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Germline and Somatic Mutations of Genes Involved in Tumor Formation in Sporadic Renal Angiomyolipoma

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Abstract

Angiomyolipoma (AML) is one of the most frequent and, at the same time, AML molecular genetics is one of the least studied among benign tumors. We performed deep sequencing of 409 genes involved in oncogenesis in tumor samples and peripheral blood of patients with sporadic AML of the kidney. We recorded mutations in the TSC2 gene in 65% of samples, which is consistent with international results. As a result of our work, we uncovered mutations in the SETD2, PDGFRA, STK36, SYNE1, PIK3CD, NF1, TOP1, and ITGB3 genes in sporadic renal AML for the first time. In two samples, we were able to clarify the clinical and morphological diagnosis by finding mutations in the genes in tumors lacking TSC2 gene lesions. Mutations in MET and CDC73 are also causative for other types of renal tumors: papillary renal cell carcinoma and CDC73-related disorders, respectively. The latter disease is accompanied by kidney cysts and hamartomas. The obtained results demonstrate a promising potential of mutational profiling of sporadic renal angiomyolipoma (sAML). Genotyping of sAML is particularly important for clarification of the clinical diagnosis in ambiguous cases, as well as for a more in-depth understanding of AML molecular genetics and etiopathogenesis, and for the identification of new molecular targets for personalized AML therapies.

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REFERENCES

  1. Al Omran, B. and Ansari, N., Aneurysm in a large sporadic renal angiomyolipoma, Oman Med. J., 2016, vol. 31, no. 3, pp. 223—226. https://doi.org/10.5001/omj.2016.42

    Article  PubMed  PubMed Central  Google Scholar 

  2. Crino, P.B., Nathanson, P.B., and Henske, E.P., The tuberous sclerosis complex, N. Engl. J. Med., 2006, vol. 355, no. 13, pp. 1345—1356. https://doi.org/10.1056/NEJMra055323

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi, N., Kitahara, R., Hishimoto, Y., et al., Malignant transformation of renal angiomyolipoma, Int. J. Urol., 2003, vol. 10, no. 5, pp. 271—273.

    Article  PubMed  Google Scholar 

  4. Parekh, V. and Shen, D., Invasive renal angiomyolipoma with cytologic atypia, Int. J. Surg. Pathol., 2017, vol. 25, no. 2, pp. 177—180. https://doi.org/10.1177/1066896916665700

    Article  PubMed  Google Scholar 

  5. Kawaguchi, K., Oda, Y., Nakanishi, K., et al., Malignant transformation of renal angiomyolipoma: a case report, Am. J. Surg. Pathol., 2002, vol. 26, no. 4, pp. 523—529.

    Article  PubMed  Google Scholar 

  6. Tate, J.G., Bamford, S., Jubb, H.C., et al., COSMIC: the Catalogue of Somatic Mutations in Cancer, Nucltic Acids Res., 2019, vol. 47, no. D1, pp. D941—D947. https://doi.org/10.1093/nar/gky1015

    Article  CAS  Google Scholar 

  7. Qin, W., Bajaj, V., Malinowska, I., et al., Angiomyolipoma have common mutations in TSC2 but no other common genetic events, PloS One, 2011, vol. 6, no. 9. e24919. https://doi.org/10.1371/journal.pone.0024919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Giannikou, K., Malinowska, I.A., Pugh, T.J., et al., Whole exome sequencing identifies TSC1/TSC2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development, PLoS Genet., 2016, vol. 12, no. 8. e1006242. https://doi.org/10.1371/journal.pgen.1006242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lek, M., Karczewski, K.J., Minikel, E.V., et al., Analysis of protein-coding genetic variation in 60 706 humans, Nature, 2016, vol. 536, no. 7616, pp. 285—291. https://doi.org/10.1038/nature19057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, K., Li, M., and Hakonarson, H., ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data, Nucleic Acids Res., 2010 V. 38, no. 16, pp. e164—e164. https://doi.org/10.1093/nar/gkq603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fokkema, I.F., Taschner, P.E., Schaafsma, G.C., et al., LOVD v. 2.0: the next generation in gene variant databases, Hum. Mutat., 2011, vol. 32, no. 5, pp. 557—563. https://doi.org/10.1002/humu.21438

    Article  CAS  PubMed  Google Scholar 

  12. Stenson, P.D., Ball, E.V., Mort, M., et al., The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution, in Current Protocols in Bioinformatics, chapter 1, Hoboken, NJ: John Wiley, 2012, unit 1.13. https://doi.org/10.1002/0471250953.bi0113s39

  13. Landrum, M.J., Lee, J.M., Benson, M., et al., ClinVar: improving access to variant interpretations and supporting evidence, Nucleic Acids Res., 2018, vol. 46, no. D1, pp. D1062—D1067. https://doi.org/10.1093/nar/gkx1153

    Article  CAS  PubMed  Google Scholar 

  14. Robinson, J.T., Thorvaldsdóttir, H., Winckler, W., et al., Integrative genomics viewer, Nat. Biotechnol., 2011, vol. 29, no. 1, pp. 24—26. https://doi.org/10.1038/nbt.1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dubbink, H.J., Atmodimedjo, P.N., van Marion, R., et al., Diagnostic detection of allelic losses and imbalances by next-generation sequencing: 1p/19q co-deletion analysis of gliomas, J. Mol. Diagn., 2016, vol. 18, no. 5, pp. 775—786. https://doi.org/10.1016/j.jmoldx.2016.06.002

    Article  CAS  PubMed  Google Scholar 

  16. Anoshkin, K.I., Mosyakova, K.M., Karandasheva, K.O., et al., Novel chromosomal regions with loss of heterozygosity in sporadic renal angiomyolipome, Med. Genet., 2018, vol. 17, no. 9, pp. 45—50. https://doi.org/10.25557/2073-7998.2018.09.45-50

    Article  Google Scholar 

  17. Birchmeier, C., Birchmeier, W., Gherardi, E., and Vande Woude, G.F., Met, metastasis, motility and more, Nat. Rev. Mol. Cell Biol., 2003, vol. 4, no. 12, pp. 915—925. https://doi.org/10.1038/nrm1261

    Article  CAS  PubMed  Google Scholar 

  18. Siminas, S., Qasem, E., Shukla, R., and Turnock, R., Inflammatory fibroid polyp: a rare benign tumor of the alimentary tract in children presenting as intussusception-case report and review of literature, Eur. J. Pediatr. Surg. Rep., 2014, vol. 2, no. 1, pp. 16—19. https://doi.org/10.1055/s-0033-1354746

    Article  Google Scholar 

  19. Wozniak, A., Gebreyohannes, Y.K., Debiec-Rychter, M., and Schöffski, P., New targets and therapies for gastrointestinal stromal tumors, Expert Rev. Anticancer Ther., 2017, vol. 17, no. 12, pp. 1117—1129. https://doi.org/10.1080/14737140.2017.1400386

    Article  CAS  PubMed  Google Scholar 

  20. Joensuu, H., Wardelmann, E., Sihto, H., et al., Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial, JAMA Oncol., 2017, vol. 3, no. 5, pp. 602—609. https://doi.org/10.1001/jamaoncol.2016.5751

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kanehisa, M., Sato, Y., Kawashima, M., et al., KEGG as a reference resource for gene and protein annotation, Nucleic Acids Res., 2016, vol. 44, no. D1, pp. D457—D462. https://doi.org/10.1093/nar/gkv1070

    Article  CAS  PubMed  Google Scholar 

  22. Shimoyama, M., De Pons, J., Hayman, G.T., et al., The rat genome database 2015: genomic, phenotypic and environmental variations and disease, Nucleic Acids Res., 2015, vol. 43, pp. D743—D750. https://doi.org/10.1093/nar/gku1026

    Article  CAS  PubMed  Google Scholar 

  23. Ho, T.H., Park, I.Y., Zhao, H., et al., High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma, Oncogene, 2016, vol. 35, no. 12, pp. 1565—1574. https://doi.org/10.1038/onc.2015.221

    Article  CAS  PubMed  Google Scholar 

  24. Fittschen, A., Wendlik, I., Oeztuerk, S., et al., Prevalence of sporadic renal angiomyolipoma: a retrospective analysis of 61 389 in- and out-patients, Abdom. Imaging, 2014, vol. 39, no. 5, pp. 1009—1013. https://doi.org/10.1007/s00261-014-0129-6

    Article  PubMed  Google Scholar 

  25. Steiner, M.S., Goldman, S.M., Fishman, E.K., and Marshall, F.F., The natural history of renal angiomyolipoma, J. Urol., 1993, vol. 150, no. 6, pp. 1782—1786.

    Article  CAS  PubMed  Google Scholar 

  26. Kim, J.K., Park, S.Y., Shon, J.H., and Cho, K.S., Angiomyolipoma with minimal fat: differentiation from renal cell carcinoma at biphasic helical CT, Radiology, 2004, vol. 230, no. 3, pp. 677—684. https://doi.org/10.1148/radiol.2303030003

    Article  PubMed  Google Scholar 

  27. Strotzer, M., Lehner, K.B., and Becker, K., Detection of fat in a renal cell carcinoma mimicking angiomyolipoma, Radiology, 1993, vol. 188, no. 2, pp. 427—428. https://doi.org/10.1148/radiology.188.2.8327690

    Article  CAS  PubMed  Google Scholar 

  28. Martin, K.R., Zhou, W., Bowman, M.J., et al., The genomic landscape of tuberous sclerosis complex, Nat. Commun., 2017, vol. 8, p. 15816. https://doi.org/10.1038/ncomms15816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was performed within the framework of the state assignment of the Ministry of Education and Science of the Russian Federation to carry out research in the year 2019.

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Authors and Affiliations

  1. Research Centre for Medical Genetics, 115522, Moscow, Russia

    K. I. Anoshkin, K. O. Karandasheva, D. V. Zaletaev, A. S. Tanas & V. V. Strelnikov

  2. Research Institute of Uronephrology and Human Reproductive Health, 119435, Moscow, Russia

    K. M. Goryacheva, Y. V. Shpot & A. Z. Vinarov

  3. First Moscow State Medical University, 119991, Moscow, Russia

    A. Z. Vinarov & D. V. Zaletaev

  4. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    D. V. Zaletaev, A. S. Tanas & V. V. Strelnikov

Authors
  1. K. I. Anoshkin
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  2. K. O. Karandasheva
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  3. K. M. Goryacheva
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  4. Y. V. Shpot
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  5. A. Z. Vinarov
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  6. D. V. Zaletaev
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  7. A. S. Tanas
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  8. V. V. Strelnikov
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Corresponding author

Correspondence to K. I. Anoshkin.

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Statement of Compliance with Standards of Research Involving Human Subjects

All procedures carried out in a study with the participation of people comply with the ethical standards of the institutional and/or national research ethics committee and the 1964 Helsinki Declaration and its subsequent changes or comparable ethical standards.

Informed voluntary consent was obtained from each of the participants in the study.

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The authors declare that they have no conflict of interest.

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Translated by I. Grishina

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Anoshkin, K.I., Karandasheva, K.O., Goryacheva, K.M. et al. Germline and Somatic Mutations of Genes Involved in Tumor Formation in Sporadic Renal Angiomyolipoma. Russ J Genet 55, 1113–1118 (2019). https://doi.org/10.1134/S1022795419090023

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