Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study

Purpose Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive bi...

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Bibliographic Details
Published in:	Journal of cancer research and clinical oncology Vol. 136; no. 6; pp. 847 - 854
Main Authors:	Jarmalaite, Sonata, Andrekute, Rasa, Scesnaite, Asta, Suziedelis, Kestutis, Husgafvel-Pursiainen, Kirsti, Jankevicius, Feliksas
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01-06-2010 Springer-Verlag Springer Springer Nature B.V
Subjects:	Adult Aged Antineoplastic agents Antineoplastic Agents - therapeutic use Apoptosis Regulatory Proteins - drug effects Apoptosis Regulatory Proteins - genetics Biological and medical sciences Biomarkers Bladder Calcium-Calmodulin-Dependent Protein Kinases - drug effects Calcium-Calmodulin-Dependent Protein Kinases - genetics Cancer Cancer Research Cystoscopy Death-Associated Protein Kinases DNA Methylation - drug effects Female Genes, p16 - drug effects Genes, p53 - drug effects Genes, Tumor Suppressor - drug effects Hematology Humans Immunotherapy Interleukin-2 - therapeutic use Internal Medicine Male Medical prognosis Medical sciences Medicine Medicine & Public Health Middle Aged Mutation - drug effects Nephrology. Urinary tract diseases Oncology Original Paper Pharmacology. Drug treatments Pilot Projects Polymerase Chain Reaction Polymorphism, Single-Stranded Conformational Promoter Regions, Genetic - drug effects Prospective Studies Receptors, Retinoic Acid - drug effects Receptors, Retinoic Acid - genetics Treatment Outcome Tumor Suppressor Proteins - drug effects Tumor Suppressor Proteins - genetics Tumors of the urinary system Urinary Bladder Neoplasms - drug therapy Urinary system involvement in other diseases. Miscellaneous Urinary tract. Prostate gland Tumour suppressor genes Promoter hypermethylation Interleukin-2 gene Bladder cancer Urinary system disease Transcription promoter Cytokine Urinary tract disease Malignant tumor p16 gene Treatment Interleukin 2 Bladder disease Cancer Tumor suppressor gene
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Summary:	Purpose Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2. Methods After complete TURB, patients with multifocal superficial BC were treated with five daily intravesical instillations of IL-2. Promoter hypermethylation in six TSGs and the TP53 gene mutations were prospectively assessed by methylation-specific PCR and automated capillary single-strand conformation polymorphism in 21 primary bladder cancer specimens and ten bladder wall biopsies collected during follow-up. Results After IL-2 treatment, 9 out of 21 (43%) patients did not develop recurrent tumour within the 1 year of follow-up period. The mean duration of recurrence-free survival in the rest of the study group was 112 days. In the current pilot study, BC with p16 gene hypermethylation had a lower risk of recurrence after treatment with IL-2, as compared to IL-2 treated BC without p16 hypermethylation (p = 0.02). Significant associations were observed between tumour grade and the mean methylation index (p = 0.003), as well as the hypermethylation of the RARβ gene (p = 0.048). Conclusion Our preliminary data suggest that DNA methylation biomarkers may assist in selection of BC patients for efficient IL-2 therapy.
Bibliography:	http://dx.doi.org/10.1007/s00432-009-0725-y ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0171-5216 1432-1335
DOI:	10.1007/s00432-009-0725-y