Genomics Research Of Urologic Cancers

All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells.Comprehensive cancer molecular genetics studies from the perspective of genomics has become the mainstream of current cancer research.With the merit of rapid development and falling cost of second-generation sequencing technology,large-scale systematic multi-omics study for a variety of tumors is no longer out of reach.In this sduty,we applied second-generation sequencing technology to systematically profile the genome,epigenome and transcriptome of kidney cancer,renal pelvis cancer and bladder cancer.We sequenced the exomes of 26 urothelial carcinoma of renal pelvis(UCRP)and provided the first comprehensive catalog of genetic alterations in UCRP.The mutation pattern was defined by a dominant prevalence of C>T transitions and a strong prevalence for transition in male.A total of 421 genes were mutated in at least two cases,and there were 72 genes with 3 or more non-silent somatic mutations.We discovered a variety of genes previously unknown to be mutated in UCRP.Notably,genetic aberrations of the chromatin modification genes(KDM6A,KDM6B,CREBBP and EP300)were identified in 46%of our 26 subjects with UCRP.Our results provided an overview of the genetic basis of UCRP and suggested that aberration of chromatin regulation might be a hallmark of renal pelvis cancer.Next,tumors and matched normal adjacent tissues obtained from 9 bladder urothelial carcinoma patients were profiled for DNA methylation(by modified methylation-specific digital karyotyping(MMSDK))and the expression of mRNAs and miRNAs(by digital gene expression(DGE)sequencing).We showed bladder cancer was mainly marked as small varied DNA methylation level and almost equally expressed mRNAs but more up-regulated miRNAs.By integrated analysis of-omics data,we found that a set of significantly enriched pathways disrupted in bladder urothelial carcinoma,primarily related to“neurogenesis”and“cell differentiation".Furthermore,we identified an intriguing collection of cancer-related genes that were deregulated at the levels of DNA methylation and mRNA expression,and we validated several of these genes(HIC1,SLIT2,RASAL1,and KRT17)by Bisulfite Sequencing PCR and Reverse Transcription qPCR in a panel of 33 bladder cancer samples.Taking the advantage of whole genome sequencing data,we analyzed the mitochondrial genome of 54 kidney cancer patients(mainly ccRCC)and systematically compared the genomic variations between cancer and normal adjacent tissues.We identified 82 somatic mutations in total,and the protein coding region mutations were mostly occupied by the non-silent mutations.The mutation rate in the mitochondrial genome was 48-88 times higher than that of the autosomes.We found 40.7%of 54 kidney cancer patients harbored mutations in D-loop region,where mtDNA replication and transcription regulatory sequences located.Mitochondria were the main venues of oxidative phosphorylation(OXPHOS)and ATP production.A large number of somatic mutations were found in genes encoding OXPHOS proteins,as well as in tRNA and rRNA genes,involving a total of 55.6%of kidney samples.The occurrence of somatic mtDNA mutations was closely related to the patient’s age,the greater the age,the more prone to mtDNA mutations.In summary,these studies not only provide a detailed and comprehensive perspective on how individual cancers have developed,but also demonstrates a paradigm for large-scale cancer genomic studies using second generation sequencing technology.