The role of functional polymorphisms in immune response genes as biomarkers of bacille Calmette-Guérin (BCG) immunotherapy outcome in bladder cancer: establishment of a predictive profile in a Southern Europe population

BJU Int. 2015 Nov;116(5):753-63. doi: 10.1111/bju.12844. Epub 2015 May 13.

Abstract

Objective: To evaluate the predictive value of genetic polymorphisms in the context of bacille Calmette-Guérin (BCG) immunotherapy outcome and create a predictive profile that may allow discrimination of the risk of recurrence.

Patients and methods: In a dataset of 204 patients treated with BCG, we evaluated 42 genetic polymorphisms in 38 genes involved in the BCG mechanism of action, using Sequenom MassARRAY(®) technology. Stepwise multivariate Cox regression was used for data mining.

Results: In agreement with previous studies we found that gender, age, tumour multiplicity and treatment scheme were associated with BCG failure. Using stepwise multivariate Cox regression analysis we propose the first predictive profile of BCG immunotherapy outcome and a risk score based on polymorphisms in immune system molecules [single nucleotide polymorphisms in tumour necrosis factor α (TNFA)-1031T/C (rs1799964), interleukin 2 receptor α (IL2RA) rs2104286 T/C, IL17A-197G/A (rs2275913), IL17RA-809A/G (rs4819554), IL18R1 rs3771171 T/C, intercellular adhesion molecule 1 (ICAM-1) K469E (rs5498), Fas ligand (FASL)-844T/C (rs763110) and TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1)-397T/G (rs79037040)] in association with clinicopathological variables. This risk score allows the categorisation of patients into risk groups: patients within the low-risk group have a 90% chance of successful treatment, whereas patients in the high-risk group present a 75% chance of recurrence after BCG treatment.

Conclusion: We have established the first predictive score of BCG immunotherapy outcome combining clinicopathological characteristics and a panel of genetic polymorphisms. Further studies using an independent cohort are warranted. Moreover, the inclusion of other biomarkers may help to improve the proposed model.

Keywords: BCG immunotherapy; bladder cancer; polymorphisms; predictive profile; risk score of recurrence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Administration, Intravesical
  • BCG Vaccine / administration & dosage*
  • Case-Control Studies
  • Europe / epidemiology
  • Fas Ligand Protein / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunotherapy / methods*
  • Intercellular Adhesion Molecule-1 / genetics
  • Interleukin-17 / genetics
  • Interleukin-18 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Male
  • Neoplasm Recurrence, Local
  • Polymorphism, Single Nucleotide / drug effects*
  • Receptors, Interleukin-17 / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Retrospective Studies
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / genetics
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / immunology*
  • White People / genetics*

Substances

  • Adjuvants, Immunologic
  • BCG Vaccine
  • FASLG protein, human
  • Fas Ligand Protein
  • IL17A protein, human
  • IL17RA protein, human
  • IL18R1 protein, human
  • IL2RA protein, human
  • Interleukin-17
  • Interleukin-18 Receptor alpha Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Interleukin-17
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1