| 11. |
- Borozan, Ivan, et al.
(författare)
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Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis
- 2022
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 31:1, s. 210-220
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations.Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations.Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes.
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| 12. |
- Lindblad-Toh, Kerstin, et al.
(författare)
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A high-resolution map of human evolutionary constraint using 29 mammals
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 478:7370, s. 476-482
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Tidskriftsartikel (refereegranskat)abstract
- The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate-and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
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| 13. |
- Salmén, Fredrik, 1984-
(författare)
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Spatially resolved and single cell transcriptomics
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, massive parallel sequencing has revolutionized the field of biology and has provided us with a vast number of new discoveries in fields such as neurology, developmental biology and cancer research. A significant area is deciphering gene expression patterns, as well as other aspects of transcriptome information, such as the impact of splice variants and mutations on biological functions and disease development. By applying RNA-sequencing, one can extract this type of information in a large-scale manner. The most recent approaches include high-resolution techniques such as single cell sequencing and in situ methods in order to circumvent the problems with gene expression averaging in homogenized samples, and loss of spatial information.The research in this thesis is focused on the development of a novel genome-wide spatial transcriptomics method. The technique is used for analysis of intact tissue sections as well as single cells from solution, with the aim to combine gene expression and morphological information. In Paper I, the method is described in detail, and it is shown that the method is able to generate spatial high quality data from mouse olfactory bulb tissue sections (a part of the forebrain) as well as from tissue sections from breast cancer samples. In Paper III, we adapt the library preparation method in order to be able to execute it on a robotic workstation, thus increasing the reproducibility and the throughput, and decreasing the hands-on time. In Paper IV, we generate 3D-data from breast cancer samples by serial sectioning. We show that the gene expression can be highly variable along all three axes of a tumor, and we track pathways with specific spatial activity, as well as perform subtype classification with three-dimensional resolution. In Paper II, we present a high-throughput method for single cell transcriptomics of cells in solution. The method is based on the same type of solid surface capture as the tissue protocol described in Papers I, III and IV. Again, we show that we can generate high-quality gene expression data, and connect this to morphological characteristics of the analyzed single cells; both using cultured cells and samples from patients with leukemia.
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