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- Kaasinen, E, et al.
(author)
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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1252-
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Journal article (peer-reviewed)abstract
- Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
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- Law, Philip J., et al.
(author)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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- Palin, K, et al.
(author)
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Contribution of allelic imbalance to colorectal cancer
- 2018
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3664-
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Journal article (peer-reviewed)abstract
- Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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- Cajuso, T, et al.
(author)
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Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4022-
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Journal article (peer-reviewed)abstract
- Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
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- Kaasinen, E, et al.
(author)
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Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: A Nordic study
- 2003
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In: European Urology. - 1873-7560. ; 43:6, s. 637-645
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Journal article (peer-reviewed)abstract
- Objectives: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. Methods: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. Results: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p = 0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p = 0.07) but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. Conclusion: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.
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- da Cunha, E., et al.
(author)
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Measurements of the Dust Properties in z similar or equal to 1-3 Submillimeter Galaxies with ALMA
- 2021
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 919:1
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Journal article (peer-reviewed)abstract
- We present Atacama Large Millimeter/submillimeter Array (ALMA) 2 mm continuum observations of a complete and unbiased sample of 99 870 mu m selected submillimeter galaxies (SMGs) in the Extended Chandra Deep Field South (ALESS). Our observations of each SMG reach average sensitivities of 53 mu Jy beam(-1). We measure the flux densities for 70 sources, for which we obtain a typical 870 mu m-to-2 mm flux ratio of 14 +/- 5. We do not find a redshift dependence of this flux ratio, which would be expected if the dust emission properties of our SMGs were the same at all redshifts. By combining our ALMA measurements with existing Herschel/SPIRE observations, we construct a (biased) subset of 27 galaxies for which the cool dust emission is sufficiently well sampled to obtain precise constraints on their dust properties using simple isothermal models. Thanks to our new 2 mm observations, the dust emissivity index is well constrained and robust against different dust opacity assumptions. The median dust emissivity index of our SMGs is beta similar or equal to 1.9 +/- 0.4, consistent with the emissivity index of dust in the Milky Way and other local and high-redshift galaxies, as well as classical dust-grain model predictions. We also find a negative correlation between the dust temperature and beta, similar to low-redshift observational and theoretical studies. Our results indicate that beta similar or equal to 2 in high-redshift dusty star-forming galaxies, implying little evolution in dust-grain properties between our SMGs and local dusty galaxy samples, and suggesting that these high-mass and high-metallicity galaxies have dust reservoirs driven by grain growth in their interstellar medium.
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