| 1. |
- Ullah, I., et al.
(författare)
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Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes
- 2018
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 128:4, s. 1355-1370
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, in which multiple metastatic subclones originated from the primary tumor and/or other distant metastases. Synchronous ALN metastasis, a well-established prognosticator of breast cancer, was not involved in seeding the distant metastasis, suggesting a hematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably an increase in apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like-associated (APOBEC-associated) mutagenesis. Our data provide genomic evidence for a role of ALN metastasis in seeding distant organ metastasis and elucidate the evolving mutational landscape during cancer progression.
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| 2. |
- Frånberg, Mattias, 1985-, et al.
(författare)
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Fast and general tests of genetic interaction for genome-wide association studies
- 2017
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Ingår i: PloS Computational Biology. - : PUBLIC LIBRARY SCIENCE. - 1553-734X .- 1553-7358. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- A complex disease has, by definition, multiple genetic causes. In theory, these causes could be identified individually, but their identification will likely benefit from informed use of anticipated interactions between causes. In addition, characterizing and understanding interactions must be considered key to revealing the etiology of any complex disease. Large-scale collaborative efforts are now paving the way for comprehensive studies of interaction. As a consequence, there is a need for methods with a computational efficiency sufficient for modern data sets as well as for improvements of statistical accuracy and power. Another issue is that, currently, the relation between different methods for interaction inference is in many cases not transparent, complicating the comparison and interpretation of results between different interaction studies. In this paper we present computationally efficient tests of interaction for the complete family of generalized linear models (GLMs). The tests can be applied for inference of single or multiple interaction parameters, but we show, by simulation, that jointly testing the full set of interaction parameters yields superior power and control of false positive rate. Based on these tests we also describe how to combine results from multiple independent studies of interaction in a meta-analysis. We investigate the impact of several assumptions commonly made when modeling interactions. We also show that, across the important class of models with a full set of interaction parameters, jointly testing the interaction parameters yields identical results. Further, we apply our method to genetic data for cardiovascular disease. This allowed us to identify a putative interaction involved in Lp(a) plasma levels between two 'tag' variants in the LPA locus (p = 2.42 . 10(-09)) as well as replicate the interaction (p = 6.97 . 10(-07)). Finally, our meta-analysis method is used in a small (N = 16,181) study of interactions in myocardial infarction.
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| 3. |
- Tofigh, Ali, et al.
(författare)
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Detecting LGTs using a novel probabilistic modelintegrating duplications, LGTs, losses, rate variation,and sequence evolution
- 2009
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The debate over the prevalence of lateral gene transfers (LGTs) has been intense.There is now to a large extent consensus around the view that LGT is an important evolutionary force as well as regarding its relative importance across species. This consensus relies, however, mainly on studies of individual gene families.Up until now, the gold standard for identifying LGTs has been phylogenetic methods where LGTs are inferred from incongruities between a species tree andan associated gene tree. Even in cases where there is evidence of LGT, several concerns have often been raised regarding the significance of the evidence. One common concern has been the possibility that other evolutionary events have caused the incongruities. Another has been the significance of the gene trees involved in the inference; there may for instance be alternative, almost equally likely, gene trees that do not provide evidence for LGT. Independently of these concerns, there has been a need for methods that can be used to quantitatively characterize the level of LGT among sets of species, but also for methods able to pinpoint where in the species tree LGTs have occurred.Here, we provide the first probabilistic model capturing gene duplication, LGT,gene loss, and point mutations with a relaxed molecular clock. We also provide allfundamental algorithms required to analyze a gene family relative to a given speciestree under this model. Our algorithms are based on Markov chain Monte Carlo(MCMC) methodology but build also on techniques from numerical analysis and involve dynamic programming (DP).
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