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Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes

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Abstract

Background

In cancer research, one of the most significant findings was to characterize the DNA repair deficiency as carcinogenic. Amongst the various repair mechanisms, mismatch repair (MMR) and direct reversal of DNA damage systems are designated as multilevel safeguards in the human genome. Defects in these elevate the rate of mutations and results in dire consequences like cancer. Of the several molecular signatures in human genome, tandem repeats (TRs) appear at various frequencies in the exonic, intronic, and regulatory regions of the DNA. Hypervariability among these repeats in the coding and non-coding regions of the genes is well characterized for solid tumours, but its significance in haematologic malignancies remains to be explored. The purpose of our study was to elucidate the role of nucleotide repeat instability in the coding and non-coding regions of 10 different repair genes in myeloid and lymphoid cell lines compared to the control samples.

Methods and Results

We selected MMR deficient extensively studied microsatellite instable colorectal cancer (HCT116), and MMR proficient breast cancer (MCF-7) cells along with underemphasized haematologic cancer cell lines to decipher the hypermutability of tandem repeats. A statistically significant TR variation was observed for MSH2 and MSH6 genes in 4 and 3 of the 6 cell lines respectively. KG1 (AML) and Daudi (Burkitt’s lymphoma) were found to have compromised DNA repair competency with highly unstable nucleotide repeats.

Conclusion

Taken together, the results suggest that mutable TRs in intronic and non-intronic regions of repair genes in blood cancer might have a tumorigenic role. Since this is a pilot study on cell lines, high throughput research in large cohorts can be undertaken to reveal novel diagnostic markers for unexplained blood cancer patients with normal karyotypes or otherwise with karyotypic defects.

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References

  1. Yang G, Zheng RY, ** ZS (2019) Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol 145:2891–2899. https://doi.org/10.1007/s00432-019-03053-4

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bhattacharya P, Patel TN (2018) Microsatellite instability and promoter hypermethylation of DNA repair genes in hematologic malignancies: a forthcoming direction toward diagnostics. Hematology 23:77–82. https://doi.org/10.1080/10245332.2017.1354428

    Article  CAS  PubMed  Google Scholar 

  3. Vieira ML, Santini L, Diniz AL, Munhoz Cde F (2016) Microsatellite markers: what they mean and why they are so useful. Genet Mol Biol 39:312–328. https://doi.org/10.1590/1678-4685-GMB-2016-0027

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sulovari A, Li R, Audano PA, Porubsky D, Vollger MR, Logsdon GA et al (2019) Human-specific tandem repeat expansion and differential gene expression during primate evolution. Proc Natl Acad Sci USA 116:23243–23253. https://doi.org/10.1073/pnas.1912175116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bolton KA, Ross JP, Grice DM, Bowden NA, Holliday EG, Avery-Kiejda KA et al (2013) STaRRRT: a table of short tandem repeats in regulatory regions of the human genome. BMC Genomics 14:795. https://doi.org/10.1186/1471-2164-14-795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li YC, Korol AB, Fahima T, Nevo E (2004) Microsatellites within genes: structure, function, and evolution. Mol Biol Evol 21:991–1007. https://doi.org/10.1093/molbev/msh073

    Article  CAS  PubMed  Google Scholar 

  7. Li K, Luo H, Huang L, Luo LH, Zhu X (2020) Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 20:16. https://doi.org/10.1186/s12935-019-1091-8

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pećina-Šlaus N, Kafka A, Salamon I, Bukovac A (2020) Mismatch repair pathway, genome stability and cancer. Front Mol Biosci 7:122. https://doi.org/10.3389/fmolb.2020.00122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Modrich P, Lahue R (1996) Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 65:101–133. https://doi.org/10.1146/annurev.bi.65.070196.000533

    Article  CAS  PubMed  Google Scholar 

  10. Chikan NA, Bukhari S, Shabir N, Amin A, Shafi S, Qadri RA et al (2015) Atomic insight into the altered O6-methylguanine-DNA methyltransferase protein architecture in gastric cancer. PLoS ONE 10:e0127741. https://doi.org/10.1371/journal.pone.0127741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rye PT, Delaney JC, Netirojjanakul C, Sun DX, Liu JZ, Essigmann JM (2008) Mismatch repair proteins collaborate with methyltransferases in the repair of O(6)-methylguanine. DNA Repair (Amst) 7:170–176. https://doi.org/10.1016/j.dnarep.2007.09.003

    Article  CAS  Google Scholar 

  12. Akagi K, Oki E, Taniguchi H, Nakatani K, Aoki D, Kuwata T et al (2020) Nationwide large-scale investigation of microsatellite instability status in more than 18,000 patients with various advanced solid cancers. J Clin Oncol 38:803–803. https://doi.org/10.1200/JCO.2020.38.4_suppl.803

    Article  Google Scholar 

  13. Magalhães M, Farre L, Bittencourt A (2011) Microsatellite instability in the smoldering form of adult T-cell leukemia/lymphoma (ATL) in Brazil. Retrovirology 8:A148. https://doi.org/10.1186/1742-4690-8-S1-A148

    Article  PubMed Central  Google Scholar 

  14. Miyashita K, Fujii K, Taguchi K, Shimokawa M, Yoshida MA, Abe Y et al (2017) A specific mode of microsatellite instability is a crucial biomarker in adult T-cell leukaemia/lymphoma patients. J Cancer Res Clin Oncol 143:399–408. https://doi.org/10.1007/s00432-016-2294-1

    Article  CAS  PubMed  Google Scholar 

  15. Sanz-Vaqué L, Colomer D, Bosch F, López-Guillermo A, Dreyling MH, Bosch F et al (2001) Microsatellite instability analysis in typical and progressed mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Haematologica 86:181–186

    PubMed  Google Scholar 

  16. Walker CJ, Eisfeld AK, Genutis LK, Bainazar M, Kohlschmidt J, Mrózek K et al (2017) No evidence for microsatellite instability in acute myeloid leukemia. Leukemia 31:1474–1476. https://doi.org/10.1038/leu.2017.97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Losso GM, Moraes Rda S, Gentili AC, Messias-Reason IT (2012) Microsatellite instability—MSI markers (BAT26, BAT25, D2S123, D5S346, D17S250) in rectal cancer. Arq Bras Cir Dig 25:240–244. https://doi.org/10.1590/s0102-67202012000400006

    Article  PubMed  Google Scholar 

  18. Liengswangwong U, Nitta T, Kashiwagi H, Kikukawa H, Kawamoto T, Todoroki T et al (2003) Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand. Int J Cancer 107:375–380. https://doi.org/10.1002/ijc.11380

    Article  CAS  PubMed  Google Scholar 

  19. Lu Y, Soong TD, Elemento O (2013) A novel approach for characterizing microsatellite instability in cancer cells. PLoS ONE 8:e63056. https://doi.org/10.1371/journal.pone.0063056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nugoli M, Chuchana P, Vendrell J, Orsetti B, Ursule L, Nguyen C et al (2003) Genetic variability in MCF-7 sublines: evidence of rapid genomic and RNA expression profile modifications. BMC Cancer 3:13. https://doi.org/10.1186/1471-2407-3-13

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhang J, Kuo CC, Chen L (2011) GC content around splice sites affects splicing through pre-mRNA secondary structures. BMC Genomics 12:90. https://doi.org/10.1186/1471-2164-12-90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Evrard C, Tachon G, Randrian V, Karayan-Tapon L, Tougeron D (2019) Microsatellite instability: diagnosis, heterogeneity, discordance, and clinical impact in colorectal cancer. Cancers 11:1567. https://doi.org/10.3390/cancers11101567

    Article  CAS  PubMed Central  Google Scholar 

  23. Nojadeh JN, Behrouz Sharif S, Sakhinia E (2018) Microsatellite instability in colorectal cancer. Excli J 17:159–168. https://doi.org/10.17179/excli2017-948

    Article  PubMed  PubMed Central  Google Scholar 

  24. Adem C, Soderberg CL, Cunningham JM, Reynolds C, Sebo TJ, Thibodeau SN et al (2003) Microsatellite instability in hereditary and sporadic breast cancers. Int J Cancer 107:580–582. https://doi.org/10.1002/ijc.11442

    Article  CAS  PubMed  Google Scholar 

  25. Rimsza LM, Kopecky KJ, Ruschulte J, Chen IM, Slovak ML, Karanes C et al (2000) Microsatellite instability is not a defining genetic feature of acute myeloid leukemogenesis in adults: results of a retrospective study of 132 patients and review of the literature. Leukemia 14:1044–1051. https://doi.org/10.1038/sj.leu.2401699

    Article  CAS  PubMed  Google Scholar 

  26. Nomdedéu JF, Perea G, Estivill C, Lasa A, Carnicer MJ, Brunet S et al (2005) Microsatellite instability is not an uncommon finding in adult de novo acute myeloid leukemia. Ann Hematol 84:368–375. https://doi.org/10.1007/s00277-005-1035-3

    Article  CAS  PubMed  Google Scholar 

  27. Inokuchi K, Ikejima M, Watanabe A, Nakajima E, Orimo H, Nomura T et al (1995) Loss of expression of the human MSH3 gene in hematological malignancies. Biochem Biophys Res Commun 214:171–179. https://doi.org/10.1006/bbrc.1995.2271

    Article  CAS  PubMed  Google Scholar 

  28. Edelmann W, Umar A, Yang K, Heyer J, Kucherlapati M, Lia M et al (2000) The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression. Cancer Res 60:803–807

    CAS  PubMed  Google Scholar 

  29. Morimoto H, Tsukada J, Kominato Y, Tanaka Y (2005) Reduced expression of human mismatch repair genes in adult T-cell leukemia. Am J Hematol 78:100–107. https://doi.org/10.1002/ajh.20259

    Article  CAS  PubMed  Google Scholar 

  30. Matheson EC, Hogarth LA, Case MC, Irving JA, Hall AG (2007) DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo. Carcinogenesis 28:1341–1346. https://doi.org/10.1093/carcin/bgl235

    Article  CAS  PubMed  Google Scholar 

  31. Nuuri K, Arroyo-Berdugo Y, Esposito MT (2020) Analysis of expression of MSH2 and MSH3 genes in Mixed Lineage Leukemia (MLL)–Acute Lymphoblastic Leukemia (ALL) human cell lines. J Young Investig 37:38–48

    Google Scholar 

  32. Rajewska M, Wegrzyn K, Konieczny I (2012) AT-rich region and repeated sequences—the essential elements of replication origins of bacterial replicons, FEMS. Microbiol Rev 36:408–434. https://doi.org/10.1111/j.1574-6976.2011.00300.x

    Article  CAS  Google Scholar 

  33. Yang Y, Jain RK, Glenn ST, Xu B, Singh PK, Wei L et al (2020) Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability. J Immunother Cancer 8:e000128. https://doi.org/10.1136/jitc-2019-000128

    Article  PubMed  PubMed Central  Google Scholar 

  34. Clark N, Wu X, Her C (2013) MutS homologues hMSH4 and hMSH5: genetic variations, functions, and implications in human diseases. Curr Genomics 14:81–90. https://doi.org/10.2174/1389202911314020002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sekine H, Ferreira RC, Pan-Hammarström Q, Graham RR, Ziemba B, de Vries SS et al (2007) Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A 104:7193–7198. https://doi.org/10.1073/pnas.0700815104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Valles-Ibáñez G, Esteve-Solé A, Piquer M, González-Navarro EA, Hernandez-Rodriguez J et al (2018) Evaluating the genetics of common variable immunodeficiency: monogenetic model and beyond. Front immunol 9:636. https://doi.org/10.3389/fimmu.2018.00636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Graham RP, Kerr SE, Butz ML, Thibodeau SN, Halling KC, Smyrk TC et al (2015) Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol 39:1370–1376. https://doi.org/10.1097/PAS.0000000000000459

    Article  PubMed  Google Scholar 

  38. Ollikainen M, Hannelius U, Lindgren CM, Abdel-Rahman WM, Kere J, Peltomäki P (2007) Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene 26:4541–4549. https://doi.org/10.1038/sj.onc.1210236

    Article  CAS  PubMed  Google Scholar 

  39. Hutter P, Wijnen J, Rey-Berthod C, Thiffault I, Verkuijlen P, Farber D et al (2002) An MLH1 haplotype is over-represented on chromosomes carrying an HNPCC predisposing mutation in MLH1. J Med Genet 39:323–327. https://doi.org/10.1136/jmg.39.5.323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Limpaiboon T, Krissadarak K, Sripa B, Jearanaikoon P, Bhuhisawasdi V, Chau-in S et al (2002) Microsatellite alterations in liver fluke related cholangiocarcinoma are associated with poor prognosis. Cancer Lett 181:215–222. https://doi.org/10.1016/s0304-3835(02)00052-6

    Article  CAS  PubMed  Google Scholar 

  41. Leeksma OC, de Miranda NF, Veelken H (2017) Germline mutations predisposing to diffuse large B-cell lymphoma. Blood Cancer J 7:e532 (Erratum in: Blood. Cancer. J. 7 (2017) e541. DOI: 10.1038/bcj.2017.15)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK et al (2014) Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer 50:987–996. https://doi.org/10.1016/j.ejca.2013.12.005

    Article  PubMed  Google Scholar 

  43. Loukola A, Vilkki S, Singh J, Launonen V, Aaltonen LA (2000) Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Am J Pathol 157:347–352. https://doi.org/10.1016/S0002-9440(10)64546-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bacher JW, Clipson L, Steffen LS, Halberg RB (2016) Microsatellite instability and its significance to hereditary and sporadic cancer. Microsatellite markers. IntechOpen, London. https://doi.org/10.5772/65065

    Chapter  Google Scholar 

  45. Geisler JP, Goodheart MJ, Sood AK, Holmes RJ, Hatterman-Zogg MA, Buller RE (2003) Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma. Cancer 98:2199–2206. https://doi.org/10.1002/cncr.11770

    Article  CAS  PubMed  Google Scholar 

  46. Sugano K, Nakajima T, Sekine S, Taniguchi H, Saito S, Takahashi M et al (2016) Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan. Cancer Sci 107:1677–1686. https://doi.org/10.1111/cas.13073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pink RC, Wicks K, Caley DP, Punch EK, Jacobs L, Carter DR (2011) Pseudogenes: pseudo-functional or key regulators in health and disease? RNA 17:792–798. https://doi.org/10.1261/rna.2658311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR (2001) Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61:827–830

    CAS  PubMed  Google Scholar 

  49. Fox EJ, Leahy DT, Geraghty R, Mulcahy HE, Fennelly D, Hyland JM et al (2006) Mutually exclusive promoter hypermethylation patterns of hMLH1 and O6-methylguanine DNA methyltransferase in colorectal cancer. J Mol Diagn 8:68–75. https://doi.org/10.2353/jmoldx.2006.050084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Amit M, Donyo M, Hollander D, Goren A, Kim E, Gelfman S et al (2012) Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Rep 1:543–556. https://doi.org/10.1016/j.celrep.2012.03.013

    Article  CAS  PubMed  Google Scholar 

  51. Zhao P, Li L, Jiang X, Li Q (2019) Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol 12:54. https://doi.org/10.1186/s13045-019-0738-1

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kelley MR, Logsdon D, Fishel ML (2014) Targeting DNA repair pathways for cancer treatment: what’s new? Future Oncol 10:1215–1237. https://doi.org/10.2217/fon.14.60

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are extremely grateful to Penn State Cancer Institute, Hershey, PA 17033, USA.for generous donation of HCT116 cell lines.

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We are thankful to Vellore Institute of Technology for providing the facilities and fund for research student without which the work would have not be completed.

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  1. Department of Integrative Biology, Vellore Institute of Technology, Vellore, India

    Priyanjali Bhattacharya & Trupti N. Patel

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Bhattacharya, P., Patel, T.N. Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes. Mol Biol Rep 49, 10293–10305 (2022). https://doi.org/10.1007/s11033-022-07761-y

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