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- Deland, Lily, et al.
(författare)
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Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma.
- 2022
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Ingår i: Cancer genomics & proteomics. - : Anticancer Research USA Inc.. - 1109-6535 .- 1790-6245. ; 19:6, s. 711-726
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Tidskriftsartikel (refereegranskat)abstract
- Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusion-positive solid tumors.Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed.Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient.We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse.
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| 2. |
- Keane, Simon, 1991
(författare)
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MOLECULAR AND GENETIC STUDIES OF DLG2 IN NEUROBLASTOMA AND COLORECTAL CANCER
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is one of the most common extra cranial solid tumors in children. It is one of the most common causes of death amongst the pediatric malignancies. There is however a large difference between the low risk neuroblastomas that are easier to treat compared to the high-risk neuroblastomas that are difficult to treat and account for a majority of the deaths. Two common groups of high-risk tumors have different genetic features, one with MYCN amplification and the other with loss of chromosome region 11q. Despite these two genetic alterations account for a high percentage of the total neuroblastoma cases they rarely occur together. Additionally, tumors with loss of 11q also tend to have decreased genome stability, resulting in increased DNA breakage. Currently, a number of candidate 11q tumor suppressor genes have been proposed, however, none of them have by themselves been able to explain the aggressive behavior of 11q-deleted neuroblastoma. For this reason, we identified and characterized DLG2, a novel tumor suppressor gene residing in the 11q-deleted region (Paper I). DLG2 resides on the reverse strand at the proximal edge of the 11q deleted region. We continued to show that there are a number of different isoforms of DLG2 with isoform 2 and isoform 7/8 the major isoforms expressed in neuroblastoma. The expression of isoform 2 remained stable so the decrease in DLG2 expression in neuroblastoma could be attributed to the loss of isoform 7/8, which alters the interactive ability of DLG2 (Paper II). In order to further elucidate the impact of DLG2 loss on DNA repair pathways, we investigated the relationship of DLG2 and genome stability by inducing dsDNA breaks by UVC irradiation or by etoposide, a topoisomerase II poison. We showed that loss of DLG2 was sufficient to result in dsDNA breaks without additional stimulus and that DNA break-age was prevented when DLG2 was present, by the removal of cells after the induction of breaks (Paper III). Finally, we showed that DLG2 was silenced by inflammation early in the development of colon cancer. We showed that DLG2 activated the inflammasome and resulted in a decrease in STAT3 phosphorylation in adjacent cells (Paper IV).
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