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CDKN2A/P16INK4A variants association with breast cancer and their in-silico analysis

  • Ayesha Aftab
  • Shaheen Shahzad
  • Hafiz Muhammad Jafar Hussain
  • Ranjha Khan
  • Samra Irum
  • Sobia Tabassum
Review Article

Abstract

CDKN2A was first identified as melanoma predisposition tumour suppressor gene and has been successively studied. The previous researches have not established any noteworthy association with breast cancer. Therefore, through extensive literature search and in-silico analysis, we have tried to focus on the role of CDKN2A in breast cancer. CDKN2A variants in breast cancer were collected from different databases. The overall percentage of variants (approximately 5.8%) and their incidence frequency in breast cancer cases were found to be very low as compared to the number of samples screened in different studies. Exon 2 was identified as the major region of alternations. Approximately 42.8% were entire gene deletions, while 24.2% were missense mutations. These variants cannot be ignored because of their pathogenic effects as interpreted by the bioinformatics tools used in the present study. Earlier studies have shown that CDKN2A excludes the predisposition of germline variants, but interestingly shares common breast cancer germline variants with other carcinomas. Most of the data have revealed this gene as rarely mutated or deleted in breast cancer. However, few association studies have shown that in addition to being a ‘multiple’ tumour suppressor gene, it is mutated/deleted more in breast cancer cell lines as compared to breast cancer tissues or blood samples; thus, this gene cannot be neglected as a breast cancer candidate gene. The deletion/malfunctioning of CDKN2A in different tumours including breast cancer has recently led to the discovery of many clinical CDK inhibitors. Furthermore, these collected genetic variants will also be helpful in developing diagnostic, preventive, and treatment approaches for patients.

Keywords

Breast cancer Variant analysis CDKN2A P16 

Notes

Compliance with ethical standards

Conflict of interest

Authors have no conflict of interest.

References

  1. 1.
    Carol ED, Jiemin M, Ann GS, Lisa AN, Ahmedin J. Breast Cancer Statistics, 2017, Racial Disparity in Mortality by State. CA Cancer J Clin. 2017;67:439–48.CrossRefGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, Xu H. Oncogenes and tumour suppressor genes: comparative genomics and network perspectives. BMC Genom. 2015;16:8.CrossRefGoogle Scholar
  4. 4.
    Schwab M (ed). CDKN2A. In: Encyclopedia cancer. 3rd ed. Berlin: Springer; 2011. p. 705–11.CrossRefGoogle Scholar
  5. 5.
    Liggett WH, Sidransky D. Role of the p16 tumour suppressor gene in cancer. J Clin Oncol. 1998;16:1197–206.CrossRefPubMedGoogle Scholar
  6. 6.
    Agarwal P, Mohammad F, Kabir L, Deinnocentes P, Bird RC. Tumour suppressor gene p16/INK4A/CDKN2A and its role in cell cycle exit, differentiation, and determination of cell fate. In: Cheng Y (ed). Tumor Suppressor Genes. InTech. 2012;1–35.Google Scholar
  7. 7.
    Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumour suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.CrossRefPubMedGoogle Scholar
  8. 8.
    Brenner AJ, Paladugu A, Wang H, Olopade OI, Dreyling MH, Aldaz CM. Preferential loss of expression of p16(INK4a) rather than p19(ARF) in breast cancer. Clin Cancer Res. 1996;2:1993–8.PubMedGoogle Scholar
  9. 9.
    Rocco JW, Sidransky D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res. 2001;264:42–55.CrossRefPubMedGoogle Scholar
  10. 10.
    Byeon I-JL, Li J, Ericson K, Selby TL, Tevelev A, Kim H-J, O’Maille P, Tsai M-D. Tumour suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol Cell. 1998;1:421–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Carraro M, Minervini G, Giollo M, et al. Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI. Hum Mutat. 2017;38:1042–50.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shah V, Boyd KD, Houlston RS, Kaiser MF. Constitutional mutation in CDKN2A is associated with long-term survivorship in multiple myeloma: a case report. BMC Cancer. 2017;17:718.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers (Basel). 2017;9:42.CrossRefGoogle Scholar
  14. 14.
    Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet. 1994;8:22–6.CrossRefGoogle Scholar
  15. 15.
    Pollock PM, Pearson JV, Hayward NK. Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer. 1996;15:77–88.CrossRefPubMedGoogle Scholar
  16. 16.
    Bian Y-S, Osterheld M-C, Fontolliet C, Bosman FT, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s oesophagus. Gastroenterology. 2002;122:1113–21.CrossRefPubMedGoogle Scholar
  17. 17.
    Silva J, Silva JM, Domínguez G, García JM, Cantos B, Rodríguez R, Larrondo FJ, Provencio M, España P, Bonilla F. Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol. 2003;199:289–97.CrossRefPubMedGoogle Scholar
  18. 18.
    Vengoechea J, Tallo C. A germline deletion of 9p21.3 presenting as familial melanoma, astrocytoma and breast cancer: clinical and genetic counselling challenges. J Med Genet. 2017;54:682–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Helgadottir H, Höiom V, Tuominen R, Nielsen K, Jönsson G, Olsson H, Hansson J. Germline CDKN2A mutation status and survival in familial melanoma cases. J Natl Cancer Inst. 2016;108:djw135.CrossRefGoogle Scholar
  20. 20.
    Zhao R, Choi BY, Lee M-H, Bode AM, Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. Ebiomedicine. 2016;8:30–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Klinker M, Masback A. High frequency of multiple melanomas and breast and pancreas carcinomas in melanoma families susceptibility to cutaneous malignant. J Natl Cancer Inst. 2001;93:323–5.CrossRefGoogle Scholar
  22. 22.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, Johnson BE, Skolnick MH. A cell cycle regulator potentially involved in genesis of many tumour types. Science. 1994;264:436–40.CrossRefPubMedGoogle Scholar
  24. 24.
    Gadhikar MA, Zhang J, Shen L, et al. CDKN2A/p16 deletion in head and neck cancer cells is associated with cdk2 activation, replication stress, and vulnerability to CHK1 inhibition. Cancer Res. 2018;78:781–97.CrossRefPubMedGoogle Scholar
  25. 25.
    Choi W, Ochoa A, McConkey DJ, et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset. Eur Urol. 2017;72:354–65.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bai M, Yu N-Z, Long F, Feng C, Wang X-J. Effects of CDKN2A (p16INK4A/p14ARF) Over-expression on proliferation and migration of human melanoma A375 cells. Cell Physiol Biochem. 2016;40:1367–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Sarkar D, Leung EY, Baguley BC, Finlay GJ, Askarian-Amiri ME. Epigenetic regulation in human melanoma: past and future. Epigenetics. 2015;10:103–21.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang H-L, Zhou P-Y, Liu P, Zhang Y. RETRACTED ARTICLE: Role of p16 gene promoter methylation in gastric carcinogenesis: a meta-analysis. Mol Biol Rep. 2014;41:4481–92.CrossRefPubMedGoogle Scholar
  29. 29.
    He D, Zhang Y, Zhang N, Zhou L, Chen J, Jiang Y, Shao C. Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein–Barr virus-associated gastric carcinomas. Med Oncol. 2015;32:92.CrossRefPubMedGoogle Scholar
  30. 30.
    Peng D, Zhang H, Sun G. The relationship between P16 gene promoter methylation and gastric cancer: a meta-analysis based on Chinese patients. J Cancer Res Ther. 2014;10 Suppl:292–5.PubMedGoogle Scholar
  31. 31.
    Berggren P, Kumar R, Sakano S, et al. Detecting homozygous deletions in the CDKN2A(p16INK4a)/ARF(p14ARF) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res. 2003;9:235–42.PubMedGoogle Scholar
  32. 32.
    de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008;14:7151–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Nagore E, Montoro A, Garcia-Casado Z, Botella-Estrada R, Insa A, Lluch A, Lopez-Guerrero JA, Guillen C. Germline mutations in CDKN2A are infrequent in female patients with melanoma and breast cancer. Melanoma Res. 2009;19:211–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Musgrove EA, Liuschkis R, Cornish AL, Lee CSL, Setlur V, Seshadri R, Sutherland RL. Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21Waf1/cip1 in human breast cancer. Int J Cancer. 1995;63:584–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Berns EM, Klijn JG, Smid M, van Staveren IL, Gruis N, Foekens J. Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br J Cancer. 1995;72:964–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Smith-Sørensen B, Hovig E. CDKN2A (p16INK4A) somatic and germline mutations. Hum Mutat. 1996;7:294–303.CrossRefPubMedGoogle Scholar
  37. 37.
    Han M-R, Deming-Halverson S, Cai Q, Wen W, Shrubsole MJ, Shu X-O, Zheng W, Long J. Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study. Breast Cancer. 2015;22:544–51.CrossRefPubMedGoogle Scholar
  38. 38.
    Jones A, Mitter R, Springall R, Graham T, Winter E, Gillett C, Hanby A, Tomlinson I, Sawyer E, Phyllodes Tumour Consortium. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoural genetic heterogeneity and new genetic changes on recurrence. J Pathol. 2008;214:533–44.CrossRefPubMedGoogle Scholar
  39. 39.
    Herman JG, Merlo A, Mao L, Herman G, Lapidus G, Issa J, Davidson E. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers DNA methylation in all common human cancers. Cancer. 1995;55:4525–30.Google Scholar
  40. 40.
    Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, Jones PA. Methylation of the 5′ CpG island of the p16/CDKN2 tumour suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995;55:4531–5.PubMedGoogle Scholar
  41. 41.
    Jovanovic J, Rønneberg JA, Tost J, Kristensen V. The epigenetics of breast cancer. Mol Oncol. 2010;4:242–54.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Spitzwieser M, Entfellner E, Werner B, Pulverer W, Pfeiler G, Hacker S, Cichna-Markl M. Hypermethylation of CDKN2A exon 2 in tumour, tumour-adjacent and tumour-distant tissues from breast cancer patients. BMC Cancer. 2017;17:260.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chan PA, Duraisamy S, Miller PJ, et al. Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28. 2007;1:683–93.CrossRefGoogle Scholar
  44. 44.
    Betts MJ, Russell RB. Amino acid properties and consequences of substitutions. In: Bioinformatics for geneticists. Chichester: Wiley, p. 289–316. https://onlinelibrary.wiley.com/doi/pdf/10.1002/0470867302.ch14.
  45. 45.
    Morris LGT, Chan TA, Sloan M, Cancer K, Program P, Sloan M, Cancer K, Sloan M, Cancer K. Therapeutic targeting of tumour suppressor genes. Cancer. 2015;121:1357–68.CrossRefPubMedGoogle Scholar
  46. 46.
    Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemotherapeutic drug response. Biosci Rep. 2012;32:361–74.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Liu Y, Hu X, Han C, Wang L, Zhang X, He X, Lu X. Targeting tumour suppressor genes for cancer therapy. Bioessays. 2015;37:1277–86.CrossRefPubMedGoogle Scholar
  48. 48.
    Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16ink4a expression in tumours: functional significance, clinical associations and future developments. Cell Cycle. 2011;10:2497–503.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Chen S, Sun H, Miao K, Deng CX. CRISPR-Cas9: from genome editing to cancer research. Int J Biol Sci. 2016;12:1427–36.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat. 2017;166:41–54.CrossRefPubMedGoogle Scholar
  51. 51.
    Ramos-Esquivel A, Hernandez-Steller H, Savard M-F, Landaverde DU. (2018) Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials. Breast Cancer.  https://doi.org/10.1007/s12282-018-0848-6.PubMedCrossRefGoogle Scholar
  52. 52.
    Iwata H. Clinical development of CDK4/6 inhibitor for breast cancer. Breast Cancer. 2018;25:402–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3:39–55.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kassem L, Shohdy KS, Lasheen S, Abdel-rahman O, Bachelot T. Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer. 2018;25:17–27.CrossRefPubMedGoogle Scholar
  55. 55.
    Ilorasertib in treating patients with CDKN2A-deficient advanced or metastatic solid cancers that cannot be removed by surgery. 2015–2017. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02540876 (Identifier: NCT02540876).
  56. 56.
    Edessa D, Sisay M. Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2 metastatic breast cancer: a focus on ribociclib. Breast Cancer Targets Ther. 2017;9:567–79.CrossRefGoogle Scholar
  57. 57.
    Tang B, Li Y, Qi G, Yuan S, Wang Z, Yu S, Li B, He S. Clinicopathological significance of CDKN2A promoter hypermethylation frequency with pancreatic cancer. Sci Rep. 2015;5:13563.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Su L, Wang H, Miao J, Liang Y. Clinicopathological significance and potential drug target of CDKN2A/p16 in endometrial carcinoma. Sci Rep. 2015;5:13238.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Chakravarti A, DeSilvio M, Zhang M, et al. Prognostic value of p16 in locally advanced prostate cancer: a study based on radiation therapy oncology group protocol 9202. J Clin Oncol. 2007;25:3082–9.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ameri A, Alidoosti A, Hosseini Y, Parvin M, Emranpour MH, Taslimi F, Salehi E, Fadavi P. Prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and CDKN2 (p16/MTS1) in prostate cancer. Chin J Cancer Res. 2011;23:306–11.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10:R75.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Quesnel B, Fenaux P, Philippe N, Fournier J, Bonneterre J, Preudhomme C, Peyrat JP. Analysis of p16 gene deletion and point mutation in breast carcinoma. Br J Cancer. 1995;72:351–3.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cancer Genome Atlas Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.CrossRefGoogle Scholar
  64. 64.
    Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Guerini-Rocco E, Piscuoglio S, Ng CKY, et al. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations. J Pathol. 2016;238:677–88.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Jones A, Mitter R, Springall R, Graham T, Winter E, Gillett C, Hanby A, Tomlinson I, Sawyer E, Phyllodes Tumour Consortium. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J Pathol. 2008;214:533–44.CrossRefPubMedGoogle Scholar
  67. 67.
    Brenner AJ, Aldaz CM. Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells. Cancer Res. 1995;55:2892–5.PubMedGoogle Scholar
  68. 68.
    Tan WJ, Lai JC, Thike AA, Lim JCT, Tan SY, Koh VCY, Lim TH, Bay BH, Tan MH, Tan PH. Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups. Breast Cancer Res Treat. 2014;145:635–45.CrossRefPubMedGoogle Scholar
  69. 69.
    Dwyer JB, Clark BZ. Low-grade fibromatosis-like spindle cell carcinoma of the breast. Arch Pathol Lab Med. 2015;139:552–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Ross JS, Badve S, Wang K, et al. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. Arch Pathol Lab Med. 2015;139:642–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Hollestelle A, Nagel JH, Smid M, et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. 2010;121:53–64.CrossRefPubMedGoogle Scholar
  73. 73.
    Hu X, Stern HM, Ge L, et al. Genetic alterations and oncogenic pathways associated with breast cancer subtypes. Mol Cancer Res. 2009;7:511–22.CrossRefPubMedGoogle Scholar
  74. 74.
    Xu L, Sgroi D, Sterner CJ, Beauchamp RL, Pinney DM, Keel S, Ueki K, Rutter JL, Buckler AJ, Louis DN. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994;54:5262–4.PubMedGoogle Scholar
  75. 75.
    Spirin K, Simpson JF, Miller CW, Koeffler HP. Molecular analysis of INK4 genes in breast carcinomas. Int J Oncol. 1997;11:737–44.PubMedGoogle Scholar
  76. 76.
    Rush EB, Abouezzi Z, Borgen PI, Anelli A. Analysis of MTS1/CDK4 in female breast carcinomas. Cancer Lett. 1995;89:223–6.CrossRefPubMedGoogle Scholar
  77. 77.
    Prowse AH, Schultz DC, Guo S, Vanderveer L, Dangel J, Bove B, Cairns P, Daly M, Godwin AK. Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred. J Med Genet. 2003;40:e102.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Monnerat C, Chompret A, Kannengiesser C, et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6:453–61.CrossRefPubMedGoogle Scholar
  79. 79.
    Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2018

Authors and Affiliations

  • Ayesha Aftab
    • 1
  • Shaheen Shahzad
    • 2
  • Hafiz Muhammad Jafar Hussain
    • 3
  • Ranjha Khan
    • 3
  • Samra Irum
    • 1
  • Sobia Tabassum
    • 1
  1. 1.Department of Bioinformatics and BiotechnologyInternational Islamic UniversityIslamabadPakistan
  2. 2.Genomics Research Lab, Department of Bioinformatics and BiotechnologyInternational Islamic UniversityIslamabadPakistan
  3. 3.The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life SciencesUniversity of Science and Technology of ChinaHefeiChina

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