|Year : 2014 | Volume
| Issue : 7 | Page : 89-94
Research progress on bladder cancer molecular genetics
Zhengjun Kang1, Yuhui Li1, Yang Yu1, Zhan Guo2
1 Department of Urology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
2 Department of Urology, Zhengzhou Children's Hospital, Zhengzhou 450053, Henan, China
|Date of Web Publication||29-Nov-2014|
Department of Urology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 3 Kangfu Qian Street, Zhengzhou 450052, Henan
Source of Support: None, Conflict of Interest: None
Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, which threats human health. With the research on bladder cancer molecular genetics, the knowledge of gene modification and the development of molecular detection methods, more tumor markers have been discovered, which may have potential for early diagnosis, clinical examination and prognosis. This article reviews the research progress on bladder cancer molecular genetics.
Keywords: Bladder cancer, marker, oncogene, tumor suppressor gene
|How to cite this article:|
Kang Z, Li Y, Yu Y, Guo Z. Research progress on bladder cancer molecular genetics. J Can Res Ther 2014;10, Suppl S3:89-94
| > Introduction|| |
Bladder cancer is ranking as the fourth most common cancer worldwide and the eighth leading cause of cancer death among men with a male to female ratio of 3:1. In 2014, an estimated 74,690 new cases of bladder cancer and 15,580 estimated deaths will occur in the United States.  In China, the incident rate and mortality rate of bladder cancer rank the highest among tumors of the male urogenital system.  There is also an increasing trend in incidence and mortality rates of bladder cancer. Various risk factors can induce bladder cancer, including geography, environment, race, gender, schistosomiasis infection, smoking, occupational exposure and genetic susceptibility. ,, Tumor progression is a complicated procedure of cancer cell development from normal epithelial cells which involve changes of different genes, including oncogenes, tumor suppressor genes, cell cycle-related genes, apoptosis-related genes and DNA damage repair genes. These are potential tumor markers in clinical practice, and more clinical studies are demanded to confirm their clinical utility. ,, Development of molecular biology has increased the understanding of the mechanism for the bladder cancer. Novel research methods also provided approaches for further studying molecular and genetic mechanisms of bladder cancer. This article reviews the recent advancements in molecular and genetic mechanisms of bladder cancer, emphasizing on genes and factors that are potential being as tumor markers in bladder cancer progression.
| > Molecular and Genetic Changes of Bladder Cancer|| |
Environmental factors could directly or indirectly trigger DNA abnormal alterations of bladder urothelial to induce uncontrolled cell growth and thus activate biological pathways for bladder cancer initiation. , Bladder cancer progression is a multistep process. Molecular and genetic changes are different associated with different stages of the cancer progression. The accumulated abnormal genotypes eventually lead to malignant phenotypes. The molecular and genetic alterations of bladder cancer include two types. The first type of changes is related to low-grade tumors. These changes promote cell proliferation; however they have little or no effects on cell microenvironment, cell differentiation, cell death and apoptosis. Another type of changes is associated with high-grade tumors. These changes cause uncontrolled cell proliferation and deregulation of cell cycle and cell apoptosis, which are closely related to cell differentiation. , Development of cancer cells from normal epithelial cells involves changes in different genes, including oncogene, tumor suppressor gene, cell cycle-related gene, apoptosis-related gene and DNA damage repair gene. 
| > Oncogene|| |
Oncogene has the potential to cause cancer; its products are mainly kinase receptors or growth factors and their receptors. These products play important roles in maintaining normal cell signal transduction and cell proliferation. Oncogenes are dominant genes in the malignant phenotype.  When a proto-oncogene converts into oncogene by mutations or other changes, the carcinogenic effect is present through over-expression of gene products or disrupted expression of proteins. Over-expression of protein products from normal proto-oncogenes is the most common carcinogenic mechanism, which makes proto-oncogenes relocated at downstream of the heterologous active promoter by gene amplification or chromosome translocation and thus initiates carcinogenic effects.
Fibroblast growth factors receptor 3
Fibroblast growth factors (FGFs) are a large family of polypeptides, which are key regulators of cell proliferation, migration and differentiation.  At present, FGF receptors (FGFR) family has four members, each of which is encoded by independent gene on different chromosomes.  FGFR gene locates on 4pl6.3.  FGF receptor 3 (FGFR3) is highly conserved and is composed of intracellular tyrosine kinase activity domain, a transmembrane domain and extracellular ligand binding domain. The gene consists of 19 exons, and the mutation of coding region causes the changes of amino acid composition and thus leads to sustained activation of the receptor. Mutation of FGFR3 could lead to activation of MAPK and phosphatidylinositol 3-kinase (PI3K).  Gene mutations of FGFR3 and Ras are mutually exclusive events, which mean that they could have biological equivalence.  In 82% of noninvasive urothelial bladder carcinoma, only one of Ras and FGFR3 mutates, which indicates that different types of noninvasive urothelial bladder carcinomas may share the same biological mechanism.  In bladder urothelial papilloma and urothelial bladder carcinoma Ta staging, approximately 68-88% had FGFR3 mutations, while, in T1 stage of urothelial bladder carcinoma, about 20% had mutations, and about 16% had mutations in T2-T4 stages.  Recent studies showed that FGFR3 expression was significantly related with staging. Other reports demonstrated that FGFR3 mutation is crucial in bladder urothelial papilloma initiation, but not tumor progression.  Given that FGFR3 mutation is an early event in bladder cancer initiation, urinalysis of this gene mutation may have high sensitivity and specificity in the diagnosis of low-grade malignant bladder cancer. Since many types of superficial bladder cancer have FGFR3 mutation, treatment targeting this gene could have potential clinical application value for early stage bladder cancer. 
Murine double minute 2
The murine double minute 2 (MDM2) gene is located on the long arm of chromosome 12ql3-14, encoding a 9 kDa nuclear protein MDM2 (p90). MDM2-p53 binding can negatively regulate the transcriptional activity of p53, form a negative feedback to prevent p53 over activation and block p53-induced apoptosis.  The gene copy number of MDM2 increased in 4-6% of urothelial carcinomas. In urothelial bladder carcinoma, the over-expression of this gene may be associated to the deactivation of p53. However, there are controversies about the association between up-regulated expression of MDM2 in urothelial bladder carcinoma with tumor stage and prognosis.  It is reported that over-expression of MDM2 is highly related to highly differentiated and early stage bladder cancer, whereas in advanced and highly malignant bladder cancer, the expression of MDM2 is low. ,, It is generally believed that high expression of MDM2 does not provide clinical pathology with independent information regarding prognosis. Nevertheless, combined MDM2 and p53 would be a prognostic marker for bladder cancer progression and prognostic survival. 
Myc gene is located on the long arm of chromosome 8, encoding nuclear phosphoproteins. Its family members are important cell proliferation regulators.  Myc could promote the expression of cyclin D and cyclin-dependent kinase 4, the two formed complex and phosphorylated retinal blastoma (RB) protein and promoted the release of transcription factor E2F.  Over-expression of Myc is found in some high-grade urothelial bladder carcinomas. Chromosome fluorescence in situ hybridization and comparative genomic hybridization analysis found increasing copies of chromosome 8 long arm in some invasive urothelial bladder carcinomas.  Recent studies showed that stability of Myc has universal significance in malignant tumors. However, there has been no clear conclusion about the association between over-expression of Myc with bladder cancer grading, recurrence and survival rate. 
DNA analysis on bladder urothelial cancer T-24 cells discovered the first human oncogene Ras. Ras gene family is composed of H-ras, K-ras and N-ras. Proteins encoded by these all have oncogenic function, but only H-ras mutation is closely related to bladder cancer. , Ras protein is a guanine nucleotide binding protein, with a similar function to G protein. Protein products after H-ras mutation maintain GTP binding activity but lose GTP hydrolysis activity, and thus lead to sustained activation of G protein, incessant transduction of mitosis signal and over-proliferation of cells. Point mutation is usually located at codon 12 (glycine-valine) on H-ras gene, codon 13 (glycine-cystine) and codon 61 (glutamine-arginine, lysine or leucine). , Some believe that over-expression of H-ras is related to recurrence of noninvasive urothelial bladder carcinoma. , In vitro study showed that H-ras could up-regulate expression of tumor cell epidermal growth factor (EGF) and could induce invasive phenotype.  The expression of mutated H-ras in urothelium of transgenic mice caused noninvasive bladder urothelial papilloma but not invasive urothelial bladder carcinoma. 
ERBB-2 (human epidermal growth factor receptor 2/neu)
The erythroblastic leukemia viral oncogene homolog (ErbB)-2, also called human epidermal growth factor receptor 2 or neu gene, is located on 17q21. It encodes an 185 kD transmembrane phosphorylated nuclear protein with tyrosine kinase activity. This protein is homologous to EGF receptor, can also stimulate cell growth.  Its ligands are members of neuregulin family (NRG1, NRG2).  In the tumor tissues of urothelial bladder carcinoma patients, ErbB-2 gene amplified and its protein products over-expressed.  Many research findings showed that ErbB-2 was associated with tumor grading, metastasis and patients' survival rate.  Some reports indicated that this gene was an independent prognostic factor in invasive urothelial bladder carcinoma. Other research found that this gene had no correlation with grading of invasive urothelial bladder carcinoma or patients' survival rate. , The over-expression of ErbB-2 on the surface of the cell membrane makes it a potential target for immunotherapy. 
p63 is a homology to p53 and located at 3q27-29. It regulates cell cycle arrest and apoptosis. It encodes two isoforms, including transcriptional active p63 (TA p63) and dominant-negative p63 (∆p63).  Among them, ∆p63 inhibits trans-activation of p53 and TA p63. TA p63 is actually rarely expressed, and ∆p63 represents gene expression of p63.  p63 is rarely mutated, while, in over 60% of the tumors, p63 is silenced by the epigenetics alterations. On the contrary, in the urothelial bladder carcinoma cell line and bladder tumor tissues, ∆p63 is highly expressed whereas it is hardly detected in the normal bladder epithelium.  Further research found that the silent expression of p63 is significantly related to the degree of tumor differentiation and the invasive depth.  In the noninvasive urothelial bladder carcinoma, only 16% of tumor cells express p63. During tumor progression, p63 controls intracellular adhesion, and it is related to staging, grading and lymphatic metastasis of urothelial bladder carcinoma.  Nevertheless, in a multivariate analysis, p63 could not be applied as an independent prognostic marker for bladder cancer patients. 
| > Tumor Suppressor Gene|| |
Cell growth and proliferation is the result of balancing promoting effect regulated by oncogenes and inhibitory effect regulated by tumor suppressor genes. Oncogenes cause cancer by activation mechanism whereas tumor suppressor genes induces cancer formation by gene inactivation. For instance, the inactivation of tumor suppressor genes lead to uncontrollable cell proliferation and cells could uncontrolledly grow under regulation of oncogenes. The most focused are p53 and the RB gene. 
The RB gene is isolated and identified as the first tumor suppressor gene. It is located at 13q14, encoding nuclear phosphoprotein with 110 kD. , RB protein is commonly expressed in the normal tissues. RB protein is in nonphosphorylated state at G1 phase, and it is phosphorylated from late G1 phase to the later stage of mitosis followed by de-phosphorylation. In G1 phase, RB protein binds and activates transcriptional factor E2F, which inhibits gene expression of some DNA synthesis-promoting genes and prevents cells entering S phase. ,, In tumor tissues, RB inactivation or deletion makes tumor cell growth escape G1 checkpoint. RB gene mutation is not common in bladder cancer. Instead, the homozygous deletion or down-regulation of RB protein in invasive bladder urothelial carcinoma is common. ,, Recent study indicated that there was no correlation between RB changes in bladder cancer specimen and RB changes in urine sediment specimen from the same patient. Further study showed that RB changes in urine sediment specimen of bladder cancer patients, healthy control patients and patients with cancer in situ remain the same. ,,
p53 gene is located on 17pl3.1, encoding stress-induced phosphoprotein with 53 kD. Normally, p53 protein is a tetramer, preventing cells from G1 phase into S phase by binding DNA to its core domain. During this process, p53 initiates intranuclear p21 transcription and binds p21 to allow repair of damaged DNA by preventing CDK2.  The changes of p53 are the most common genetic changes relating to human tumors. ,, This gene functions as DNA damage detector. p53 becomes a key initiating factor of apoptosis when the damage could not be repaired. In bladder cancer, p53 mutation mostly occurred in invasive urothelial bladder carcinoma, but rarely in noninvasive urothelial bladder carcinoma, which is consistent with RB abnormality.  The inactivation of p53 and RB signaling pathways is probably necessary to the initiation of invasive urothelial bladder carcinoma.  Studies on urothelial bladder carcinoma cell lines showed that these two signaling pathways had different degrees of changes including p53 mutation, pl4 homozygous deletion, RB gene hypermethylation or pl6 homozygous deletion. ,,[ 70] Studies on other 12 invasive urothelial bladder carcinoma tumor tissues showed the same results of two signaling pathway changes. , Mutated p53 protein could not exert cell cycle regulatory function. p53 protein products are hard to detect in normal human tissues while mutated p53 protein has a prolonged half-life and is easily to detect. p53 mutations are related to smoking where p53 mutation spectrum in smoking patients is different from that in nonsmoking patients.  p53 is an important independent prognostic marker. 
Secreted frizzled-related protein 1
Deletion of chromosome 8p is often seen in bladder cancer tissues.  It is usually related to disease progression. Secreted frizzled-related protein 1 (sFRPl) gene, located at 8p, is involved in the regulation of WNT signal pathway, and it is the antagonizing factor of Fz receptor.  Recent cDNA array analyses demonstrated that the sFRPl gene was down-regulated in bladder cancer at location 8pl2-11.1. This phenomenon was confirmed in more than 25% of urothelial carcinomas.  It is mainly caused by methylation of gene promoter domain. It is suggested that sFRPl is a promising target for bladder cancer pathogenesis and patient prognosis, and DNA methylation inhibitors may be a treatment for sFRPl hypermethylated cancer patients. , Down-regulation of sFRPl is associated with tumor high stage, high-grade, poor prognosis and short survival period. ,,
PTEN gene is located at 10q23, encoding a phosphatidylinositol phospholipase. It negatively regulates PI3K-mediated signal transduction.  The inactivation of this gene by loss of heterozygosity (LOH) or mutation is found in high-grade urothelial bladder carcinoma, glioma retinae, melanoma and endometrial cancer.  In transgenic mice with heterozygous deletion, PTEN presented broad proliferation promoting effects.  The PTEN-deficient cell line transfected with PTEN could decrease protein kinase B (AKT/PKB) activity. AKT/PKB, a serine-tyrosine kinase, is involved in PI3K signaling dependent metabolism/proliferation and anti-apoptosis.  After the recovery expression in PTEN-deficient urothelial bladder carcinoma cell line, cell chemotaxis and anchorage-dependent growth are affected. In vivo study showed that PTEN inhibited tumor growth. Studies at cellular level and molecular level found that LOH with 10q and PTEN gene mutation mainly occurred in muscle-invasive urothelial bladder carcinoma.  Recent studies indicated that PTEN deletions may cause aggressive tumor and poor outcome. Thus, PTEN may be a potential prognostic marker in early bladder cancer, , and decreased PTEN may be associated with high-grade and high-stage papillary tumors. 
p16 gene is located on CDKN2/ARF locus at 9p21. It encodes proteins p16 and p14 ARF , negatively regulating RB and p53 pathways. p16 homozygous deletions are found in about 14% noninvasive urothelial bladder carcinoma and can prevent RB and p53 signaling pathways. , Superficial bladder cancer patients with INK4a homozygous deletion have large tumor masses and high recurrence rates.  Besides deletion, methylation of promoter domain is also the reason of silent p16 expression.  Nevertheless, INK4a point mutation or primary methylation does not affect clinical results. Further study revealed antitumor growth effect of systemic transduction of p16INK4A antitumor peptide in bladder tumor cell grafted mouse, indicating a potential treatment for bladder cancer. 
Tuberous sclerosis complex 1
In bladder cancer, 9q34 deletion domain is consistent with tuberous sclerosis complex (TSC1) gene locus. Mutation analysis showed that it might be a target gene in 9q34. TSC1 locus LOH is found in 34% of bladder cancers and a specific point mutation is found in 30% bladder cancers, indicating that TSC1 may be tumor suppressor gene for urothelial bladder carcinoma. ,,,, The heterozygous analysis of 9q22.3 reported that LOH in this region could be related to PTCH.  Recent research suggested that it was related to bladder cancer recurrence by regulating cell cycle through P27KIP1, which could be a potential prognostic marker. ,
| > Conclusion|| |
In summary, the changes of many genes are involved in cancer progression from normal epithelial cells to tumor cells, including oncogene, tumor suppressor gene, cell cycle-related gene, apoptosis-related gene and DNA damage repair-related gene. The development of molecular biology promotes the understanding of bladder cancer pathogenesis. Some new targets with high specificity and high sensitivity have been discovered, some of which have promising clinical values. As bladder cancer molecular markers, the clinical applications are limited. They are usually used as a reference assisting for the testing and more studies are needed to overcome the difficulties. However, novel research approaches and techniques as well as understanding of molecular pathways in disease initiation make people believe that investigations on bladder cancer molecular genetics mechanism can achieve substantial progress in the near future.
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