the Central Asian region during the Second World War 
when Ashkenazi Jews from Nazi-occupied countries 
and the Soviet Union were evacuated to Uzbekistan, but 
many Jewish people moved out of Central Asia after the 
break down of Soviet Union in 1991.  

It should be noted there are several limitations of 
this study. First, selection of high-risk breast cancer 

patients in Tashkent and surrounding regions may not 
have accurately reflected the true prevalence of the 
BRCA1mutation in the geographically and ethnically 
diverse population of Uzbekistan. A large-scale 
multiregional study is needed to evaluate the prevalence 
of BRCA mutations on a country-wide scale. The small 
sample size of this study is another limitation, which we 
plan to address in our future work. Since the annual 
incidence of breast cancers in Uzbekistan in 2010 was 
2273 people, the 67 women with breast cancer represent 
3% of total annual incidence of breast cancers in 
Uzbekistan.   

Despite the small sample size and detecting only 3 
cases with the BRCA1 5382insC mutation, the present 
and future contributions of this mutation to the 
incidence of breast cancer in Uzbekistan can be 
significant due to the so-called "founder" effect. The 
culture of Uzbekistan, which supports early marriage, 
early reproduction, and large family size, generally 
supports the spread of "founder" mutations. Thus, even 
in cases of early onset breast cancer (≤35 years old), 
Uzbek women with the BRCA1 mutation would have 
already had children; therefore, they would have 
transmitted the mutation to the next generation. 

In discussing the importance of testing the offspring 
of mutation carriers identified in this study and in future 
research and clinical programs, it is necessary to 
emphasize the need to test the female as well as the 
male offspring. Oncogenetic testing of male members of 
the family is reasonable, not only because they are 
might be carriers of BRCA mutations and transmit the 
mutations to their future granddaughters, but also 
because men who carry the mutated BRCA1 gene have 
a four times greater chance of developing prostate 
cancer than other males.36 Knowledge about the 
mutation status for males may potentially have an 
impact on the screening and treatment procedures with 
regard to prostate cancer. It should also be noted that we 
have studied only a small portion of possible mutations 
(5382insC, 4153delA, 185delAG and 300T> G in the 

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BRCA1 gene, and 6174delT in the BRCA2 gene) in 
women with breast cancer in Uzbekistan. Therefore, 
sequencing all exons of BRCA1 and BRCA2 genes is 
needed to evaluate the full spectrum of BRCA1 
mutations in Uzbekistan.  

 

Conclusion 

These pilot results suggest that there may be a 
potential contribution of BRCA1 5382insC mutation to 
breast cancer development in the Uzbek population. 
Women with confirmed mutations in the BRCA1 gene 
should be referred for a comprehensive medical 
examination for the early detection of breast and ovarian 
cancers or recieve preventive medical interventions. 
Diagnosis of genetic predispositions for the 
development of breast cancer is extremely important, as 
this knowledge will help to better prepare healthcare 
systems to organize programs for the prevention of 
adverse health outcomes associated with these 
mutations. It is very important to continue research in 
this area, as more data are needed on 5382insC mutation 
in women with breast cancer in Uzbekistan. 

 

Acknowledgements 

We thank Committee for Coordination Science 
and Technology Development under the Cabinet of 
Ministers of Uzbekistan. This project was supported by 
the Uzbekistan State Research Grant (№ADCC-27-5) 
“Development of complex method for breast cancer 
screening and prevention based on detection of several 
molecular biomarkers in women of Uzbek population”.       

 

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ABDIKHAKIMOV 

 
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of its D-Scribe Digital Publishing Program and is cosponsored by the University of Pittsburgh Press. 
 

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Table 1.Oligonucleotide primers used in the study 

Mutation Primer Sequence 

BRCA1 5382insC 

Common 
wt 

mut 

5'-AGAACCTGTGTGAAAGTATCTAGCACTG-3' 
5'-AAGCGAGCAAGAGAATTCCAG-3' 

5'-AGCGAGCAAGAGAATTCCCA-3' 

BRCA1 4153delA 

Common 
wt 

mut 

5'-GACTGCAAATACAAACACCCA-3' 
5'-AGCCCGTTCCTCTTTCTTC-3' 

5'-AGCCCGTTCCTCTTTCTCA-3' 

BRCA1 185delAG 

Common 
wt 

mut 

5'-CAGTTAAGGAAATCAGCAATTACAATAGC-3' 
5'-GCTATGCAGAAAATCTTAGAGTGTCC-3' 

5'-ATGCTATGCAGAAAATCTTAGTGTCC-3' 

BRCA1 300T>G 

Common 
wt 

mut 

5'-ATTATCTTTTCATGGCTATTTG-3' 
5'-TATATCATTCTTACATAAAGGAA-3' 

5'-TATATCATTCTTACATAAAGGAC-3' 

BRCA2 6174delT 

common 
wt 

mut 

5'-CATAACCAAAATATGTCTGGATTGGAG-3' 
5'-CTGATACCTGGACAGATTTTCCAC-3' 

5'-CCTGGACAGATTTTCCCTTGC-3' 

 

 

 

 

 

 

 
  

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Central Asian Journal of Global Health 

Volume 5, No. 1 (2016) |  ISSN 2166-7403 (online) | DOI 10.5195/cajgh.2016.228|http://cajgh.pitt.edu 

 
 

Figure.1 Allele-specific PCR detection of BRCA1 5382insC mutation.  

A) Negative control DNA(wild type) DNA samples show clear difference between cycle 

thresholds (delta Ct) of amplification of wild-type(1) and mutated alleles(2) upon real-time 

PCR analysis  

B) Positive control DNA– 5382insC heterozygote mutation is characterized by simultaneous 

amplification of both wild-type and mutated alleles. 

C) 5382insC heterozygote mutation in patient №22 

  

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A 

B 

C 

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ABDIKHAKIMOV 

 
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Central Asian Journal of Global Health 
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Table 2. The frequency of BRCA1 and BRCA2 mutations in patients with 

breast cancer and control group 

gene mutation 
Breast cancer 

patients 
Control group 

(n=103) 

BRCA1 

5382insC 3(4.5%) 0(0%) 

4153delA 0(0%) 0(0%) 

185delAG 0(0%) 0(0%) 

300T>G 0(0%) 0(0%) 

BRCA2 6174delT 0(0%) 0(0%) 

  

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Central Asian Journal of Global Health 

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Table 3. Association between 5382insC mutation and breast cancer (χ2 test, df = 1, 

dominant model of inheritance). 

Genotypes 
Cases Controls 

χ2 p 
OR 

n = 67 n = 103 value 95% CI 

wt/wt 0.955 1.000 

4.69 0.03 

0.09 0.00 – 1.75 

wt/5382insC+ 

5382insC/5382insC 
0.045 1.000 11.23 0.57 – 221.04 

 

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	The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan
	Abstract
	Keywords: BRCA1, BRCA2, Founder mutation, Real-time PCR, Breast cancer, Uzbek population
	The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan
	Research

