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Genetics and Genomics of Uterine Fibroids

Chapter
Part of the Comprehensive Gynecology and Obstetrics book series (CGO)

Abstract

Uterine fibroids are benign smooth muscle tumors of monoclonal origin that arise from the uterus. African-American women have a higher risk of developing the disease than do Caucasian women, and a family history of uterine fibroids is a risk factor for their development. The relative risk for uterine fibroids is significantly higher in monozygotic twins than in dizygotic twins, suggesting a correlation of the disease susceptibility with the patient’s genetic background. Chromosomal abnormalities are observed in approximately 40% of cases, where nonrandom and tumor-specific chromosomal abnormalities caused by chromosomal rearrangements affect alterations in the driver genes of uterine fibroids, such as high-mobility group AT-hook 2 (HMGA2) overexpression. Hereditary leiomyomatosis and renal cell cancer are caused by biallelic inactivation of the fumarase hydratase (FH) gene. Alport syndrome associated with diffuse leiomyomatosis is caused by deletions of collagen type IV alpha 5 chain (COL4A5) and alpha 6 chain (COL4A6). Somatic alterations of these genes are also observed in non-syndromic uterine fibroids. Whole-genome sequencing (WGS) revealed that approximately 70% of uterine fibroids have somatic mutations of Mediator complex 12 (MED12), which is the most frequently observed driver gene alteration in these tumors. Through WGS, uterine fibroids have been categorized into at least four subgroups according to the types of driver gene alterations: MED12 mutation, HMGA2 overexpression, biallelic FH inactivation, and COL4A5 and COL4A6 deletions. Each alteration is mutually exclusive in the fibroid nodule. In addition, the role of microRNAs in the development of uterine fibroids is extensively examined.

Keywords

Chromosomal rearrangement MED12 HMGA2 Whole-genome sequencing microRNA 

References

  1. 1.
    Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a systematic review. BJOG. 2017;124(10):1501–12.  https://doi.org/10.1111/1471-0528.14640.CrossRefPubMedGoogle Scholar
  2. 2.
    Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol. 2010;202:514–21.  https://doi.org/10.1016/j.ajog.2010.02.039.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Van Voorhis BJ, Romitti PA, Jones MP. Family history as a risk factor for development of uterine leiomyomas. Results of a pilot study. J Reprod Med. 2002;47:663–9.PubMedGoogle Scholar
  4. 4.
    Hodge JC, Morton CC. Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hum Mol Genet. 2007;16(1):R7–13.  https://doi.org/10.1093/hmg/ddm043.CrossRefPubMedGoogle Scholar
  5. 5.
    Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet. 1995;51:127–31.CrossRefGoogle Scholar
  6. 6.
    Luoto R, Kaprio J, Rutanen EM, Taipale P, Perola M, Koskenvuo M. Heritability and risk factors of uterine fibroids—the Finnish Twin Cohort study. Maturitas. 2000;37:15–26.CrossRefGoogle Scholar
  7. 7.
    Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab. 1998;83:1875–80.  https://doi.org/10.1210/jcem.83.6.4890.CrossRefPubMedGoogle Scholar
  8. 8.
    Hashimoto K, Azuma C, Kamiura S, Kimura T, Nobunaga T, Kanai T, et al. Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene. Gynecol Obstet Investig. 1995;40:204–8.CrossRefGoogle Scholar
  9. 9.
    Cai YR, Diao XL, Wang SF, Zhang W, Zhang HT, Su Q. X-chromosomal inactivation analysis of uterine leiomyomas reveals a common clonal origin of different tumor nodules in some multiple leiomyomas. Int J Oncol. 2007;31:1379–89.PubMedGoogle Scholar
  10. 10.
    Zhang P, Zhang C, Hao J, Sung CJ, Quddus MR, Steinhoff MM, et al. Use of X-chromosome inactivation pattern to determine the clonal origins of uterine leiomyoma and leiomyosarcoma. Hum Pathol. 2006;37:1350–6.  https://doi.org/10.1016/j.humpath.2006.05.005.CrossRefPubMedGoogle Scholar
  11. 11.
    Mashal RD, Fejzo ML, Friedman AJ, Mitchner N, Nowak RA, Rein MS, et al. Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata. Genes Chromosomes Cancer. 1994;11:1–6.CrossRefGoogle Scholar
  12. 12.
    Townsend DE, Sparkes RS, Baluda MC, McClelland G. Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis by glucose-6-phosphate dehydrogenase. Am J Obstet Gynecol. 1970;107:1168–73.CrossRefGoogle Scholar
  13. 13.
    Cha PC, Takahashi A, Hosono N, Low SK, Kamatani N, Kubo M, et al. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat Genet. 2011;43:447–50.  https://doi.org/10.1038/ng.805.CrossRefPubMedGoogle Scholar
  14. 14.
    Eggert SL, Huyck KL, Somasundaram P, Kavalla R, Stewart EA, Lu AT, et al. Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata. Am J Hum Genet. 2012;91:621–8.  https://doi.org/10.1016/j.ajhg.2012.08.009.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wise LA, Ruiz-Narvaez EA, Palmer JR, Cozier YC, Tandon A, Patterson N, et al. African ancestry and genetic risk for uterine leiomyomata. Am J Epidemiol. 2012;176:1159–68.  https://doi.org/10.1093/aje/kws276.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hodge JC, Park PJ, Dreyfuss JM, Assil-Kishawi I, Somasundaram P, Semere LG, et al. Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis. Genes Chromosomes Cancer. 2009;48:865–85.  https://doi.org/10.1002/gcc.20692.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dal Cin P, Moerman P, Deprest J, Brosens I, Van den Berghe H. A new cytogenetic subgroup in uterine leiomyoma is characterized by a deletion of the long arm of chromosome 3. Genes Chromosomes Cancer. 1995;13:219–20.CrossRefGoogle Scholar
  18. 18.
    Pandis N, Bardi G, Sfikas K, Panayotopoulos N, Tserkezoglou A, Fotiou S. Complex chromosome rearrangements involving 12q14 in two uterine leiomyomas. Cancer Genet Cytogenet. 1990;49:51–6.CrossRefGoogle Scholar
  19. 19.
    Hu J, Surti U. Subgroups of uterine leiomyomas based on cytogenetic analysis. Hum Pathol. 1991;22:1009–16.CrossRefGoogle Scholar
  20. 20.
    Mehine M, Kaasinen E, Makinen N, Katainen R, Kampjarvi K, Pitkanen E, et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med. 2013;369:43–53.  https://doi.org/10.1056/NEJMoa1302736.CrossRefPubMedGoogle Scholar
  21. 21.
    Mehine M, Makinen N, Heinonen HR, Aaltonen LA, Vahteristo P. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil Steril. 2014;102:621–9.  https://doi.org/10.1016/j.fertnstert.2014.06.050.CrossRefPubMedGoogle Scholar
  22. 22.
    Hodge JC, Kim TM, Dreyfuss JM, Somasundaram P, Christacos NC, Rousselle M, et al. Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profilingof the t(12;14) and evidence in support of predisposing genetic heterogeneity. Hum Mol Genet. 2012;21:2312–29.  https://doi.org/10.1093/hmg/dds051.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Klemke M, Meyer A, Nezhad MH, Bartnitzke S, Drieschner N, Frantzen C, et al. Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease. Genes Chromosomes Cancer. 2009;48:171–8.  https://doi.org/10.1002/gcc.20627.CrossRefPubMedGoogle Scholar
  24. 24.
    Quade BJ, Weremowicz S, Neskey DM, Vanni R, Ladd C, Dal Cin P, et al. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res. 2003;63:1351–8.PubMedGoogle Scholar
  25. 25.
    Takahashi T, Nagai N, Oda H, Ohama K, Kamada N, Miyagawa K. Evidence for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma. Genes Chromosomes Cancer. 2001;30:196–201.CrossRefGoogle Scholar
  26. 26.
    Nezhad MH, Drieschner N, Helms S, Meyer A, Tadayyon M, Klemke M, et al. 6p21 rearrangements in uterine leiomyomas targeting HMGA1. Cancer Genet Cytogenet. 2010;203:247–52.  https://doi.org/10.1016/j.cancergencyto.2010.08.005.CrossRefPubMedGoogle Scholar
  27. 27.
    Kazmierczak B, Dal Cin P, Wanschura S, Borrmann L, Fusco A, Van den Berghe H, et al. HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors. Genes Chromosomes Cancer. 1998;23:279–85.CrossRefGoogle Scholar
  28. 28.
    Sargent MS, Weremowicz S, Rein MS, Morton CC. Translocations in 7q22 define a critical region in uterine leiomyomata. Cancer Genet Cytogenet. 1994;77:65–8.CrossRefGoogle Scholar
  29. 29.
    Ozisik YY, Meloni AM, Surti U, Sandberg AA. Deletion 7q22 in uterine leiomyoma. A cytogenetic review. Cancer Genet Cytogenet. 1993;71:1–6.CrossRefGoogle Scholar
  30. 30.
    Moore SD, Herrick SR, Ince TA, Kleinman MS, Dal Cin P, Morton CC, et al. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res. 2004;64:5570–7.  https://doi.org/10.1158/0008-5472.can-04-0050.CrossRefPubMedGoogle Scholar
  31. 31.
    Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Familial Cancer. 2011;10:397–411.  https://doi.org/10.1007/s10689-011-9428-z.CrossRefPubMedGoogle Scholar
  32. 32.
    Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle, WA: University of Washington, Seattle; 1993–2017.Google Scholar
  33. 33.
    Kampjarvi K, Makinen N, Mehine M, Valipakka S, Uimari O, Pitkanen E, et al. MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. Br J Cancer. 2016;114:1405–11.  https://doi.org/10.1038/bjc.2016.130.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kashtan CE. Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine. 1999;78:338–60.CrossRefGoogle Scholar
  35. 35.
    Hertz JM. Alport syndrome. Molecular genetic aspects. Dan Med Bull. 2009;56:105–52.PubMedGoogle Scholar
  36. 36.
    Makinen N, Kampjarvi K, Frizzell N, Butzow R, Vahteristo P. Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer. 2017;16:101.  https://doi.org/10.1186/s12943-017-0672-1.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mehine M, Kaasinen E, Heinonen HR, Makinen N, Kampjarvi K, Sarvilinna N, et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci U S A. 2016;113:1315–20.  https://doi.org/10.1073/pnas.1518752113.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Makinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011;334:252–5.  https://doi.org/10.1126/science.1208930.CrossRefPubMedGoogle Scholar
  39. 39.
    McGuire MM, Yatsenko A, Hoffner L, Jones M, Surti U, Rajkovic A. Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS One. 2012;7:e33251.  https://doi.org/10.1371/journal.pone.0033251.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Croce S, Chibon F. MED12 and uterine smooth muscle oncogenesis: state of the art and perspectives. Eur J Cancer. 2015;51:1603–10.  https://doi.org/10.1016/j.ejca.2015.04.023.CrossRefPubMedGoogle Scholar
  41. 41.
    Allen BL, Taatjes DJ. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol. 2015;16:155–66.  https://doi.org/10.1038/nrm3951.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Makinen N, Heinonen HR, Sjoberg J, Taipale J, Vahteristo P, Aaltonen LA. Mutation analysis of components of the Mediator kinase module in MED12 mutation-negative uterine leiomyomas. Br J Cancer. 2014;110(9):2246.  https://doi.org/10.1038/bjc.2014.138.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bertsch E, Qiang W, Zhang Q, Espona-Fiedler M, Druschitz S, Liu Y, et al. MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol. 2014;27:1144–53.  https://doi.org/10.1038/modpathol.2013.243.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Halder SK, Laknaur A, Miller J, Layman LC, Diamond M, Al-Hendy A. Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. Mol Gen Genomics. 2015;290:505–11.  https://doi.org/10.1007/s00438-014-0938-x.CrossRefGoogle Scholar
  45. 45.
    Matsubara A, Sekine S, Yoshida M, Yoshida A, Taniguchi H, Kushima R, et al. Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours. Histopathology. 2013;62:657–61.  https://doi.org/10.1111/his.12039.CrossRefPubMedGoogle Scholar
  46. 46.
    Schwetye KE, Pfeifer JD, Duncavage EJ. MED12 exon 2 mutations in uterine and extrauterine smooth muscle tumors. Hum Pathol. 2014;45:65–70.  https://doi.org/10.1016/j.humpath.2013.08.005.CrossRefPubMedGoogle Scholar
  47. 47.
    Perot G, Croce S, Ribeiro A, Lagarde P, Velasco V, Neuville A, et al. MED12 alterations in both human benign and malignant uterine soft tissue tumors. PLoS One. 2012;7:e40015.  https://doi.org/10.1371/journal.pone.0040015.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    de Graaff MA, Cleton-Jansen AM, Szuhai K, Bovee JV. Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. Hum Pathol. 2013;44:1597–604.  https://doi.org/10.1016/j.humpath.2013.01.006.CrossRefPubMedGoogle Scholar
  49. 49.
    Mittal P, Shin YH, Yatsenko SA, Castro CA, Surti U, Rajkovic A. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J Clin Invest. 2015;125:3280–4.  https://doi.org/10.1172/jci81534.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Al-Hendy A, Laknaur A, Diamond MP, Ismail N, Boyer TG, Halder SK. Silencing Med12 gene reduces proliferation of human leiomyoma cells mediated via Wnt/beta-catenin Signaling pathway. Endocrinology. 2017;158:592–603.  https://doi.org/10.1210/en.2016-1097.CrossRefPubMedGoogle Scholar
  51. 51.
    Gross KL, Neskey DM, Manchanda N, Weremowicz S, Kleinman MS, Nowak RA, et al. HMGA2 expression in uterine leiomyomata and myometrium: quantitative analysis and tissue culture studies. Genes Chromosomes Cancer. 2003;38:68–79.  https://doi.org/10.1002/gcc.10240.CrossRefPubMedGoogle Scholar
  52. 52.
    Wei JJ, Chiriboga L, Mittal K. Expression profile of the tumorigenic factors associated with tumor size and sex steroid hormone status in uterine leiomyomata. Fertil Steril. 2005;84:474–84.  https://doi.org/10.1016/j.fertnstert.2005.01.142.CrossRefPubMedGoogle Scholar
  53. 53.
    Helmke BM, Markowski DN, Muller MH, Sommer A, Muller J, Moller C, et al. HMGA proteins regulate the expression of FGF2 in uterine fibroids. Mol Hum Reprod. 2011;17:135–42.  https://doi.org/10.1093/molehr/gaq083.CrossRefPubMedGoogle Scholar
  54. 54.
    Wang T, Zhang X, Obijuru L, Laser J, Aris V, Lee P, et al. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer. 2007;46:336–47.  https://doi.org/10.1002/gcc.20415.CrossRefPubMedGoogle Scholar
  55. 55.
    Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P, et al. Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res. 2008;6:663–73.  https://doi.org/10.1158/1541-7786.mcr-07-0370.CrossRefPubMedGoogle Scholar
  56. 56.
    Lehtonen R, Kiuru M, Vanharanta S, Sjoberg J, Aaltonen LM, Aittomaki K, et al. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol. 2004;164:17–22.  https://doi.org/10.1016/s0002-9440(10)63091-x.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Miettinen M, Felisiak-Golabek A, Wasag B, Chmara M, Wang Z, Butzow R, et al. Fumarase-deficient uterine leiomyomas: an immunohistochemical, molecular genetic, and clinicopathologic study of 86 cases. Am J Surg Pathol. 2016;40:1661–9.  https://doi.org/10.1097/pas.0000000000000703.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Harrison WJ, Andrici J, Maclean F, Madadi-Ghahan R, Farzin M, Sioson L, et al. Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings. Am J Surg Pathol. 2016;40:599–607.  https://doi.org/10.1097/pas.0000000000000573.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Garcia-Torres R, Cruz D, Orozco L, Heidet L, Gubler MC. Alport syndrome and diffuse leiomyomatosis. Clinical aspects, pathology, molecular biology and extracellular matrix studies. A synthesis. Nephrologie. 2000;21:9–12.PubMedGoogle Scholar
  60. 60.
    Sado Y, Kagawa M, Naito I, Ueki Y, Seki T, Momota R, et al. Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem. 1998;123:767–76.CrossRefGoogle Scholar
  61. 61.
    Marsh EE, Lin Z, Yin P, Milad M, Chakravarti D, Bulun SE. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril. 2008;89(6):1771.  https://doi.org/10.1016/j.fertnstert.2007.05.074.CrossRefPubMedGoogle Scholar
  62. 62.
    Marsh EE, Steinberg ML, Parker JB, Wu J, Chakravarti D, Bulun SE. Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production. Fertil Steril. 2016;106:766–72.  https://doi.org/10.1016/j.fertnstert.2016.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Qiang W, Liu Z, Serna VA, Druschitz SA, Liu Y, Espona-Fiedler M, et al. Down-regulation of miR-29b is essential for pathogenesis of uterine leiomyoma. Endocrinology. 2014;155:663–9.  https://doi.org/10.1210/en.2013-1763.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Chuang TD, Khorram O. Mechanisms underlying aberrant expression of miR-29c in uterine leiomyoma. Fertil Steril. 2016;105:236–45.e1.  https://doi.org/10.1016/j.fertnstert.2015.09.020.CrossRefPubMedGoogle Scholar
  65. 65.
    Fitzgerald JB, Chennathukuzhi V, Koohestani F, Nowak RA, Christenson LK. Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas. Fertil Steril. 2012;98:726–34.e2.  https://doi.org/10.1016/j.fertnstert.2012.05.040.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ling J, Wu X, Fu Z, Tan J, Xu Q. Systematic analysis of gene expression pattern in has-miR-197 over-expressed human uterine leiomyoma cells. Biomed Pharmacother. 2015;75:226–33.  https://doi.org/10.1016/j.biopha.2015.07.039.CrossRefPubMedGoogle Scholar
  67. 67.
    Chuang TD, Khorram O. miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis. PLoS One. 2014;9:e95370.  https://doi.org/10.1371/journal.pone.0095370.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Guan Y, Guo L, Zukerberg L, Rueda BR, Styer AK. MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma. Reprod Biol Endocrinol. 2016;14:45.  https://doi.org/10.1186/s12958-016-0180-y.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Reproductive Medicine, Graduate School of MedicineChiba UniversityChibaJapan

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