Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia–associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10−9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10−8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10−9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10−5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)–related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.
Detailed information of samples. Table S2. Analysis of rare coding variants. Table S3. Description and summary of quality control steps of whole-exome sequencing samples. Table S4. Exome sequencing coverage in genes included in the WES analyses. Table S5. Gene-based SKAT-O association test p-values and per gene counts of WES variants that passed filtering steps. Table S6. Gene-based Cochranâ Mantelâ Haenszel association test results based on WES variant counts in Chinese and Europeans. Table S7. Previously reported variants that are likely causal for ALS identified in individuals in our study. Table S8. NEK1, SOD1, TBK1 variants identified in SKAT-O and/or ALS specific variant/gene testing. Table S9. Not previously reported variants of probable/possible/unknown significance in ALS-related genes identified in at least one individual in our study. Table S10. Individuals identified with two or more variants considered relevant for ALS (oligogenic). Table S11. Previously reported variants that are unlikely causal (due to high minor allele frequency) identified in individuals in our study. (XLSX 7252 kb)
There are many resources that contain information about binary interactions between proteins. However, protein interactions are defined by only a subset of residues in any protein. We have implemented a web resource that allows the investigation of protein interactions in the Protein Data Bank structures at the level of Pfam domains and amino acid residues. This detailed knowledge relies on the fact that there are a large number of multidomain proteins and protein complexes being deposited in the structure databases. The resource called iPfam is hosted within the Pfam UK website. Most resources focus on the interactions between proteins; iPfam includes these as well as interactions between domains in a single protein.iPfam is available on the Web for browsing at http://www.sanger.ac.uk/Software/Pfam/iPfam/; the source-data for iPfam is freely available in relational tables via the ftp site ftp://ftp.sanger.ac.uk/pub/databases/Pfam/database_files/.
In humans, congenital spinal defects occur with an incidence of 0.5–1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.
Abstract Acute myeloid leukemia (AML), which is the most common acute leukemia in adults, is a particularly devastating disease that is universally fatal without therapy and has the longest hospital length of stay of any cancer. In addition there are a number of familial diseases described that have as a feature an increased susceptibility to AML. Examples of this are MDS/AML associated with germline mutations in the gene encoding the transcription factor GATA2, the ribosomopathies such as Diamond Blackfan Anemia, and Fanconi Anemia (FA) which is caused by bi-allelic mutations in any of the genes in FA complementation groups. Interestingly genes associated with predisposition to hematological malignancy, such as CEBPA, RUNX1 and GATA2 have also been described as targets of somatic mutation in AML. The application of next-generation whole-genome and whole-exome sequencing is greatly facilitating the dissection of the pathways altered during AML development. The discovery of new classes of mutations is increasing knowledge of the leukemogenesis process, improving disease classification and providing potential therapeutic targets. We have performed whole exome capture and next generation sequencing (NGS) of a series of 96 diagnostic AML samples. Analysis of the NGS data and comparison with genotyping performed using traditional methods, and a custom-designed Sequenom mutation panel, has confirmed the sensitivity and specificity of the NGS approach. Novel variants have been grouped into gene networks using a number of approaches, including pathway analysis, protein interaction databases, and known functional relationships. We have identified novel variants in a number of cancer susceptibility genes, and in particular we are characterising potential pathogenic mutations in a network of genes involved in the pathogenesis of Fanconi Anemia. Given that FA patients have a greatly increased predisposition to AML (at least 600-fold), we are performing functional assays to determine the significance for AML of somatic and germline variants in this network. Data will also be presented describing the clinical characteristics, mutation profile, gene expression signatures, and treatment outcomes for patients with mutations in this network. Citation Format: Anna L. Brown, James X. Gray, Paul Leo, Maung Kway Zeya, Mahmoud Bassal, Grant Engler, Sarah Bray, Brooke Gardiner, Mhairi Marshall, Ing Soo Tiong, Nik Cummings, Andrew Wei, Bik To, Ian Lewis, Alan D'Andrea, Thomas Gonda, Richard D'Andrea. Somatic mutation of cancer susceptibility genes in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 23. doi:10.1158/1538-7445.CANSUSC14-23
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