Haplotype and linkage disequilibrium of TP53-WRAP53 locus in Iranian-Azeri women with breast cancer

Nasser Pouladi, Sepehr Abdolahi, Davoud Farajzadeh, Mohammad Ali Hosseinpour Feizi, Nasser Pouladi, Sepehr Abdolahi, Davoud Farajzadeh, Mohammad Ali Hosseinpour Feizi

Abstract

Among the cancer susceptibility genes, TP53 is one of the crucial genes involved in cell cycle regulations and, therefore, it greatly affects breast cancer initiation and progression. In addition, WRAP53-a natural antisense transcript-regulates TP53 transcription and, as a protein, modulates the normal cell cycle, which results in breast cancer susceptibility. In this study, we aimed to analyze a haplotype comprising four SNPs, including rs1042522, rs17878362, rs2287499, and rs2287498, which are located at 5' regions of the TP53 and WRAP53 genes, in 118 patients and 110 healthy controls of the Iranian-Azeri population. In silico studies were conducted using the SIFT, Polyphen2, Fanthmm, RNAsnp, and SNP&GO online servers. Linkage disequilibrium (LD) and D' for each combination of the markers were calculated via the Haploview program. Our results showed that the GA1CC haplotype was the most frequent in the studied population. Additionally, no significant LD between any pairwise haplotypes was observed. The GA1CC and CA2GC haplotypes were significantly associated with breast cancer susceptibility. Moreover, the in silico analysis revealed the negative effects of rs2287499 and rs1042522 on WRAP53 and P53, respectively. In conclusion, the CA1GC haplotype was strongly identified as a breast cancer risk factor, and the GA1CC haplotype was assumed to be a protective factor against breast cancer risk. Hence, these markers may potentially be used as molecular prognostic and predictive biomarkers for breast cancer.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. The schematic of haplotype block-…
Fig 1. The schematic of haplotype block- formed by rs1042522, rs17878362, rs2287499, and rs2287498 SNPs in TP53-WRAP53.
NM_00546 and NM_018081 are the mRNA reference sequence numbers of the TP53 and WRAP53 genes, respectively. The 5−UTR is the 5− untranslated region of the TP53 gene. Solid squares indicate exons. The SNPs were represented in haplotype block sequentially from rs1042522, rs17878362, rs2287499, and rs2287498 (left to right).
Fig 2. RNAsnp analysis of rs2287499, rs1042522…
Fig 2. RNAsnp analysis of rs2287499, rs1042522 and rs2287498 SNPs.
Local regions for a1) R72P substitution in TP53, a2) R68G substitution in WRAP53, a3) F150F substitution in WRAP53. a4) black lines demonstrate insignificant alteration (P >0.02) and other colors are demonstration of significant changes. Secondary RNA structure of R72P substitution in b1) mutation and b2) wild-type. Secondary RNA structure of R68G substitution in c1) mutation and c2) wild-type. Secondary RNA structure of F150F substitution in d1) mutation and d2) wild-type.

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jmel A, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6): 394–424. 10.3322/caac.21492
    1. Sung H, Ren J, Li J, Pfeiffer RM, Wang Y, Guida JL, et al. Breast cancer risk factors and mammographic density among high-risk women in urban China. NPJ breast cancer. 2018;4(1): 3 10.1038/s41523-018-0055-9
    1. Kim G, Ouzounova M, Quraishi AA, Davis A, Tawakkol N, Clouthier SG, et al. SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene. 2014;34(6): 671–680. 10.1038/onc.2014.4
    1. Nikkhoo A, Rostami N, Hojjat‐Farsangi M, Azizi G, Yousefi B, Ghalamfarsa G, et al. Smac as novel promising mimetics modulators of apoptosis in the treatment of breast cancer. J Cell Biochem. 2019;120(6): 9300–9314. 10.1002/jcb.28205
    1. Uehara I, Tanaka N. Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression. Cancers (Basel). 2018;10: 219 10.3390/cancers10070219
    1. Bellazzo A, Sicari D, Valentino E, Del Sal G, Collavin L. Complexes formed by mutant p53 and their roles in breast cancer. Breast Cancer. 2018;10: 101–112. 10.2147/BCTT.S145826
    1. Leroy B, Ballinger ML, Baran-Marszak F, Bond GL, Braithwaite A, Concin N, et al. Recommended guidelines for validation, quality control, and reporting of TP53 variants in clinical practice. Cancer Res. 2017;77: 1250–1260. 10.1158/0008-5472.CAN-16-2179
    1. Joruiz SM, Bourdon J-C. p53 isoforms: key regulators of the cell fate decision. Cold Spring Harb perspect med. 2016;6(8): a026039 10.1101/cshperspect.a026039
    1. Toledo F, Wahl GMJNRC. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6(12): 909 10.1038/nrc2012
    1. Farnebo M, Bykov VJ, Wiman KG. The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochem Biophys Res Commun. 2010;396(1): 85–89. 10.1016/j.bbrc.2010.02.152
    1. Zhang Y, Gao J-S, Tang X, Tucker LD, Quesenberry P, Rigoutsos I, et al. MicroRNA 125a and its regulation of the p53 tumor suppressor gene. FEBS Lett. 2009;583(22): 3725–3730. 10.1016/j.febslet.2009.10.002
    1. Farnebo M. Wrap53, a novel regulator of p53. Cell Cycle. 2009;8(15): 2343–2346. 10.4161/cc.8.15.9223
    1. Henriksson S, Farnebo M. On the road with WRAP53β: guardian of Cajal bodies and genome integrity. Front Genet. 2015;6: 91 10.3389/fgene.2015.00091
    1. Pouladi N, Kouhsari SM, Feizi MH, Gavgani RR, Azarfam P. Overlapping region of p53/wrap53 transcripts: mutational analysis and sequence similarity with microRNA-4732-5p. Asian Pac J Cancer Prev. 2013;14(6): 3503–3507. 10.7314/apjcp.2013.14.6.3503
    1. Enwerem II, Velma V, Broome HJ, Kuna M, Begum RA, Hebert MD, et al. Coilin association with Box C/D scaRNA suggests a direct role for the Cajal body marker protein in scaRNP biogenesis. Biol Open. 2014;3(4): 240–249. 10.1242/bio.20147443
    1. Rassoolzadeh H, Böhm S, Hedström E, Gad H, Helleday T, Henriksson S, et al. Overexpression of the scaffold WD40 protein WRAP53β enhances the repair of and cell survival from DNA double-strand breaks. Cell death dis. 2016;7: e2267 10.1038/cddis.2016.172
    1. Yuan JM, Li XD, Liu ZY, Hou GQ, Kang JH, Huang DY, et al. Cisplatin induces apoptosis via upregulating Wrap53 in U-2OS osteosarcoma cells. Asian Pac Cancer Prev. 2011;12(12): 3465–3469.
    1. Stracquadanio G, Wang X, Wallace MD, Grawenda AM, Zhang P, Hewitt J, et al. The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nat Rev Cancer. 2016;16(4): 251–265. 10.1038/nrc.2016.15
    1. Cao H, Wang S, Zhang Z, Lou J. Association between the WRAP53 gene rs2287499 C> G polymorphism and cancer risk: A meta-analysis. Genet Mol Res. 2016;15(3). 10.4238/gmr.15037976
    1. Devi KR, Chenkual S, Majumdar G, Ahmed J, Kaur T, Zonunmawia JC, et al. TLR2Δ 22 (-196-174) significantly increases the risk of breast cancer in females carrying proline allele at codon 72 of TP53 gene: a case–control study from four ethnic groups of North Eastern region of India. Tomur Biol. 2015;36(12): 9995–10002. 10.1007/s13277-015-3795-2
    1. Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003;4(8): 587–597. 10.1038/nrg1123
    1. Edvardsen H, Kulle B, Tsalenko A, Grenaker Alnaes GI, Ekeberg Johansen F, Enerly E, et al. Haplotypes associated to gene expression in breast cancer: can they lead us to the susceptibility markers?. BioRxiv. 2018.
    1. Vitiello GAF, Guembarovski RL, Hirata BKB, Amarante MK, de Oliveira CEC, Oliveira KB, et al. Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis. J Cancer Res Clin Oncol. 2018;144(4): 645–655. 10.1007/s00432-018-2585-9
    1. Surowy H, Varga D, Burwinkel B, Marmé F, Sohn C, Luedeke M, et al. A low‐frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early‐onset breast cancer (< 60 years) and is associated with reduced DNA repair capacity. Int J Cancer. 2018;142(5): 757–768. 10.1002/ijc.31105
    1. Dehghan R, Hosseinpour Feizi MA, Pouladi N, Babaei E, Montazeri V, Fakhrjoo A, et al. Association of P53 (− 16ins-Pro) Haplotype with the Decreased Risk of Differentiated Thyroid Carcinoma in Iranian-Azeri Patients. Pathol Oncol Res. 2015;21(2): 449–454. 10.1007/s12253-014-9846-y
    1. Dehghan R, Hosseinpour Feizi MA, Pouladi N, Adampourezare M, Farajzadeh D. The TP53 intron 6 G13964C Polymorphism and Risk of Thyroid and Breast Cancer Development in the Iranian Azeri Population. Asian Pac J Cancer Prev. 2015;16(7): 3073–3077. 10.7314/apjcp.2015.16.7.3073
    1. Bonab AS, Pouladi N, Hosseinpourfeizi MA, Gavgani RR, Dehghan R, Azarfam P, et al. Single-strand conformational polymorphism analysis of a common single nucleotide variation in WRAP53 gene, rs2287499, and evaluating its association in relation to breast cancer risk and prognosis among Iranian-Azeri population. Med Oncol. 2014;31(9): 168 10.1007/s12032-014-0168-4
    1. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2): 263–265. 10.1093/bioinformatics/bth457
    1. Medrek K, Magnowski P, Masojc B, Chudecka-Glaz A, Torbe B, Menkiszak J, et al. Association of common WRAP 53 variant with ovarian cancer risk in the Polish population. Mol Biol Rep. 2013;40(3): 2145–2147. 10.1007/s11033-012-2273-9
    1. Lin HY, Yang MC, Huang CH, Wu WJ, Yu T-, Lung FW. Polymorphisms of TP53 are markers of bladder cancer vulnerability and prognosis. Urol Oncol. 2013;31(7):1231–1241. 10.1016/j.urolonc.2011.11.031
    1. Naccarati A, Pardini B, Polakova V, Smerhovsky Z, Vodickova L, Sousek P, et al. Genotype and haplotype analysis of TP53 gene and the risk of pancreatic cancer: an association study in the Czech Republic. Carcinogenesis. 2010;31(4): 666–670. 10.1093/carcin/bgq032
    1. Vymetalkova V, Soucek P, Kunicka T, Jiraskova K, Brynychova V, Pardini B, et al. Genotype and Haplotype Analyses of TP53 Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes. PLoS One. 2015;10(7): e0134463 10.1371/journal.pone.0134463
    1. Ni X, Trakalo J, Valente J, Azevedo MH, Pato MT, Pato CN, et al. Human p53 tumor suppressor gene (TP53) and schizophrenia: case–control and family studies. Neurosci Lett. 2005;388(3): 173–178. 10.1016/j.neulet.2005.06.050
    1. Alonso S, Izagirre N, López S, Smith-Zubiaga I, Hervella M, Boyano MD, et al. The diversity profile of TP53 is influenced by positive selection on the immediately upstream locus WDR79. Hum hered. 2010;69(1): 34–44. 10.1159/000243152
    1. Pouladi N, Abdolahi S, Farajzadeh D, Hosseinpour Feizi MA. Association of the 17p13.1 region gene variants rs1042522 and rs2287499 with risk of breast cancer in Iranian-Azeri population. Meta Gene. 2019;19: 117–122.
    1. Buyru N, Altinisik J, Demokan S, Dalay N. p53 genotypes and haplotypes associated with risk of breast cancer. Cancer Detect Prev. 2007;31(3): 207–213. 10.1016/j.cdp.2007.04.004
    1. Zee RYL, Cook NR, Kim C-A, Fernandez-Cruz A, Lindpaintner K. TP53 haplotype-based analysis and incidence of post-angioplasty restenosis. Hum Genet. 2004;114(4): 386–390. 10.1007/s00439-003-1080-8
    1. Hao W, Xu X, Shi H, Zhang C, Chen X. No association of TP53 codon 72 and intron 3 16-bp duplication polymorphisms with breast cancer risk in Chinese Han women: new evidence from a population-based case-control investigation. Eur J Med Res. 2018;23(1): 47 10.1186/s40001-018-0345-6

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться