ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
Subject(s)
Carcinoma, Renal Cell/genetics , Genes, Neurofibromatosis 2 , Histone-Lysine N-Methyltransferase/genetics , Histones/metabolism , Kidney Neoplasms/genetics , Nuclear Proteins/genetics , Oxidoreductases, N-Demethylating/genetics , Carcinoma, Renal Cell/pathology , Cell Hypoxia/genetics , Chromatin/metabolism , Gene Expression Regulation, Neoplastic , Histone Demethylases , Humans , Kidney Neoplasms/pathology , Mutation/genetics , Sequence Analysis, DNAABSTRACT
Homozygosity for Slc25a21(tm1a(KOMP)Wtsi) results in mice exhibiting orofacial abnormalities, alterations in carpal and rugae structures, hearing impairment and inflammation in the middle ear. In humans it has been hypothesised that the 2-oxoadipate mitochondrial carrier coded by SLC25A21 may be involved in the disease 2-oxoadipate acidaemia. Unexpectedly, no 2-oxoadipate acidaemia-like symptoms were observed in animals homozygous for Slc25a21(tm1a(KOMP)Wtsi) despite confirmation that this allele reduces Slc25a21 expression by 71.3%. To study the complete knockout, an allelic series was generated using the loxP and FRT sites typical of a Knockout Mouse Project allele. After removal of the critical exon and neomycin selection cassette, Slc25a21 knockout mice homozygous for the Slc25a21(tm1b(KOMP)Wtsi) and Slc25a21(tm1d(KOMP)Wtsi) alleles were phenotypically indistinguishable from wild-type. This led us to explore the genomic environment of Slc25a21 and to discover that expression of Pax9, located 3' of the target gene, was reduced in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice. We hypothesize that the presence of the selection cassette is the cause of the down regulation of Pax9 observed. The phenotypes we observed in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice were broadly consistent with a hypomorphic Pax9 allele with the exception of otitis media and hearing impairment which may be a novel consequence of Pax9 down regulation. We explore the ramifications associated with this particular targeted mutation and emphasise the need to interpret phenotypes taking into consideration all potential underlying genetic mechanisms.
Subject(s)
Dicarboxylic Acid Transporters/genetics , Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/genetics , Mouth Abnormalities/genetics , Otitis Media/genetics , Paired Box Transcription Factors/genetics , Alleles , Animals , Dicarboxylic Acid Transporters/deficiency , Exons , Female , Gene Expression Regulation , Genetic Engineering , Homozygote , Humans , Male , Membrane Transport Proteins/deficiency , Mice , Mice, Knockout , Mitochondrial Membrane Transport Proteins/deficiency , Mouth Abnormalities/pathology , Mutation , Otitis Media/pathology , PAX9 Transcription Factor , Paired Box Transcription Factors/deficiency , Signal TransductionABSTRACT
Labour is an emotional experience and involves both physiological and psychological mechanisms.The pain of labour is severe but despite this its memory diminishes with time.Labour pain has two components: visceral pain which occurs during the early first stage and the second stage of childbirth, and somatic pain which occurs during the late first stage and the second stage.The pain of labour in the first stage is mediated by T10 to L1 spinal segments, whereas that in the second stage is carried by T12 to L1, and S2 to S4 spinal segments.Pain relief in labour is complex and often challenging without regional analgesia.Effective management of labour pain plays a relatively minor role in a woman's satisfaction with childbirth.