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| 2. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 3. |
- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 4. |
- Duran-Ferrer, Marti, et al.
(författare)
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The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
- 2020
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Ingår i: NATURE CANCER. - : Springer Nature. - 2662-1347. ; 1:11, s. 1066-1081
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Tidskriftsartikel (refereegranskat)abstract
- We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.
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| 5. |
- Aoude, Lauren G, et al.
(författare)
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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:2, s. 408-408
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Tidskriftsartikel (refereegranskat)abstract
- The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
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| 6. |
- Balbin, Milagros, et al.
(författare)
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A sequence variation in the human cystatin D gene resulting in an amino acid (Cys/Arg) polymorphism at the protein level
- 1993
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Ingår i: Human Genetics. - 1432-1203. ; 90:6, s. 668-669
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Tidskriftsartikel (refereegranskat)abstract
- A polymorphism in the coding region of the human cystatin D gene has been detected by direct sequencing of amplified DNA from different individuals. The variation, resulting from a T/C transition in exon 1 of the gene, causes an amino acid variation, Cys/Arg, at the protein level. An allele-specific oligonucleotide hybridization assay was developed and used to demonstrate this polymorphism in the population. The deduced frequencies were 0.55 and 0.45 for the Cys and Arg variant-encoding alleles, respectively.
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| 7. |
- Balbin, Milagros, et al.
(författare)
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Structural and functional characterization of two allelic variants of human cystatin D sharing a characteristic inhibition spectrum against mammalian cysteine proteinases
- 1994
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 269:37, s. 23156-23162
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Tidskriftsartikel (refereegranskat)abstract
- Human cystatin D is a novel member of the cystatin superfamily of cysteine proteinase inhibitors present in saliva and tears. Two alleles of the cystatin D gene (CST5), encoding protein variants with either Cys or Arg as residue 26 in their 122-residue polypeptide chains, are present in the population. Expression of the two alleles was investigated by immunochemical analyses of the secreted cystatin D in saliva from individuals homozygous for each of the two alleles, with results demonstrating that both are expressed at similar levels. The inhibitory characteristics of the two cystatin D variants were studied, by determination of dissociation equilibrium constants (Ki) for their complexes with papain and with the mammalian cysteine proteinases, cathepsins B, H, L, and S. The results demonstrate that 1) cystatin D has a characteristic inhibition profile since it does not inhibit cathepsin B (Ki > 1 microM), and when compared to cystatin C and all other known cystatins it is a much poorer inhibitor of cathepsin L (mean Ki 25 nM) but binds cathepsin H and S relatively tightly (mean Ki values of 8.5 and 0.24 nM, respectively); and 2) the inhibitory activities of the two cystatin D variants are not significantly different, demonstrating that the presence of an extra cysteine residue in the cystatin D molecule affects neither the stability nor the functional activity of the inhibitor, thus explaining the widespread distribution of the Cys26-cystatin D encoding allele in the population. The inhibitory properties displayed by cystatin D suggest that it has a function in saliva as inhibitor of either endogenous or exogenous enzymes with cathepsin S- or H-like properties.
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| 8. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 9. |
- Fluckiger, Aurélie, et al.
(författare)
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Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6506, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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| 10. |
- Freije, José P, et al.
(författare)
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Human cystatin D: cDNA cloning, characterization of the E. coli expressed inhibitor, and identification of the native protein in saliva
- 1993
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 268:21, s. 15737-15744
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Tidskriftsartikel (refereegranskat)abstract
- A cDNA coding for cystatin D, a human member of the cystatin protein family, has been cloned after specific amplification of reverse- transcribed parotid gland RNA. After replacing the segment encoding the putative 20-residue signal peptide with one encoding the Escherichia coli OmpA leader sequence, the cDNA was expressed in E. coli. The isolated recombinant protein exhibited Ki values of 1.2 nM and > 1 microM for papain and cathepsin B, respectively. An antiserum raised against recombinant cystatin D recognized a protein in human saliva with electrophoretical mobility identical to that of the recombinant protein. Immunoenzymatic analysis revealed that this cysteine proteinase inhibitor is present in human saliva and tears at concentrations of 3.8 and 0.5 mg/liter, respectively, while it was not detected in seminal plasma, blood plasma, milk, or cerebrospinal fluid. Cystatin D purified from human saliva by immunosorption displayed a heterogeneous N-terminal end, with sequences starting at residues 5, 7, 9, and 11 of the predicted N-terminal portion of the mature protein. On the basis of structural and functional properties, cystatin D represents a novel cysteine proteinase inhibitor possibly playing a protective role against proteinases present in the oral cavity.
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