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Re: Sequence Variant on 8q24 Confers Susceptibility to Urinary Bladder Cancer
european urology 55 (2009) 1233–1240
Re: Sequence Variant on 8q24 Confers Susceptibility to Urinary Bladder Cancer Kiemeney LA, Thorlacius S, Sulem P, et al Nat Genet 2008;40:1307–12 Expert’s summary: A genomewide single-nucleotide polymorphism association study was performed on cases of urinary bladder cancer (1803) and controls (34 336) from Iceland and the Netherlands. The obtained results were tested in seven additional case-control groups (2165 cases and 3800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, with a specific odds ratio of 1.22 ( p = 9.34 10 12). Approximately 20% of individuals of European ancestry are homozygous for this marker, and their estimated risk of developing bladder cancer is 1.49 times that of noncarriers. A weaker signal, but of genomewide significance nonetheless, was found on chromosome 3q28 (rs710521[A]). When risk profile was analyzed in a subgroup, those with low-risk tumors had a higher frequency of the chromosome 8 variant than those with high-risk tumors. Expert’s comments: The knowledge of the complete human genome started an intensive search for causal genes for different diseases. In breast and prostate cancers, candidate genes were presented with much attention and, in some cases, were patented. In bladder cancer, the search was focused on chromosome 9, as loss of one copy is a common finding. No candidate gene was presented, and, for the other cancers, it was evident that a single-gene theory was not realistic. It is now known that the genetic background of most cancers is very complex and best described as a landscape of ‘‘mountains and hills’’ [1]. The former are few and represent the genes that are mutated in a large proportion of tumors. Most of the mutations are infrequent and represented in the many hills. Genomewide association studies (GWAS) have recently become very popular, due to high-throughput, cost-effective methods for genotyping. GWAS are defined as any study of genetic variation across
Re: Evaluating the Learning Curve for RobotAssisted Laparoscopic Radical Cystectomy Pruthi RS, Smith A, Wallen EM J Endourol 2008;22:2469–74
1237
the entire human genome that is designed to identify genetic associations with observable traits or the presence or absence of a disease or condition. When assessing genetic alternations, it must also be considered that bladder cancer has a multifactorial etiology, and it was estimated that only 7% of the occurrence is due to genetic effects in the germline [2]. Environmental effects are much stronger, but gene–environment interaction plays a role, as exemplified by the NAT2 enzyme and smoking. Slow acetylation–phenotype individuals have reduced detoxification capacity compared with those with a faster phenotype and have been reported to have a higher risk of smoking-induced bladder cancer [3]. Several other independent GWAS are under way in bladder cancer, and it will be of interest to know if the results of the present study will be reproduced. The experiences from other fields indicate that, as for the single-gene theory, many new association loci will be reported and will complicate matters. The practical results for the individual might not be important if certain variants can be correlated to important clinical issues like high risk of progression. Conflicts of interest: The author has nothing to disclose.
References [1] Wood LD, Williams Parsons D, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007;318:1108–13. [2] Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer 2002;99:260–6. [3] Lubin JH, Kogevinas M, Silverman D, et al. Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study. Int J Epidemiol 2007;36:236–41. Per-Uno Malmstro¨m University Hospital, Urology, Sjukhusva¨gen 1, Uppsala, 75185, Sweden E-mail address: [email protected] DOI: 10.1016/j.eururo.2009.01.056
Expert’s summary: This study from an experienced group describes their learning curve with robot-assisted laparoscopic radical cystectomy. They describe their initial experience with 50 consecutive patients over a
Re: Sequence Variant on 8q24 Confers Susceptibility to Urinary Bladder Cancer Kiemeney LA, Thorlacius S, Sulem P, et al Nat Genet 2008;40:1307–12 Expert’s summary: A genomewide single-nucleotide polymorphism association study was performed on cases of urinary bladder cancer (1803) and controls (34 336) from Iceland and the Netherlands. The obtained results were tested in seven additional case-control groups (2165 cases and 3800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, with a specific odds ratio of 1.22 ( p = 9.34 10 12). Approximately 20% of individuals of European ancestry are homozygous for this marker, and their estimated risk of developing bladder cancer is 1.49 times that of noncarriers. A weaker signal, but of genomewide significance nonetheless, was found on chromosome 3q28 (rs710521[A]). When risk profile was analyzed in a subgroup, those with low-risk tumors had a higher frequency of the chromosome 8 variant than those with high-risk tumors. Expert’s comments: The knowledge of the complete human genome started an intensive search for causal genes for different diseases. In breast and prostate cancers, candidate genes were presented with much attention and, in some cases, were patented. In bladder cancer, the search was focused on chromosome 9, as loss of one copy is a common finding. No candidate gene was presented, and, for the other cancers, it was evident that a single-gene theory was not realistic. It is now known that the genetic background of most cancers is very complex and best described as a landscape of ‘‘mountains and hills’’ [1]. The former are few and represent the genes that are mutated in a large proportion of tumors. Most of the mutations are infrequent and represented in the many hills. Genomewide association studies (GWAS) have recently become very popular, due to high-throughput, cost-effective methods for genotyping. GWAS are defined as any study of genetic variation across
Re: Evaluating the Learning Curve for RobotAssisted Laparoscopic Radical Cystectomy Pruthi RS, Smith A, Wallen EM J Endourol 2008;22:2469–74
1237
the entire human genome that is designed to identify genetic associations with observable traits or the presence or absence of a disease or condition. When assessing genetic alternations, it must also be considered that bladder cancer has a multifactorial etiology, and it was estimated that only 7% of the occurrence is due to genetic effects in the germline [2]. Environmental effects are much stronger, but gene–environment interaction plays a role, as exemplified by the NAT2 enzyme and smoking. Slow acetylation–phenotype individuals have reduced detoxification capacity compared with those with a faster phenotype and have been reported to have a higher risk of smoking-induced bladder cancer [3]. Several other independent GWAS are under way in bladder cancer, and it will be of interest to know if the results of the present study will be reproduced. The experiences from other fields indicate that, as for the single-gene theory, many new association loci will be reported and will complicate matters. The practical results for the individual might not be important if certain variants can be correlated to important clinical issues like high risk of progression. Conflicts of interest: The author has nothing to disclose.
References [1] Wood LD, Williams Parsons D, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007;318:1108–13. [2] Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer 2002;99:260–6. [3] Lubin JH, Kogevinas M, Silverman D, et al. Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study. Int J Epidemiol 2007;36:236–41. Per-Uno Malmstro¨m University Hospital, Urology, Sjukhusva¨gen 1, Uppsala, 75185, Sweden E-mail address: [email protected] DOI: 10.1016/j.eururo.2009.01.056
Expert’s summary: This study from an experienced group describes their learning curve with robot-assisted laparoscopic radical cystectomy. They describe their initial experience with 50 consecutive patients over a