Genetic susceptibility to bladder cancer

Cover Page

Cite item

Full Text

Abstract

Background. Bladder cancer (BC) is one of the most common cancers worldwide, representing an urgent problem of modern oncology. Various external and internal environmental factors increase the disease risk. Genetic susceptibility to BC is unquestioned and actively researched nowadays.

Aim. To analyze current advances in genetic factors of BC and to assess the prospects for further research in this area.

Materials and methods. A systematic analysis of modern literature available in the PubMed database was conducted.

Results and conclusion. A small part of BC cases is associated with hereditary syndromes, which are characterized by BC development. Genes regulating cellular metabolism, DNA repair, and cell cycle are associated with BC. Today, there is a clear understanding that high-risk genes are rarely involved in the development of most BC cases, but there are many polymorphic loci with low penetrance and moderate effects that acting together increase BC risk, indicating a complex polygenic inheritance pattern for this disease.

About the authors

A. R. Zaripova

Ufa Federal Research Centre of the Russian Academy of Sciences

Email: marina_berm@mail.ru
ORCID iD: 0000-0001-6975-5151

Institute of Biochemistry and Genetics

Russian Federation, 71 Prospekt Oktyabrya, Ufa 450054

Marina A. Bermisheva

Ufa Federal Research Centre of the Russian Academy of Sciences; Bashkir State Medical University, Ministry of Health of Russia

Author for correspondence.
Email: marina_berm@mail.ru
ORCID iD: 0000-0002-0584-3969

Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences

Russian Federation, 71 Prospekt Oktyabrya, Ufa 450054; 3 Lenina St., Ufa 450008

I. R. Gilyazova

Ufa Federal Research Centre of the Russian Academy of Sciences; Bashkir State Medical University, Ministry of Health of Russia

Email: marina_berm@mail.ru
ORCID iD: 0000-0001-9499-5632

Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences

Russian Federation, 71 Prospekt Oktyabrya, Ufa 450054; 3 Lenina St., Ufa 450008

A. A. Izmailov

Republican Clinical Oncology Dispensary, Ministry of Health of the Republic of Bashkortostan, Ufa

Email: marina_berm@mail.ru
ORCID iD: 0000-0002-8461-9243
Russian Federation, 73/1 Prospekt Oktyabrya, Ufa 450054

References

  1. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209–49. doi: 10.3322/caac.21660
  2. State of oncological care in Russia in 2022. Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shachzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022. 239 p. (In Russ.).
  3. Malignant tumors in Russia in 2021 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, G.V. Petrova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022. 252 p. (In Russ.).
  4. Knowles M.A., Hurst C.D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015;15(1):25–41. doi: 10.1038/nrc3817
  5. Sylvester R.J., van der Meijden A.P.M., Oosterlinck W. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49(3):466–77. doi: 10.1016/j.eururo.2005.12.031
  6. Mitash N., Agnihotri S., Mittal B. et al. Molecular cystoscopy: micro-RNAs could be a marker for identifying genotypic changes for transitional cell carcinoma of the urinary bladder. Indian J Urol 2016;32(2):149. doi: 10.4103/0970-1591.174775
  7. Lobo N., Mount C., Omar K. et al. Landmarks in the treatment of muscle-invasive bladder cancer. Nat Rev Urol 2017;14(9):565–74. doi: 10.1038/nrurol.2017.82
  8. Freedman N.D. Association between smoking and risk of bladder cancer among men and women. JAMA 2011;306(7):737. doi: 10.1001/jama.2011.1142
  9. Fraumeni J.F. Malignant bladder tumors in a man and his three sons. JAMA J Am Med Assoc 1967;201(7):507. doi: 10.1001/jama.1967.03130070027006
  10. Koutros S., Decker K.L., Baris D. et al. Bladder cancer risk associated with family history of cancer. Int J Cancer 2021;148(12):2915–23. doi: 10.1002/ijc.33486
  11. Pemov A., Wegman-Ostrosky T., Kim J. et al. Identification of genetic risk factors for familial urinary bladder cancer: an exome sequencing study. JCO Precis Oncol 2021;(5):1830–9. doi: 10.1200/PO.21.00115
  12. Nassour A.J., Jain A., Hui N. et al. Relative risk of bladder and kidney cancer in Lynch syndrome: systematic review and meta-analysis. Cancers (Basel) 2023;15(2):506. doi: 10.3390/cancers15020506
  13. Lynch H.T., Snyder C.L., Shaw T.G. et al. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 2015;15(3):181–94. doi: 10.1038/nrc3878
  14. Kunkel T.A., Erie D.A. Eukaryotic mismatch repair in relation to DNA replication. Annu Rev Genet 2015;49(1):291–313. doi: 10.1146/annurev-genet-112414-054722
  15. Li K., Luo H., Huang L. et al. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 2020;20:16. doi: 10.1186/s12935-019-1091-8
  16. Reyes G.X., Schmidt T.T., Kolodner R.D., Hombauer H. New insights into the mechanism of DNA mismatch repair. Chromosoma 2015;124:443–62. doi: 10.1007/s00412-015-0514-0
  17. Pecina-Šlaus N., Kafka A., Salamon I., Bukovac A. Mismatch repair pathway, genome stability and cancer. Front Mol Biosci 2020;7:122. doi: 10.3389/fmolb.2020.00122
  18. Duraturo F., Liccardo R., De Rosa M. et al. Genetics, diagnosis and treatment of Lynch syndrome: old lessons and current challenges (Review). Oncol Lett 2019;17(3):3048–54. doi: 10.3892/ol.2019.9945
  19. Wischhusen J.W., Ukaegbu C., Dhingra T.G. et al. Clinical factors associated with urinary tract cancer in individuals with Lynch Syndrome. Cancer Epidemiol Biomarkers Prev 2020;29(1):193–9. doi: 10.1158/1055-9965.EPI-19-0213
  20. Van der Post R.S., Kiemeney L.A., Ligtenberg M.J.L. et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 2010;47:464–70. doi: 10.1136/jmg.2010.076992
  21. Skeldon S.C., Semotiuk K., Aronson M. et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol 2013;63(2):379–85. doi: 10.1016/j.eururo.2012.07.047
  22. Møller P., Seppälä T.T., Bernstein I. et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 2018;67:1306–16. doi: 10.1136/gutjnl-2017-314057
  23. Schmidt M.H., Pearson C.E. Disease-associated repeat instability and mismatch repair. DNA Repair 2016;38:117–2. doi: 10.1016/j.dnarep.2015.11.008
  24. Hause R.J., Pritchard C.C., Shendure J., Salipante S.J. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016;22:1342–50. doi: 10.1038/nm.4191
  25. McGrail D.J., Garnett J., Yin J. et al. Proteome instability is a therapeutic vulnerability in mismatch repair-deficient cancer. Cancer Cell 2020;37:371–86.e12. doi: 10.1016/j.ccell.2020.01.011
  26. Yamamoto H., Imai K. An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol 2019;46:261–70. doi: 10.1053/j.seminoncol.2019.08.003
  27. Rosenthal S.H., Sun W., Zhang K. et al. Development and validation of a 34-gene inherited cancer predisposition panel using next-generation sequencing. Biomed Res Int 2020:3289023. doi: 10.1155/2020/3289023
  28. Gripp K.W., Morse L.A., Axelrad M. et al. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am J Med Genet Part A 2019;179(9):1725–44. doi: 10.1002/ajmg.a.61270
  29. Aoki Y., Niihori T., Kawame H. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005;37(10):1038–40. doi: 10.1038/ng1641
  30. Bertola D., Buscarilli M., Stabley D.L. et al. Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp. Am J Med Genet Part A 2017;173(5):1309–18. doi: 10.1002/ajmg.a.38178
  31. Gripp K.W., Kolbe V., Brandenstein L.I. et al. Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics. Clin Genet 2017;92(3):332–7. doi: 10.1111/cge.12980
  32. Astiazaran-Symonds E., Ney G.M., Higgs C. et al. Cancer in Costello syndrome: a systematic review and meta-analysis. Br J Cancer 2023;128(11):2089–96. doi: 10.1038/s41416-023-02229-7
  33. Andreou A., Lamy A., Layet V. et al. Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (Pro253Arg). Am J Med Genet A 2006;140:2245–7. doi: 10.1002/ajmg.a.31430
  34. Morak M., Heidenreich B., Keller G. et al. Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet 2014;22(11):1334–7. doi: 10.1038/ejhg.2014.15
  35. Win A.K., Reece J.C., Dowty J.G. et al. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer 2016;139(7):1557–63. doi: 10.1002/ijc.30197
  36. Nassar A.H., Abou Alaiwi S., AlDubayan S.H. et al. Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma. Genet Med 2020;22(4):709–18. doi: 10.1038/s41436-019-0720-x
  37. Carlo M.I., Ravichandran V., Srinavasan P. et al. Cancer susceptibility mutations in patients with urothelial malignancies. J Clin Oncol 2020;38(5):406–14. doi: 10.1200/JCO.19.01395
  38. Prakash R., Zhang Y., Feng W. et al. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol 2015;7(4):a016600. doi: 10.1101/cshperspect.a016600
  39. Loizidou M.A., Neophytou I., Papamichael D. et al. The mutational spectrum of Lynch syndrome in Cyprus. PLoS One 2014;9(8):e105501. doi: 10.1371/journal.pone.0105501
  40. Andersen S.D., Liberti S.E., Lützen A. et al. Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. Hum Mutat 2012;33(12):1647–55. doi: 10.1002/humu.22153
  41. Meijers-Heijboer H., van den Ouweland A., Klijn J. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002;31(1):55–9. doi: 10.1038/ng879
  42. Bermisheva M., Takhirova Z., Bogdanova N., Khusnutdinova E. Frequency of mutations in the CHEK2 gene in breast cancer patients from the Republic of Bashkortostan. Molekulyarnaya biologiya = Molecular Biology 2014;48(1):55–61. (In Russ.). doi: 10.7868/S0026898414010029
  43. Sweis R.F., Heiss B., Segal J. et al. Clinical activity of olaparib in urothelial bladder cancer with DNA damage response gene mutations. JCO Precis Oncol 2018;2:1–7. doi: 10.1200/PO.18.00264
  44. Abbas N., Chehade L., Shamseddine A. Personalized treatment with PARP inhibitors in advanced urothelial carcinoma: a case report and literature review. Ther Adv Med Oncol 2024;16:1–8. doi: 10.1177/17588359241245283
  45. Tripathi A., Lerner S.P. Poly(ADP-ribose)polymerase inhibition in advanced urothelial carcinoma. JCO Precis Oncol 2023;7:e2300293. doi: 10.1200/PO.23.00293
  46. Fabbri L., Bost F., Mazure N.M. Primary cilium in cancer hallmarks. Int J Mol Sci 2019;20(6):1336. doi: 10.3390/ijms20061336
  47. Higgins M., Obaidi I., McMorrow T. Primary cilia and their role in cancer (Review). Oncol Lett 2019;17(3):3041–7. doi: 10.3892/ol.2019.9942
  48. Liu H., Kiseleva A.A., Golemis E.A. Ciliary signalling in cancer. Nat Rev Cancer 2018;18(8):511–24. doi: 10.1038/s41568-018-0023-6
  49. Andrew A.S., Gui J., Sanderson A.C. et al. Bladder cancer SNP panel predicts susceptibility and survival. Hum Genet 2009;125(5–6): 527–39. doi: 10.1007/s00439-009-0645-6
  50. Goetz S.C., Anderson K.V. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 2010;11(5):331–44. doi: 10.1038/nrg2774
  51. Ishikawa H., Marshall W.F. Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 2011;12(4):222–34. doi: 10.1038/nrm3085
  52. Youn Y.H., Hou S., Wu C.C. et al. Primary cilia control translation and the cell cycle in medulloblastoma. Genes Dev 2022;36(11–12): 737–51. doi: 10.1101/gad.349596.122
  53. De Maturana E.L., Rava M., Anumudu C. et al. Bladder cancer genetic susceptibility. A systematic review. Bladder Cancer 2018;4(2):215–26. doi: 10.3233/BLC-170159
  54. Selinski S., Blaszkewicz M., Ickstadt K. et al. Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer. Carcinogenesis 2017;38(12):1167–79. doi: 10.1093/carcin/bgx102
  55. Figueroa J.D., Middlebrooks C.D., Banday A.R. et al. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. Hum Mol Genet 2016;25(6):1203–14. doi: 10.1093/hmg/ddv492
  56. Figueroa J.D., Ye Y., Siddiq A. et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 2014;23(5):1387–98. doi: 10.1093/hmg/ddt519
  57. Rafnar T., Sulem P., Thorleifsson G. et al. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer. Hum Mol Genet 2014;23(20):5545–57. doi: 10.1093/hmg/ddu264
  58. Rothman N., Garcia-Closas M., Chatterjee N. et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 2010;42(11):978–84. doi: 10.1038/ng.687
  59. Wu X., Ye Y., Kiemeney L.A. et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet 2009;41(9):991–5. doi: 10.1038/ng.421
  60. Kiemeney L.A., Sulem P., Besenbacher S. et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 2010;42(5):415–9. doi: 10.1038/ng.558
  61. Matsuda K., Takahashi A., Middlebrooks C.D. et al. Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population. Hum Mol Genet 2015;24(4):1177–84. doi: 10.1093/hmg/ddu512
  62. Wang M., Li Z., Chu H. et al. Genome-wide association study of bladder cancer in a Chinese cohort reveals a new susceptibility locus at 5q12.3. Cancer Res 2016;76(11):3277–84. doi: 10.1158/0008-5472.CAN-15-2564
  63. Wu J., Wang M., Chen H. et al. The rare variant rs35356162 in UHRF1BP1 increases bladder cancer risk in han Chinese population. Front Oncol 2020;10:134. doi: 10.3389/fonc.2020.00134
  64. Chen M., Rothman N., Ye Y. et al. Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development. Genes Cancer 2016;7(7–8): 229–39. doi: 10.18632/genesandcancer.113
  65. García-Closas M., Malats N., Silverman D. et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366(9486):649–59. doi: 10.1016/S0140-6736(05)67137-1
  66. Moore L.E., Baris D.R., Figueroa J.D. et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis 2011;32(2):182–9. doi: 10.1093/carcin/bgq223
  67. Koutros S., Kiemeney L.A., Pal Choudhury P. et al. Genome-wide association study of bladder cancer reveals new biological and translational insights. Eur Urol 2023;84(1):127–37. doi: 10.1016/j.eururo.2023.04.020
  68. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507(7492):315–22. doi: 10.1038/nature12965
  69. Kourie H.R., Zouein J., Succar B. et al. Genetic polymorphisms involved in bladder cancer: a global review. Oncol Rev 2023;17:10603. doi: 10.3389/or.2023.10603
  70. Larsson S.C., Chen J., Ruan X. et al. Genome-wide association study and Mendelian randomization analyses reveal insights into bladder cancer etiology. JNCI Cancer Spectrum 2025;9(2):pkaf014. doi: 10.1093/jncics/pkaf014

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2026 Zaripova A.R., Bermisheva M.A., Gilyazova I.R., Izmailov A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-36986 от  21.07.2009.