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- La Fleur, Linnea, et al.
(författare)
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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
- 2019
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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| 2. |
- Smeds, Linnea, et al.
(författare)
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The evolutionary history of grey wolf Y chromosomes
- 2019
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Ingår i: Molecular Ecology. - : John Wiley & Sons. - 0962-1083 .- 1365-294X. ; 28:9, s. 2173-2191
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of Y chromosome haplotypes uniquely provide a paternal picture of evolutionary histories and offer a very useful contrast to studies based on maternally inherited mitochondrial DNA (mtDNA). Here we used a bioinformatic approach based on comparison of male and female sequence coverage to identify 4.7 Mb from the grey wolf (Canis lupis) Y chromosome, probably representing most of the male-specific, nonampliconic sequence from the euchromatic part of the chromosome. We characterized this sequence and then identified approximate to 1,500 Y-linked single nucleotide polymorphisms in a sample of 145 resequenced male wolves, including 75 Finnish wolf genomes newly sequenced in this study, and in 24 dogs and eight other canids. We found 53 Y chromosome haplotypes, of which 26 were seen in grey wolves, that clustered in four major haplogroups. All four haplogroups were represented in samples of Finnish wolves, showing that haplogroup lineages were not partitioned on a continental scale. However, regional population structure was indicated because individual haplotypes were never shared between geographically distant areas, and genetically similar haplotypes were only found within the same geographical region. The deepest split between grey wolf haplogroups was estimated to have occurred 125,000 years ago, which is considerably older than recent estimates of the time of divergence of wolf populations. The distribution of dogs in a phylogenetic tree of Y chromosome haplotypes supports multiple domestication events, or wolf paternal introgression, starting 29,000 years ago. We also addressed the disputed origin of a recently founded population of Scandinavian wolves and observed that founding as well as most recent immigrant haplotypes were present in the neighbouring Finnish population, but not in sequenced wolves from elsewhere in the world, or in dogs.
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