Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients
One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker....
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| Zitieren: | Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients / I.V. Deryusheva, M.M. Tsyganov, E.Y. Garbukov, M.K. Ibragimova, Ju.G. Kzhyshkovska, Е.М. Slonimskaya, N.V. Cherdyntseva, N.V. Litviakov // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 145–150. — Бібліогр.: 34 назв. — англ. |
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irk-123456789-1379752018-06-18T03:12:55Z Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients Deryusheva, I.V. Tsyganov, M.M. Garbukov, E.Y. Ibragimova, M.K. Kzhyshkovska, Ju.G. Slonimskaya, E.M. Cherdyntseva, N.V. Litviakov, N.V. Original contributions One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker. Aim: To perform genome-wide study on LOH in association with metastasisfree survival in breast cancer. Materials and Methods: The study involved 68 patients with breast cancer. LOH status was detected by microarray analysis, using a high density DNA-chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis Suite 3.1 (Affymetrix, USA) software was used for result processing. Results: 13,815 genes were examined, in order to detect LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). Conclusions: The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients, indicating their potential value as prognostic markers. 2017 Article Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients / I.V. Deryusheva, M.M. Tsyganov, E.Y. Garbukov, M.K. Ibragimova, Ju.G. Kzhyshkovska, Е.М. Slonimskaya, N.V. Cherdyntseva, N.V. Litviakov // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 145–150. — Бібліогр.: 34 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137975 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Deryusheva, I.V. Tsyganov, M.M. Garbukov, E.Y. Ibragimova, M.K. Kzhyshkovska, Ju.G. Slonimskaya, E.M. Cherdyntseva, N.V. Litviakov, N.V. Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients Experimental Oncology |
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One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker. Aim: To perform genome-wide study on LOH in association with metastasisfree survival in breast cancer. Materials and Methods: The study involved 68 patients with breast cancer. LOH status was detected by microarray analysis, using a high density DNA-chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis Suite 3.1 (Affymetrix, USA) software was used for result processing. Results: 13,815 genes were examined, in order to detect LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). Conclusions: The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients, indicating their potential value as prognostic markers. |
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Article |
| author |
Deryusheva, I.V. Tsyganov, M.M. Garbukov, E.Y. Ibragimova, M.K. Kzhyshkovska, Ju.G. Slonimskaya, E.M. Cherdyntseva, N.V. Litviakov, N.V. |
| author_facet |
Deryusheva, I.V. Tsyganov, M.M. Garbukov, E.Y. Ibragimova, M.K. Kzhyshkovska, Ju.G. Slonimskaya, E.M. Cherdyntseva, N.V. Litviakov, N.V. |
| author_sort |
Deryusheva, I.V. |
| title |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| title_short |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| title_full |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| title_fullStr |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| title_full_unstemmed |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| title_sort |
genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2017 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/137975 |
| citation_txt |
Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients / I.V. Deryusheva, M.M. Tsyganov, E.Y. Garbukov, M.K. Ibragimova, Ju.G. Kzhyshkovska, Е.М. Slonimskaya, N.V. Cherdyntseva, N.V. Litviakov // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 145–150. — Бібліогр.: 34 назв. — англ. |
| series |
Experimental Oncology |
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| fulltext |
Experimental Oncology 39, 145–150, 2017 (June) 145
GENOME-WIDE ASSOCIATION STUDY OF LOSS
OF HETEROZYGOSITY AND METASTASIS-FREE SURVIVAL
IN BREAST CANCER PATIENTS
I.V. Deryusheva1, M.M. Tsyganov1, 2, E.Y. Garbukov1, M.K. Ibragimova1, 2, Ju.G. Kzhyshkovska2, 3,
Е.М. Slonimskaya1, N.V. Cherdyntseva1, 2, N.V. Litviakov1, 2, *
1Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences,
Tomsk 634050, Russia
2National Research Tomsk State University, Tomsk 634050, Russia
3Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University;
German Red Cross Blood Service Baden-Württemberg — Hessen; Mannheim, Germany
One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic varia-
tions, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH
in some genes could be a good prognostic marker. Aim: To perform genome-wide study on LOH in association with metastasis-
free survival in breast cancer. Materials and Methods: The study involved 68 patients with breast cancer. LOH status was detected
by microarray analysis, using a high density DNA-chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis
Suite 3.1 (Affymetrix, USA) software was used for result processing. Results: 13,815 genes were examined, in order to detect
LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and
CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). Conclusions:
The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients,
indicating their potential value as prognostic markers.
Key Words: breast cancer, loss of heterozigosity, microarray, metastasis-free survival, prognosis.
It is well known that one of the factors determining
the individual diversity and heterogeneity of the tumor,
including breast cancer, is a normal genetic variability
caused by gene polymorphism (single nucleotide poly-
morphism — SNP). SNP in the tumor tissue can be mani-
fested as the phenomenon of allelic imbalance (AI). Also,
the special case — the loss of heterozygosity (LOH) —
is often detected. LOH is a loss (structural or functional)
of one of the alleles of a heterozygous genotype, result-
ing in a reduced frequency of heterozygous genotypes
compared with genomic DNA. AI is presented by allelic
deletions (loss of one copy of the locus), duplication
or amplification of one allele [1]. A. Knudson was the first
to describe the phenomenon of AI in tumors in 1971. Ac-
cording to his two-hit carcinogenesis model, the inactiva-
tion of tumor suppressor genes required two successive
mutational events — loss of one allele as a result of LOH
and somatic mutation in the other allele. The loss of the
allele provides the opportunity of a manifestation of lethal
recessive mutation in the remaining allele [2, 3].
In addition, LOH and AI can lead to the activation
of oncogenes and inactivation of tumor suppressor genes,
which can result in uncontrolled cell growth and metastasis
[4, 5]. Currently, allele imbalance and LOH are well explored
and shown for many genes in different types of cancer.
The biological meaning of LOH in carcinogenesis is sug-
gested to be associated with inactivation of heterozygous
loci of pathogenetically significant genes, thus providing
tumor progression, including metastasizing [6–12]. From
perspective of breast cancer (BC), the most important
AI and LOH were shown for cancer-related genes, such
as the ERBB2 (HER2) [13], BRCA1 and BRCA2 [14–16].
Recently, a large study on LOH in BC was performed for
the following genes: EGFR, TERT, TP53, CASP8, PARP2,
GATA3, and BRCA1 [17]. Also, it was demonstrated that
the LOH in telomeric sites of chromosomes in BC and ovar-
ian tumor cells appeared to be a good predictor of clinical
course of diseases [18]. However, most studies on AI,
especially the LOH in BC, were focused on genes, con-
tributing to malignant transformation of normal epithelial
breast cells, but not on cancer progression [19].
Thus, the genome-wide LOH study in relation
to cancer progression is necessary to understand its
contribution to disease outcome and also to find new
effective prognostic markers. In this work we per-
formed the genome-wide study on the LOH in as-
sociation with metastasis-free survival in BC patients.
MATERIALS AND METHODS
The study group. A total of 68 patients aged from
28 to 68 years (median age 53 years) were enrolled
in the study (Table 1). The diagnosis of BC was verified
morphologically. The tumor stages were IIA–IIIB. In ac-
cordance with the Consensus Conference on Neo-
adjuvant Chemotherapy in Carcinoma of the Breast,
April 26–28, 2003, Philadelphia, Pennsylvania [20],
all patients underwent 2–4 courses of neoadjuvant
chemotherapy (NAC) by FAC scheme (5-fluorouracil,
doxorubicin, cyclophosphamide), CAX scheme (cy-
Submitted: March 16, 2017.
*Correspondence: E-mail: nvlitv72@yandex.ru
Abbreviations used: AI — allelic imbalanced; BC — breast cancer;
cnLOH — copy-neutral loss of heterozygosity; LOH — loss of hete-
rozygosity; NAC — neoadjuvant chemotherapy; SNP — single
nucleotide polymorphism.
Exp Oncol 2017
39, 2, 145–150
146 Experimental Oncology 39, 145–150, 2017 (June)
clophosphamide, doxorubicin, capecitabine). Surgery
was performed 3–5 weeks after the completion of NAC
followed by two cycles of adjuvant chemotherapy with
FAC regimen. Radiotherapy and/or hormonal treat-
ment were given if required.
The study was carried out in accordance with Hel-
sinki Declaration of 1964 (amended in 1975 and 1983)
and was approved by The Ethical Committee of the
Institute of Oncology. Signed informed consent was
obtained from all participants.
Table 1. The clinicopathological parameters of BC patients (n = 68)
Trait Value Number of patients,
n (%)
Age, years ≤ 45 21 (30.9)
> 45 47 (69.1)
Menstrual status Premenopausal 36 (52.9)
Postmenopausal 32 (47.1)
Histological type Invasive ductal carcinoma 58 (85.3)
Invasive lobular carcinoma 3 (4.4)
Medullary carcinoma 2 (2.9)
Others 5 (7.4)
Tumor size T1 9 (13.2)
T2 52 (76.5)
T3 3 (4.4)
T4 4 (5.9)
Lymph node status N0 27 (39.7)
N1 31 (45.6)
N2 4 (5.9)
N3 6 (8.8)
Estrogen receptor Positive 33 (48.5)
Negative 31 (42.6)
No data 4 (5.9)
Progesterone receptor Positive 35 (51.5)
Negative 29 (42.3)
No data 4 (5.9)
HER2 0/+ 47 (69.1)
++ 10 (14.7)
+++ 6 (8.8)
No data 5 (7.4)
Molecular subtype Luminal B 40 (59.7)
Triple negative 17 (25.4)
HER2-positive 10 (14.9)
Histological form Unicentric 45 (66.2)
Multicentric 23 (33.8)
NAC regimen CAX 28 (41.2)
FAC 40 (58.8)
DNA extraction. Biopsies of tumor tissues were
obtained before treatment under ultrasound guidance.
The tissues were placed in RNAlater (Ambion, USA),
incubated for 24 h at room temperature and stored at
–80 °С until DNA and RNA extraction.
DNA was extracted from 68 biopsy specimens
of tumor tissues using QIAamp DNA mini Kit (Qiagen,
Germany). DNA concentration and purity were as-
sessed using NanoDrop 2000 instrument (Thermo
Scientific, USA). The concentration varied between
50 to 150 ng/µl and А260/А280 and А260/А230 ratios
were 2.10–2.35 and 2.15–2.40, respectively. The integrity
of DNA was assessed using TapeStation instrument (Agi-
lent Technologies, USA); the fragments of the DNA were
no longer than 48 kbp, thus suggesting its high integrity.
Microarray analysis. The CytoScanTM HD Array
chips (Affymetrix, USA) were used. They contained
probes for 2,670,000 markers including 1,900,000 non-
polymorphic markers for the analysis of copy number
variations and more than 750,000 SNPs. The sample
processing, arrays hybridization and scanning were
performed according to the manufacturer’s protocols
for Affymetrix GeneChip® Scanner 3000 7G. The re-
sults were analysed using Chromosome Analysis Suite
3.1 software (Affymetrix, USA).
Statistical analysis. Statistical analysis was per-
formed using STATISTICA 8.0 software package (Stat-
Soft Inc., USA). A significance level of p < 0.05 was
considered for statistically significant differences
between treatment groups. p-value < 0.05 was con-
sidered statistically significant. The Kaplan — Meier
curves were used for the analysis of overall and meta-
stasis-free survival [21]. Comparison of survival curves
of the treatment groups was done using the log-rank
test. Two-sided Fisher’s exact test was used for ana-
lyzing comparison of frequencies for qualitative data.
RESULTS AND DISCUSSION
First of all the frequency of LOH in genes from the
OMIM (Online Mendelian Inheritance in Man) database
was studied (http://omim.org/). A total of 13,815 genes
were evaluated for heterozygosity loss in tumors of BC pa-
tients. The frequency of LOH varied from 0% to 63% for
certain genes, thus 63% of patients showed LOH in some
genes. The LOH frequency for 13,815 genes annotated
in the OMIM database is presented in Fig. 1. In accor-
dance with the localization of genes on the chromosomes,
they are plotted on the abscissa, and the percentage
of patients with the LOH in the certain gene is depicted
on the ordinate. Fig. 1 clearly shows that the highest
incidence of the LOH events is characteristic for genes
on chromosomes 17 and X.
The highest LOH frequency (from 30 to 63%) was
observed in loci of ZNF267, PAGE3, MAGEH1, RRAGB,
KLF8, UBQLN2, SPIN2B, SPIN2A, FAAH2, ZXDB, ZXDA,
ARHGEF9, FAM123B, MSN, MIR223, VSIG4, HEPH,
EDA2R, AR, SLC16A2, RLIM, KIAA2022, ABCB7, UPRT,
ZDHHC15, MAGEE2, and MAGEE1 genes. It is impor-
tant to test the functional significance of these genes
as tumor suppressors. In concordance with the infor-
mation of the OMIM database, chromosomes 6, 7,
11 and 14 possess large regions, where the LOH was
not observed in any of the 68 BC samples examined.
In total, no LOH was detected in 873 out of 13,815 genes,
annotated in the OMIM database. Well-known tumor
suppressor genes, such as TP53, RB1, BRCA1 etc.,
also showed the low LOH frequency (Table 2).
Table 2. Frequency of LOH in known tumor suppressor genes
Tumor suppressor genes Frequency
of LOH, n (%)
MEN1, TNFAIP3 0 (0.0)
CEBPA, JAK2, WRN 1 (0.7)
CDK6, CDKN2A, DCC, FBXW7, FOXP1, IL2, MSH2,
PALB2, SOCS1, SYK
2 (1.4)
BCL11B, BMPR1A, CREB1, CREBBP, CYLD, IDH1,
MDM4, NR4A3, PTEN, SDHB, STK11, SUFU, TCF3,
TSC1, TSC2, VHL, WT1
3 (2.0)
APC, ATM, CDH11, EXT1, EXT2, NF2, RUNX1, SDHD,
SMARCA4
4 (2.7)
CARS, CHEK2, FH, MLH1, NOTCH1, NPM1, NUP98,
SMARCB1
5 (3.4)
BLM, BRCA2, CBFA2T3, PML, RB1 6 (4.1)
FLT3, MAP2K4 7 (4.8)
CDH1, SUZ12 8 (5.4)
CDKN2C, NF1, TP53 9 (6.1)
BRCA1 10 (6.8)
GPC3 11 (7.5)
DDX5 12 (8.2)
Experimental Oncology 39, 145–150, 2017 (June) 147
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148 Experimental Oncology 39, 145–150, 2017 (June)
The next step of investigation was to analyze the
relationship between distant metastasis of breast tu-
mors and the LOH frequency in OMIM genes. Distant
metastases occurred in 17 (25%) of the 68 patients
within 10 to 77 months from the time of diagnosis.
The two-, three- and five-year metastasis-free survival
rates were 86.8; 82.4, and 76.5%, respectively.
The patients were divided into two groups: the first
group consisted of 17 patients with metastases and
the second group consisted of 51 patients without
metastases.
Based on a difference between the frequency of the
normal status of the gene and the LOH in patients with
metastases and without metastases, we have selected
genes in which this difference reached the maximum
value. In result of our study seven genes were selected,
namely, FGD1, GNL3L, TRO, EDA2R, PGK1, TAF9B,
and CYSLTR1 for those the difference ranged from
25.5 to 35.3%.
The next step was to evaluate the association
between the LOH and metastasizing, using a Fish-
er’s exact test. The association between the LOH and
metastasizing was demonstrated only for 4 genes:
EDA2R, PGK1, TAF9B, and CYSLTR1. Using the Ka-
plan — Meier survival analysis, we showed that the
metastasis-free survival rate in patients with the LOH
in these genes was significantly lower, compared with
those observed in the group of patients, who had
a normal status of these genes (Fig. 2).
It should be noted that all of the genes identi-
fied in the study were located on the X chromosome
(http://www.genecards.org/). EDA2R gene was lo-
calized on the long arm of the X chromosome (Xq12),
while PGK1, TAF9B, and CYSLTR1 genes were loca-
lized in Xq21.1.
Deletions with LOH can provide a decrease
in the expression of genes with LOH at the expense
of to gene deficiency. Amplification with LOH results
in an increase in gene expression. The copy-neutral
LOH (cnLOH) may increase or decrease the expres-
sion of the gene with cnLOH. cnLOH might confer
a phenotypic advantage for tumor cells due to gain
of imprinting through duplication of a methylated allele
(decrease the expression of the gene with cnLOH),
loss of imprinting through duplication of unmethylated
allele (increase the expression of the gene) or ho-
mozygosity of an initial heterozygous mutation [22].
The expression of genes with LOH it was necessary
to explore in order to understand the impact of LOH
on gene expression.
a b
c d
n
p = 0.023
Su
rv
iva
l,
%
LOH
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0 10 20 30 40 50 60 70 80 90
Time, months
n
p = 0.006
p = 0.006p = 0.006
Su
rv
iva
l,
%
LOH
0 10 20 30 40 50 60 70 80 90
Time, months
n
Su
rv
iva
l,
%
LOH
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.2
0.1
0.0
0.3
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.2
0.1
0.0
0.3
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.2
0.1
0.0
0.3
0 10 20 30 40 50 60 70 80 90
Time, months
n
Su
rv
iva
l,
%
LOH
0 10 20 30 40 50 60 70 80 90
Time, months
Fig. 2. Metastasis-free survival of BC patients with the detected LOH in a set of genes: (a) Ectodysplasin A2 Receptor (EDA2R)
gene; (b) phosphoglycerate kinase 1 (PGK1) gene; (c) RNA polymerase II, TATA Box-Binding Protein-Associated Factor (TAF9B)
gene; (d) cysteinyl leukotriene receptor 1 (CYSLTR1) gene.
Note: a red line — patients with the LOH in genes examined; a blue line — patients with the normal status of genes examined. p —
a significance value, calculated by a log-rank test
Experimental Oncology 39, 145–150, 2017 (June) 149
In the study Ching et al. [23] was to explicate the
underlying chromosomal copy number alterations
and LOH implicated in a cohort of Malaysian hospital-
based primary breast carcinoma samples (n = 70)
using a SNP-array platform. The most prevalent
gains (≥ 30%) were detected at the 8q arm, whilst the
most ubiquitous losses (≥ 20%) were noted at the 8p
and 17p regions. The frequency of deletion with LOH
of PGK1, TAF9B, and CYSLTR1 genes were 10%.
cnLOH was characterized as the most prevailing
LOH event, in which the most frequent distributions
(≥ 30%) were revealed at 3p21.31, 5q33.2, 12q24.12,
12q24.12-q24.13, and 14q23.1. The frequency
of cnLOH EDA2R gene (ectodysplasin A2 receptor)
was 24%, which along with TNFR1 and Fas (CD95)
is one of the receptors of death. Yan et al. [24] showed
that EDA2R gene appeared to activate expression
of tumor necrosis factor gene. Studies suggest that
EDA2R is a potential downstream effector of p53-
induced apoptosis in cancer cells [25, 26] and may
therefore be a potential tumor suppressor, it is down-
regulated in breast and colorectal cancers [27,
28], and mutations and promoter hypermethylation
of EDA2R have been identified in colorectal cancer
cells [25, 26]. A recent study conducted in 2016 us-
ing a microarray CytoScan HD Arraу showed that the
presence of cnLOH in EDA2R gene and in several other
genes was associated with ameloblastoma cases [29].
The protein encoded by PGK1 gene is a glycolytic
enzyme that catalyzes the conversion of 1,3-diphos-
phoglycerate to 3-phosphoglycerate. Additionally, this
protein is secreted by tumor cells where it participates
in angiogenesis by functioning to reduce disulfide
bonds in the serine protease, plasmin, which conse-
quently leads to the release of the tumor blood vessel
inhibitor angiostatin (http://www.genecards.org/cgi-bin/
carddisp.pl?gene=PGK1&keywords=PGK1). CpG-island
methylation was evaluated on a 56-gene cancer-specific
biomarker microarray in metastatic vs non-metastatic
BC in a multi-institutional case series of 123 BC patients.
This identified 11 genes (including the PGK1 signaling
kinase gene) as the highest differentially methy lated
genes between progressing and non-progressing
BC [30]. The PGK1 gene showed differential splicing
in TNBC, non-TNBC (luminal A and B) and HER2-positive
BC subtypes [31].
The TAF9B (TATA-Box Binding Protein Associated
Factor 9b) is involved in transcriptional activation
as well as repression of distinct but overlapping sets
of genes. Among it related pathways is RNA Poly-
merase II transcription initiation. Microarray screen-
ing identified a TAF9B gene whose expression was
significantly changed by combination treatment with
inhibitors of LSD1 and HDAC of human BC cells [32].
Collectively, p53, SNHG1, sno-miR-28, and TAF9B
form a regulatory loop which affects p53 stability and
downstream p53-regulated pathways [33].
CYSLTR1 (Cysteinyl Leukotriene Receptor 1) is in-
volved in mediating bronchoconstriction via activation
of a phosphatidylinositol-calcium second messenger
system. Upregulation of this gene is associated with
asthma and dysregulation may also be implicated
in cancer. Patients with breast tumors characterized
by high CysLT1R and low CysLT2R expression levels
exhibited increased risk of cancer-induced death
in univariate analysis for both the total patient group
(hazard ratio [HR] = 2.88, 95% confidence interval
[CI] = 1.11–7.41) [34].
Thus, the presence of LOH in EDA2R, PGK1,
TAF9B, and CYSLTR1 genes were shown to be as-
sociated with low metastasis-free survival in patients
with BC, indicating their potential value as prognostic
markers.
ACkNOWLEDGMENTS
This work was supported by RFBR grant 16-54-
76015 ERA and Tomsk State University Competitive-
ness Improvement Program.
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