INVESTIGATION OF NEW CANDIDATE GENES IN THE PATHOGENESIS OF SARCOMAS

Abstract

Objective: Sarcomas are rare cancers that develop in the bones and soft tissues, including fat, muscles, blood vessels, nerves, deep skin tissues, and fibrous tissues. Most sarcomas have no known cause although there are several factors that can increase a person’s risk of developing sarcoma, such as genetic predisposition due to the family history, previous history of radiation therapy, chemical exposure, and long-term swelling. The causes and genetic basis of sarcomas are not fully elucidated. Materials and Methods: Whole-exome sequencing (WES) was performed in patients selected from 2 different families, who were thought to be at high risk, with various sarcoma diagnoses in their families, to determine which gene or genes caused the disease. Results: At the end of the study, a total of 17 variants with a pathogenic record in the first family were identified, while a total of 8 pathogenic variants belonging to 7 different genes, including KLKB1, IRGM, PRSS1, MBL2, PTPRJ, FGFR4 and SLC34A3, were associated with various cancer risks. In the second family, 4 pathogenic variants belonging to 4 different genes, namely FGFR4, MBL2, MUTYH, and NQO1, have been identified. Conclusion: The examination of people at high risk for sarcoma and the discovery of genes that may be associated with the disease made important contributions to the follow-up protocol of both patients and risky family members. In addition, according to the results obtained, family members with cancer predisposition were selected after the risk analysis made in the families, and the necessary tests and screenings were recommended in order to provide the advantage of early diagnosis.

Keywords

• sarcoma
• genetics
• gene mutation
• whole exome sequencing

SARKOM PATOGENEZİNDE ETKİLİ OLABİLECEK YENİ ADAY GENLERİN ARAŞTIRILMASI

Abstract

Amaç: Sarkomlar, yağ, kas, kan damarları, sinir, derin cilt dokuları ile fibröz dokular dahil olmak üzere kemiklerde ve yumuşak dokularda gelişen nadir kanserlerdir. Kişinin sarkom geliştirme riskini artırabilecek genetik yatkınlık, radyoterapi öyküsü ve kimyasal maruziyet gibi bazı faktörler olmasına rağmen, çoğu sarkomun bilinen bir nedeni yoktur ve günümüzde genetik temeli tam olarak aydınlatılmamıştır. Gereç ve Yöntem: Ailesinde çeşitli sarkom tanıları bulunan yüksek risk taşıdığı düşünülen 2 farklı aileden seçilmiş hastalarda hastalığın hangi gen ya da genler aracılığı ile geliştiğini belirlemek amacıyla tüm ekzom dizileme (WES) işlemi yapılmıştır. Bulgular: Çalışma sonunda ilk ailede patojenik kaydı bulunan toplam 17 varyant tanımlanırken bu varyantlardan KLKB1, IRGM, PRSS1, MBL2, PTPRJ, FGFR4 ve SLC34A3 olmak üzere 7 farklı gene ait toplam 8 patojenik varyant çeşitli kanser riskleri ile ilişkilendirilmiştir. İkinci ailede ise FGFR4, MBL2, MUTYH, NQO1 olmak üzere 4 farklı gene ait 4 patojenik varyant tanımlanmıştır. Sonuç: Sarkom açısından yüksek risk taşıyan kişilerin incelenmesi ve hastalık ile ilişkili olabilecek genlerin bulunması ile gerek hastaların gerekse riskli aile bireylerinin takip protokolüne önemli katkılar sağlanmıştır. Ayrıca çıkan sonuçlar doğrultusunda ailelerde yapılmış risk analizi sonrası kanser yatkınlığı olan aile bireyleri seçilmiş ve erken tanı avantajı sağlanabilmesi için gerekli tetkik ve taramalar önerilmiştir.

Keywords

• sarkom
• genetik
• gen mutasyonu
• tüm ekzom dizileme

References

1. 1. Carrasco Salas P, Lapunzina P, Perez-Martinez A. Genetic predisposition to childhood cancer. An Pediatr (Barc) 2017;87(3):125-7. google scholar
2. 2. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10(8):789-99. google scholar
3. 3. Mirabello L, Troisi RJ, Savage SA. İnternational osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. İnt J Cancer 2009;125(1): 229-34. google scholar
4. 4. Savage, SA and L Mirabello, Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma 2011;2011:548151. google scholar
5. 5. Rickel K, Fang F, Tao J. Molecular genetics of osteosarcoma. Bone 2017;102:69-79. google scholar
6. 6. Brodeur GM, Nichols KE, Plon SE, Schiffman JD, Malkin D. Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr. Clin Cancer Res 2017;23(11):e1-e5. google scholar
7. 7. Czarnecka AM, Synoradzki K, Firlej W, Bartnik E, Sobczuk P, Fiedorowicz M et al. Molecular Biology of Osteosarcoma. Cancers (Basel) 2020;12(8):2130. google scholar
8. 8. Stoppa-Lyonnet D, Houdayer C. New generation sequencing in medical genetics. Med Sci (Paris) 2012;28(2):123-4. google scholar

9. 9. Liang WS, Stephenson K, Adkins J, Christofferson A, Helland A, Cuyugan L, et al. Whole Exome Library Construction for Next Generation Sequencing. Methods Mol Biol 2018;1706:163-74. google scholar
10. 10. Chung DW, Fujikawa K, McMullen BA, Davie EW. Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry 1986; 25(9):2410-7. google scholar
11. 11. Barco S, Sollfrank S, Trinchero A, Adenaeuer A, Abolghasemi H, Conti L et al. Severe plasma prekallikrein deficiency: Clinical characteristics, novel KLKB1 mutations, and estimated prevalence. J Thromb Haemost 2020;18(7):1598-617. google scholar
12. 12. Wong J, Sia YY, Misso NL, Aggarwal S, Ng A, Bhoola KD. Effects of the demethylating agent, 5-azacytidine, on expression of the kallikrein-kinin genes in carcinoma cells of the lung and pleura. Patholog Res Int 2011;2011:167046. google scholar
13. 13. Hasegawa T, Lewis H, Esquela-Kerscher A. Chapter 12 - The Role of Noncoding RNAs in Prostate Cancer, in Translating MicroRNAs to the Clinic, J. Laurence, Editor. Academic Press: Boston, 2017.p.329-69. google scholar
14. 14. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 2007;39(7):830-2. google scholar
15. 15. Song JH, Kim SY, Chung KS, Moon CM, Kim SW, Kim EY et al. Association between genetic variants in the IRGM gene and tuberculosis in a Korean population. Infection 2014;42(4):655-60. google scholar
16. 16. Singh SB, Davis AS, Taylor GA, Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 2006;313(5792):1438-41. google scholar
17. 17. Crotzer VL, Blum JS. Autophagy and adaptive immunity. Immunology 2010;131(1):9-17. google scholar
18. 18. Virgin HW, Levine B. Autophagy genes in immunity. Nat Immunol 2009;10(5):461-70. google scholar
19. 19. Yao QM, Zhu YF, Wang W, Song ZY, Shao XQ, Li L et al. Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases. Biomed Res Int 2018;2018:7959707. google scholar
20. 20. Burada F, Plantinga TS, Ioana M, Rosentul D, Angelescu C, Joosten LA et al. IRGM gene polymorphisms and risk of gastric cancer. J Dig Dis 2012;13(7):360-5. google scholar
21. 21. Song Z, Guo C, Zhu L, Shen P, Wang H, Guo C et al. Elevated expression of immunity-related GTPase family M in gastric cancer. Tumour Biol 2015;36(7):5591-6. google scholar
22. 22. Zou WB, Tang XY, Zhou DZ, Qian YY, Hu LH, Yu FF et al. SPINK1, PRSS1, CTRC, and CFTR genotypes influence disease onset and clinical outcomes in chronic pancreatitis. Clin Transl Gastroenterol 2018;9(11):204. google scholar
23. 23. Bouwman LH, Roep BO, Roos A. Mannose-binding lectin: clinical implications for infection, transplantation, and autoimmunity. Hum Immunol 2006;67(4-5):247-56. google scholar
24. 24. Peterslund NA, Koch C, Jensenius JC, Thiel S. Association between deficiency of mannose-binding lectin and severe infections after chemotherapy. Lancet 2001;358(9282):637-8. google scholar
25. 25. Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Parsa AT. Cancer and the complement cascade. Mol Cancer Res 2010;8(11):1453-65. google scholar
26. 26. Bernig, T, Boersma BJ, Howe TM, Welch R, Yadavalli S, Staats B et al. The mannose-binding lectin (MBL2) haplotype and breast cancer: an association study in African-American and Caucasian women. Carcinogenesis 2007;28(4):828-36. google scholar
27. 27. Baccarelli A, Hou L, Chen J, Lissowska J, El-Omar EM, Grillo P et al. Mannose-binding lectin-2 genetic variation and stomach cancer risk. Int J Cancer 2006;119(8):1970-5. google scholar
28. 28. Zanetti KA, Haznadar M, Welsh JA, Robles AI, Ryan BM, McClary AC et al. 3’-UTR and functional secretor haplotypes in mannose-binding lectin 2 are associated with increased colon cancer risk in African Americans. Cancer Res 2012;72(6):1467-77. google scholar
29. 29. Pine SR, Mechanic LE, Ambs S, Bowman ED, Chanock SJ, Loffredo C et al. Lung cancer survival and functional polymorphisms in MBL2, an innate-immunity gene. J Natl Cancer Inst 2007;99(18):1401-9. google scholar
30. 30. Ytting H, Christensen IJ, Steffensen R, Alsner J, Thiel S, Jensenius JC et al. Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) genotypes in colorectal cancer. Scand J Immunol 2011;73(2):122-7. google scholar
31. 31. Toland AE, Rozek LS, Presswala S, Rennert G, Gruber SB. PTPRJ haplotypes and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2008;17(10):2782-5. google scholar
32. 32. Ruivenkamp CA, van Wezel T, Zanon C, Stassen AP, Vlcek C, Csikos T et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 2002;31(3):295-300. google scholar
33. 33. Iuliano R, Le Pera I, Cristofaro C, Baudi F, Arturi F, Pallante P et al. The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis. Oncogene 2004;23(52):8432-8. google scholar
34. 34. Lesueur F, Pharoah PD, Laing S, Ahmed S, Jordan C, Smith PL et al. Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum Mol Genet 2005;14(16):2349-56. google scholar
35. 35. Akdeniz Odemis D, Tuncer SB, Adamnejad Ghafour A, Jabbarli K, Gider Y, Celik B et al. FGFR4 c.1162G > A (p.Gly388Arg) polymorphism analysis in Turkish patients with retinoblastoma. J Oncol 2020;2020:9401038. google scholar
36. 36. Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M et al. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res 2002;62(3):840-7. google scholar
37. 37. Leung HY, Gullick WJ, Lemoine NR. Expression and functional activity of fibroblast growth factors and their receptors in human pancreatic cancer. Int J Cancer 1994;59(5): 667-75. google scholar
38. 38. Wang J, Stockton DW, Ittmann M. The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Clin Cancer Res 2004;10(18 Pt 1):6169-78. google scholar
39. 39. Brito LP, Lerario AM, Bronstein MD, Soares IC, Mendonca BB, Fragoso MC. Influence of the fibroblast growth factor receptor 4 expression and the G388R functional polymorphism on Cushing’s disease outcome. J Clin Endocrinol Metab 2010;95(10):E271-9. doi: 10.1210/jc.2010-0047. google scholar
40. 40. Akdeniz D, Tuncer SB, Kebudi R, Celik B, Kuru G, Kilic S et al. Investigation of new candidate genes in retinoblastoma using the TruSight One “clinical exome” gene panel. Mol Genet Genomic Med 2019;7(8):e785. doi: 10.1002/mgg3.785 google scholar
41. 41. Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985;312(10):611-7. google scholar
42. 42. Tahbazlahafi B, Paknejad M, Khaghani S, Sadegh-Nejadi S, Khalili E. Vitamin D Represses the Aggressive Potential of Osteosarcoma. Endocr Metab Immune Disord Drug Targets 2021;21(7):1312-8. google scholar
43. 43. Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 2006;91(10):4022-7. google scholar
44. 44. Hureaux, M, E Ashton, K Dahan, P Houillier, A Blanchard, C Cormier, et al., High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. Kidney Int 2019;96(6):1408-16. google scholar
45. 45. Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology 2008;135(2):499-507. google scholar
46. 46. Zai CC, AK Tiwari, V Basile, V de Luca, DJ Muller, AN Voineskos, et al., Oxidative stress in tardive dyskinesia: genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(1):50-6. google scholar
47. 47. Smith MT. Benzene NQO1 and genetic susceptibility to cancer. Proc Natl Acad Sci USA 1999;96(14):7624-6. google scholar
48. 48. Chhetri J, AE King, and N Gueven, Alzheimer’s Disease and NQO1: Is there a Link? Curr Alzheimer Res 2018;15(1):56-66. google scholar
49. 49. Chao C, Zhang ZF, Berthiller J, Boffetta P, Hashibe M. NAD(P) H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006;15(5): 979-87. google scholar
50. 50. Valenzuela M, Glorieux C, Stockis J, Sid B, Sandoval JM, Felipe KB, et al., Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells. Br J Cancer 2014;111(5):874-82. google scholar