Evaluating the Association between CCR5delta32 Polymorphism (rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population
-
Amir TAJBAKHSH
,
Zahra FARJAMI
,
Abolfazl NESAEI-BAJESTANI
,
Fahimeh AFZALJAVAN
,
Mahdi RIVANDI
,
Atefeh MOEZZI
,
Soheila ABEDINI
,
Mahla ASGHARI
,
Mohammad Mahdi KOOSHYAR
,
Fatemeh HOMAEI SHANDIZ
,
Alireza PASDAR
Abstract
Background: CC chemokine receptor 5 (CCR5) is introduced as an immune response modulator. The activity of CCR5 influences breast tumour development in a p53-dependent manner. This study aimed to investigate the frequency of CCR5delta32 and its association with the risk of breast cancer in 1038 blood samples in North East of Iran.
Methods: In this case-control study, we genotyped 570 control samples and 468 breast cancer patients by a gel electrophoresis-based gap-polymerase chain reaction (gap-PCR) method Mashhad, Iran. The data were analyzed using the SPSS software.
Results: Of 570 controls included, 542 (95.09%) had CCR5delta32 wild/wild(W/W) genotype, 28 samples (4.91%) had CCR5delta32 wild/deletion (W/D) genotype and none of them were CCR5delta32 deletion/deletion (D/D) genotype (0%). While 428 samples of patients (91.45%) had CCR5delta32 W/W genotype, 40 samples (8.55%) had CCR5delta32 W/D and CCR5delta32 D/D homozygous was nil (0%) amongst cases. All samples were in the Hardy–Weinberg equilibrium (P>0.05). According to the allele frequency, D allele, as a risky allele, in the cases was more than the control samples (0.0427 vs 0.0245, respectively) (P=0.0206). Hence, W/D genotype may confer a risk effect (OR=1.77, CI: 1.09-2.90; P=0.0206) compared with WW genotype between case and control groups.
Conclusion: There is a statistically significant association between CCR5W/D and breast cancer risk. CCR5 may be regarded as a target for the prevention of breast cancer in certain conditions such as interaction with p53 variants, which remains to be further investigated.
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2. Turashvili G, Bouchal J, Burkadze G, Kolar Z (2005). Differentiation of tumours of ductal and lobular origin: II. Genomics of invasive ductal and lobular breast carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 149 (1): 63-8.
3. Hashemi M, Fazaeli A, Ghavami S, et al (2013). Functional polymorphisms of FAS and FASL gene and risk of breast cancer–pilot study of 134 cases. Plos One, 8 (1): e53075.
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5. Tajbakhsh A, Javan FA, Rivandi M, et al (2019). Significant association of TOX3/LOC643714 locus-rs3803662 and breast cancer risk in a cohort of Iranian population. Mol Biol Rep, 46(1):805-811.
6. Tajbakhsh A, Pasdar A, Rezaee M, et al (2018). The current status and perspectives regarding the clinical implication of intracellular calcium in breast cancer. J Cell Physiol, 233 (8): 5623-5641.
7. Tajbakhsh A, Mokhtari-Zaer A, Rezaee M, et al (2017). Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives. J Cell Biochem, 118 (9): 2502-2515.
8. Easton DF, Pooley KA, Dunning AM, et al (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 447 (7148): 1087-93.
9. Tajbakhsh A, Farjami Z, Darroudi S, et al (2019). Association of rs4784227-CASC16 (LOC643714 locus) and rs4782447-ACSF3 polymorphisms and their association with breast cancer risk among Iranian population. EXCLI J, 18: 429-438.
10. Ghilardi G, Biondi ML, La Torre A, et al (2005). Breast cancer progression and host polymorphisms in the chemokine system: role of the macrophage chemoattractant protein-1 (MCP-1)− 2518 G allele. Clin Chem, 51 (2): 452-5.
11. Vaday GG, Peehl DM, Kadam PA, Lawrence DM (2006). Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate, 66 (2): 124-34.
12. Eskandari-Nasab E, Hashemi M, Ebrahimi M, et al (2014). Evaluation of CCL5-403 G> A and CCR5 Δ32 gene polymorphisms in patients with breast cancer. Cancer Biomark, 14 (5): 343-51.
13. Rotondi M, Chiovato L (2011). The chemokine system as a therapeutic target in autoimmune thyroid diseases: a focus on the interferon-γ inducible chemokines and their receptor. Curr Pharm Des, 17 (29): 3202-16.
14. Rotondi M, Lazzeri E, Romagnani P, Serio M (2003). Role for interferon-γ inducible chemokines in endocrine autoimmunity: an expanding field. J Endocrinol Invest, 26 (2): 177-80.
15. Wu X, Lee VC, Chevalier E, Hwang ST (2009). Chemokine receptors as targets for cancer therapy. Curr Pharm Des, 15 (7): 742-57.
16. Bièche I, Lerebours F, Tozlu S, et al (2004). Molecular profiling of inflammatory breast cancer. Clin Cancer Res, 10 (20): 6789-95.
17. Valdivia-Silva JE, Franco-Barraza J, Silva ALE, et al (2009). Effect of pro-inflammatory cytokine stimulation on human breast cancer: implications of chemokine receptor expression in cancer metastasis. Cancer Lett, 283 (2): 176-85.
18. Jiao XM, Velasco M, Li ZP et al (2016). CCR5 contributes to breast cancer stem cell expansion by enhancing DNA damage repair. Cancer Res, 78 (7): 1657-71.
19. Song JK, Park MH, Choi DY, et al (2012). Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-kappaB and upregulation of IL-1Ra in melanoma model. PLoS One, 7 (5): e33747.
20. Mañes S, Mira E, Colomer R, et al (2003). CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. J Exp Med, 198 (9): 1381-9.
21. Velasco-Velázquez M, Jiao X, De La Fuente M, et al (2012). CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res, 72 (15): 3839-50.
22. Robinson SC, Scott KA, Wilson JL, et al (2003). A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res, 63 (23): 8360-5.
23. Ng-Cashin J, Kuhns JJ, Burkett SE, et al (2003). Host absence of CCR5 potentiates dendritic cell vaccination. J Immunol, 170 (8): 4201-8.
24. Halama N, Zoernig I, Berthel A, et al (2016). Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell, 29 (4): 587-601.
25. Lucotte G, Dieterlen F (2003). More about the Viking hypothesis of origin of the Δ32 mutation in the CCR5 gene conferring resistance to HIV-1 infection. Infect Genet Evol, 3 (4): 293-5.
26. Kucukgergin C, Isman FK, Dasdemir S, et al (2012). The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer. Gene, 511 (1): 7-11.
27. Zambra FMB, Biolchi V, Brum IS, Chies JAB (2013). CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. Human Immunology, 74 (8): 1003-1008.
28. Lucotte G (2002). Frequencies of 32 base pair deletion of the (Δ32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis. Infect Genet Evol, 1 (3): 201-5.
29. Carrington M, Dean M, Martin MP, O'Brien SJ (1999). Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. Hum Mol Genet, 8 (10): 1939-45.
30. Miller SA, Dykes DD, Polesky HF (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16 (3): 1215.
31. Mardan-Nik M, Saffar Soflaei S, Biabangard-Zak A, et al (2019). A method for improving the efficiency of DNA extraction from clotted blood samples. J Clin Lab Anal, 33 (6): e22892.
32. Sandford AJ, Zhu S, Bai TR, et al (2001). The role of the CC chemokine receptor-5 Δ32 polymorphism in asthma and in the production of regulated on activation, normal T cells expressed and secreted. J Allergy Clin Immunol,108 (1): 69-73.
33. Stone MJ, Hayward JA, Huang C, et al (2017). Mechanisms of Regulation of the Chemokine-Receptor Network. Int J Mol Sci, 18 (2):342.
34. de Oliveira CE, Oda JM, Losi Guembarovski R, et al (2014). CC chemokine receptor 5: the interface of host immunity and cancer. Dis Markers, 2014: 126954.
35. Martinson JJ, Chapman NH, Rees DC, et al (1997). Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet, 16 (1): 100-3.
36. Stephens JC, Reich DE, Goldstein DB, et al (1998). Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet, 62 (6): 1507-1515.
37. Lee YH, Song GG (2015). Association between chemokine receptor 5 delta32 polymorphism and susceptibility to cancer: A meta-analysis. J Recept Signal Transduct Res, 35 (6): 509-15.
38. Span PN, Pollakis G, Paxton WA, et al (2015). Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations. Int J Cancer, 136 (1): 91-7.
39. Degerli N, Yilmaz E, Bardakci F (2005). The Δ32 allele distribution of the CCR5 gene and its relationship with certain cancers in a Turkish population. Clinical Biochemistry, 38 (3): 248-52.
40. Azhar A, Fatima F, Hameed A, Saleem S (2015). Delta 32 mutation in CCR5 gene and its association with breast cancer. J Clin Oncol, 33 (28_suppl): 17.
41. Fatima F, Saleem S, Hameed A, et al (2019). Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Delta32) among breast cancer patients of Pakistan. Mol Biol Rep, 46 (2): 2387-2394.
42. Panse J, Friedrichs K, Marx A, et al (2008). Chemokine CXCL13 is overexpressed in the tumour tissue and in the peripheral blood of breast cancer patients. Br J Cancer, 99 (6): 930-8.
43. Ying HQ, Wang J, Gao XR (2014). CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk: a meta-analysis based on 20,625 subjects. Tumour Biol, 35 (6): 5895-904.
44. Banin-Hirata BK, Losi-Guembarovski R, Oda JMM, et al (2016). CCR2-V64I genetic polymorphism: a possible involvement in HER2+breast cancer. Clin Exp Med, 16 (2): 139-45.
45. Guleria K, Sharma S, Manjari M, et al (2012). p.R72P, PIN3 Ins16bp Polymorphisms of TP53 and CCR5 Delta 32 in North Indian Breast Cancer Patients. Asian Pacific Journal of Cancer Prevention, 13 (7): 3305-3311.
46. Aoki MT, Do Amaral Herrera ACDS, Amarante MK, et al (2009). CCR5 and p53 codon 72 gene polymorphisms: Implications in breast cancer development. Int J Mol Med, 23 (3): 429-35.
47. Gonzalez-Martin A, Gomez L, Lustgarten J, et al (2011). Maximal T Cell-Mediated Antitumor Responses Rely upon CCR5 Expression in Both CD4(+) and CD8(+) T Cells. Cancer Res, 71 (16): 5455-66.
48. Liu JY, Li F, Wang LP, et al (2015). CTL- vs T-reg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer, 113 (5): 747-55.
49. Paxton WA, Neumann AU, Kang S, et al (2001). RANTES production from CD4+ lymphocytes correlates with host genotype and rates of human immunodeficiency virus type 1 disease progression. The Journal of Infectious Diseases, 183 (11): 1678-1681.
50. Woods DB, Vousden KH (2001). Regulation of p53 function. Exp Cell Res, 264 (1): 56-66.
2. Turashvili G, Bouchal J, Burkadze G, Kolar Z (2005). Differentiation of tumours of ductal and lobular origin: II. Genomics of invasive ductal and lobular breast carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 149 (1): 63-8.
3. Hashemi M, Fazaeli A, Ghavami S, et al (2013). Functional polymorphisms of FAS and FASL gene and risk of breast cancer–pilot study of 134 cases. Plos One, 8 (1): e53075.
4. Hashemi M, Eskandari-Nasab E, Fazaeli A, et al (2012). Bi-directional PCR allele-specific amplification (bi-PASA) for detection of caspase-8− 652 6N ins/del promoter polymorphism (rs3834129) in breast cancer. Gene, 505 (1): 176-179.
5. Tajbakhsh A, Javan FA, Rivandi M, et al (2019). Significant association of TOX3/LOC643714 locus-rs3803662 and breast cancer risk in a cohort of Iranian population. Mol Biol Rep, 46(1):805-811.
6. Tajbakhsh A, Pasdar A, Rezaee M, et al (2018). The current status and perspectives regarding the clinical implication of intracellular calcium in breast cancer. J Cell Physiol, 233 (8): 5623-5641.
7. Tajbakhsh A, Mokhtari-Zaer A, Rezaee M, et al (2017). Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives. J Cell Biochem, 118 (9): 2502-2515.
8. Easton DF, Pooley KA, Dunning AM, et al (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 447 (7148): 1087-93.
9. Tajbakhsh A, Farjami Z, Darroudi S, et al (2019). Association of rs4784227-CASC16 (LOC643714 locus) and rs4782447-ACSF3 polymorphisms and their association with breast cancer risk among Iranian population. EXCLI J, 18: 429-438.
10. Ghilardi G, Biondi ML, La Torre A, et al (2005). Breast cancer progression and host polymorphisms in the chemokine system: role of the macrophage chemoattractant protein-1 (MCP-1)− 2518 G allele. Clin Chem, 51 (2): 452-5.
11. Vaday GG, Peehl DM, Kadam PA, Lawrence DM (2006). Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate, 66 (2): 124-34.
12. Eskandari-Nasab E, Hashemi M, Ebrahimi M, et al (2014). Evaluation of CCL5-403 G> A and CCR5 Δ32 gene polymorphisms in patients with breast cancer. Cancer Biomark, 14 (5): 343-51.
13. Rotondi M, Chiovato L (2011). The chemokine system as a therapeutic target in autoimmune thyroid diseases: a focus on the interferon-γ inducible chemokines and their receptor. Curr Pharm Des, 17 (29): 3202-16.
14. Rotondi M, Lazzeri E, Romagnani P, Serio M (2003). Role for interferon-γ inducible chemokines in endocrine autoimmunity: an expanding field. J Endocrinol Invest, 26 (2): 177-80.
15. Wu X, Lee VC, Chevalier E, Hwang ST (2009). Chemokine receptors as targets for cancer therapy. Curr Pharm Des, 15 (7): 742-57.
16. Bièche I, Lerebours F, Tozlu S, et al (2004). Molecular profiling of inflammatory breast cancer. Clin Cancer Res, 10 (20): 6789-95.
17. Valdivia-Silva JE, Franco-Barraza J, Silva ALE, et al (2009). Effect of pro-inflammatory cytokine stimulation on human breast cancer: implications of chemokine receptor expression in cancer metastasis. Cancer Lett, 283 (2): 176-85.
18. Jiao XM, Velasco M, Li ZP et al (2016). CCR5 contributes to breast cancer stem cell expansion by enhancing DNA damage repair. Cancer Res, 78 (7): 1657-71.
19. Song JK, Park MH, Choi DY, et al (2012). Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-kappaB and upregulation of IL-1Ra in melanoma model. PLoS One, 7 (5): e33747.
20. Mañes S, Mira E, Colomer R, et al (2003). CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. J Exp Med, 198 (9): 1381-9.
21. Velasco-Velázquez M, Jiao X, De La Fuente M, et al (2012). CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res, 72 (15): 3839-50.
22. Robinson SC, Scott KA, Wilson JL, et al (2003). A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res, 63 (23): 8360-5.
23. Ng-Cashin J, Kuhns JJ, Burkett SE, et al (2003). Host absence of CCR5 potentiates dendritic cell vaccination. J Immunol, 170 (8): 4201-8.
24. Halama N, Zoernig I, Berthel A, et al (2016). Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell, 29 (4): 587-601.
25. Lucotte G, Dieterlen F (2003). More about the Viking hypothesis of origin of the Δ32 mutation in the CCR5 gene conferring resistance to HIV-1 infection. Infect Genet Evol, 3 (4): 293-5.
26. Kucukgergin C, Isman FK, Dasdemir S, et al (2012). The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer. Gene, 511 (1): 7-11.
27. Zambra FMB, Biolchi V, Brum IS, Chies JAB (2013). CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. Human Immunology, 74 (8): 1003-1008.
28. Lucotte G (2002). Frequencies of 32 base pair deletion of the (Δ32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis. Infect Genet Evol, 1 (3): 201-5.
29. Carrington M, Dean M, Martin MP, O'Brien SJ (1999). Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. Hum Mol Genet, 8 (10): 1939-45.
30. Miller SA, Dykes DD, Polesky HF (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16 (3): 1215.
31. Mardan-Nik M, Saffar Soflaei S, Biabangard-Zak A, et al (2019). A method for improving the efficiency of DNA extraction from clotted blood samples. J Clin Lab Anal, 33 (6): e22892.
32. Sandford AJ, Zhu S, Bai TR, et al (2001). The role of the CC chemokine receptor-5 Δ32 polymorphism in asthma and in the production of regulated on activation, normal T cells expressed and secreted. J Allergy Clin Immunol,108 (1): 69-73.
33. Stone MJ, Hayward JA, Huang C, et al (2017). Mechanisms of Regulation of the Chemokine-Receptor Network. Int J Mol Sci, 18 (2):342.
34. de Oliveira CE, Oda JM, Losi Guembarovski R, et al (2014). CC chemokine receptor 5: the interface of host immunity and cancer. Dis Markers, 2014: 126954.
35. Martinson JJ, Chapman NH, Rees DC, et al (1997). Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet, 16 (1): 100-3.
36. Stephens JC, Reich DE, Goldstein DB, et al (1998). Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet, 62 (6): 1507-1515.
37. Lee YH, Song GG (2015). Association between chemokine receptor 5 delta32 polymorphism and susceptibility to cancer: A meta-analysis. J Recept Signal Transduct Res, 35 (6): 509-15.
38. Span PN, Pollakis G, Paxton WA, et al (2015). Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations. Int J Cancer, 136 (1): 91-7.
39. Degerli N, Yilmaz E, Bardakci F (2005). The Δ32 allele distribution of the CCR5 gene and its relationship with certain cancers in a Turkish population. Clinical Biochemistry, 38 (3): 248-52.
40. Azhar A, Fatima F, Hameed A, Saleem S (2015). Delta 32 mutation in CCR5 gene and its association with breast cancer. J Clin Oncol, 33 (28_suppl): 17.
41. Fatima F, Saleem S, Hameed A, et al (2019). Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Delta32) among breast cancer patients of Pakistan. Mol Biol Rep, 46 (2): 2387-2394.
42. Panse J, Friedrichs K, Marx A, et al (2008). Chemokine CXCL13 is overexpressed in the tumour tissue and in the peripheral blood of breast cancer patients. Br J Cancer, 99 (6): 930-8.
43. Ying HQ, Wang J, Gao XR (2014). CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk: a meta-analysis based on 20,625 subjects. Tumour Biol, 35 (6): 5895-904.
44. Banin-Hirata BK, Losi-Guembarovski R, Oda JMM, et al (2016). CCR2-V64I genetic polymorphism: a possible involvement in HER2+breast cancer. Clin Exp Med, 16 (2): 139-45.
45. Guleria K, Sharma S, Manjari M, et al (2012). p.R72P, PIN3 Ins16bp Polymorphisms of TP53 and CCR5 Delta 32 in North Indian Breast Cancer Patients. Asian Pacific Journal of Cancer Prevention, 13 (7): 3305-3311.
46. Aoki MT, Do Amaral Herrera ACDS, Amarante MK, et al (2009). CCR5 and p53 codon 72 gene polymorphisms: Implications in breast cancer development. Int J Mol Med, 23 (3): 429-35.
47. Gonzalez-Martin A, Gomez L, Lustgarten J, et al (2011). Maximal T Cell-Mediated Antitumor Responses Rely upon CCR5 Expression in Both CD4(+) and CD8(+) T Cells. Cancer Res, 71 (16): 5455-66.
48. Liu JY, Li F, Wang LP, et al (2015). CTL- vs T-reg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer, 113 (5): 747-55.
49. Paxton WA, Neumann AU, Kang S, et al (2001). RANTES production from CD4+ lymphocytes correlates with host genotype and rates of human immunodeficiency virus type 1 disease progression. The Journal of Infectious Diseases, 183 (11): 1678-1681.
50. Woods DB, Vousden KH (2001). Regulation of p53 function. Exp Cell Res, 264 (1): 56-66.
| Files | ||
| Issue | Vol 50 No 3 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v50i3.5604 | |
| Keywords | ||
| CCR5D32 p53 pathway Breast carcinoma Immunogenetics Metastasis | ||
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How to Cite
1.
TAJBAKHSH A, FARJAMI Z, NESAEI-BAJESTANI A, AFZALJAVAN F, RIVANDI M, MOEZZI A, ABEDINI S, ASGHARI M, KOOSHYAR MM, HOMAEI SHANDIZ F, PASDAR A. Evaluating the Association between CCR5delta32 Polymorphism (rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population. Iran J Public Health. 2021;50(3):583-591.
