ANALYSIS OF ALLELIC IMBALANCE IN GLIOBLASTOMA: NEW CHROMOSOMAL REGIONS OF LOSS OF HETEROZYGOSITY AND NEW CANDIDATE GENES

By means of microsatellite analysis we have evaluated allelic status of eleven chromosome loci for which allelic imbalance (AI) had never been described in glioblastoma. Two of the eleven loci, 18q11.2 and 21q21.1, revealed no allelic imbalance in 108 glioblastoma samples. However, AI was identified at 2q31.2, 3p25.1, 5q14.3, 6p21.1, 7q21.2, 9q21.33, 12q21.33, 16p13.12, 19p13.2 with the frequencies of 5,0%, 19,0%, 11,1%, 3,8%, 28,6%, 3,6%, 5,9%, 9,6%, 17,0%, respectively, demonstrating the necessity to expand molecular genetic studies of glioblastoma. To test if our sampling is representative we have analyzed 8q21.3 and 14q13.3 loci where AI had been previously described. AI at these loci was confirmed with the frequencies of 15.8% and 42.3%, respectively, which is consistent with the previously published data. We discuss potential candidate genes located in the chromosomal loci for which LOH has been identified in this study. 

1. Алексеева Е.А., Шубина М.В., Горбачева Ю.В. и др. Молекулярно-генетическая диагностика в таргетной терапии опухолей головного мозга // Медицинская генетика. — 2012. — №2. — С. 3—10.

2. Алексеева Е.А., Горбачева Ю.В., Бабенко О.В. и др. Молекулярно-генетическая дифференциальная диагностика опухолей головного мозга // Медицинская генетика. — 2012. — №1. — С. 10—14.

3. Кузнецова Е.Б., Пудова Е.А., Танас А.С., Залетаев Д.В., Стрельников В.В. SEMA6B — кандидат на роль гена супрессора опухолевого роста в критическом хромосомном районе 19р13.3 // Медицинская генетика. — 2013. — Т. 12, №2. — С. 32—36.

4. Стрельников В.В., Малышева А.С., Землякова В.В., Кузнецова Е.Б., Алексеева Е.А., Смолин А.В., Прозоренко Е.В., Залетаев Д.В.. Делеции области расположения гена MGMT на хромосоме 10q26.3 в глиомах // Молекулярная медицина. — 2011. — №2. — С. 28—31.

5. Abkevich V., Timms K.M., Hennessy B.T. et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer // British journal of cancer. — 2012. — Vol. 107(10). — P. 1776—1782.

6. Adamson C., Kanu O.O., Mehta A.I. et al. Glioblastoma multiforme: a review of where we have been and where we are going // Informa healthcare. — 2009. — Vol. 18(8). — P. 1061—1083.

7. Cairncross J.G., Ueki K., Zlatescu M.C. et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas // J. Natl. Inst. — 1998. — Vol. 90. — P. 1473—1479.

8. Cifola I., Spinelli R., Beltrame L. et al. Genome-wide screening of copy number alterations and LOH events in renal cell carcinomas and integration with gene expression profile // Molecular cancer. — 2008. — Vol. 7(1). — P. 6.

9. Davis F.G., McCarthy B.J. Current epidemiological trends and surveillance in brain tumors // Anticancer Ther. — 2001. — Vol. 1, №3. — P. 395—401.

10. Frank B., Wiestler M., Kropp S. et al. Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis // J. Natl. Cancer. — 2008. — Vol. 100. — P. 437—442.

11. Furnari F.B., Fenton T., Bachoo R.M. et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment // Genes. Dev. — 2007. — Vol. 21. — P. 2683—2710.

12. Ginzinger D.G., Godfrey T.E., Nigro J. et al. Measurement of DNA copy number at microsatellite loci using quantitative PCR analysis // Cancer research. — 2000. — Vol. 60(19). — P. 5405—5409.

13. Harris T., Pan Q., Sironi J. et al. Both gene amplification and allelic loss occur at 14q13.3 in lung cancer // Clinical Cancer Research. — 2011. — Vol. 17(4). — P. 690—699.

14. Heaphy C.M., Bissofi M., Griffith J.K. Diagnostic significance of allelic imbalance in cancer // Informa healthcare. — 2007. — Vol. 1(2). — P. 159—168.

15. Heroux M.S., Chesnik M.A., Halligan B.D. et al. Comprehensive characterization of glioblastoma tumor tissue for biomarker identification using mass spectrometry-based label-free quantitative proteomics // Physiol. Genomics. — 2014. — Vol. 46. — P. 467—481.

16. Kim N., Hong Y., Kwon D. et al. Somatic Mutaome Profile in Human Cancer Tissues // Genomics and Informatics. — 2013. — Vol. 11(4). — P. 239—244.

17. Kim S.J., Sohn I., Do I.-G. et al. Gene expression profiles for the prediction of progression-free survival in diffuse large B cell lymphoma: results of a DASL assay // Ann. Hematol. — 2014. — Vol. 93. — P. 437—447.

18. Lapointe C.P., Wickens M. The Nucleic Acid-binding Domain and Translational Repression Activity of a Xenopus Terminal Uridylyl Transferase // J. Biol. Chem. — 2013. — Vol. 288(28). — P. 20723—20733.

19. Li Y., Wang Y., Yu L. miR-146b-5p inhibits glioma migration and invasion by targeting MMP16 // Cancer Letters. — 2013. — Vol. 339(2). — P. 260—269.

20. Mizoguchi M., Kuga D., Guan Y. Loss of heterozygosity analysis in malignant gliomas // Brain Tumor Pathol. — 2011. — Vol. 28. — P. 191—196.

21. Morita T., Mayanagi T., Sobue K. Dual roles of myocardin-related transcription factors in epithelial-mesenchymal transition via slug induction and actin remodeling // The J. of Cell Biology. — 2007. — Vol. 179. — P. 1027—1042.

22. Nigro J.M., Takahashi M.A., Ginzinger D.G. et al. Detection of 1p and 19q loss in oligodendroglioma by quantitative microsatellite analysis, a real-time quantitative polymerase chain reaction assay // The American journal of pathology. — 2001. — Vol. 158(4). — P. 1253—1262.

23. Ruano Y., Mollejo M., Ribalta T. et al. Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling // Molecular Cancer. — 2006. — Vol. 5. — P. 39.

24. Sainio A., Nyman M., Lund R. et al. Lack of Decorin Expression by Human Bladder Cancer Cells Offers New Tools in the Therapy of Urothelial Malignancies // Plos One. — 2013. — Vol. 8. — P. 1—8.

25. Tao L.-J., Chen Y.-S., Yao L. et al. PIN1 promoter polymorphism (842G>C) contributes to a decreased risk of cancer: Evidence from meta-analysis // Oncology Letters. — 2014. — Vol. 8. — P. 1360—1366.

26. Van Meir E.G., Hadjipanayis C.G., Norden A.D. et al. Exciting New Advances in Neuro-Oncology: the Avenue to a Cure for Malignant Glioma // CA Cancer J. Clin. — 2010. — Vol. 60(3). — P. 166—193.

27. Yu J., Madison J.M., Mundlos S. Characterization of a Human Homologue of the Saccharomyces cerevisiae Transcription Factor Spt3 (SUPT3H) // Genomics. — 1998. — Vol. 53. — P. 90—96.