Multiple components of PKA and TGF-beta pathways are mutated in pseudomyxoma peritonei

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http://hdl.handle.net/10138/196937

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Saarinen , L , Nummela , P , Thiel , A , Lehtonen , R , Järvinen , P , Järvinen , H , Aaltonen , L A , Lepisto , A , Hautaniemi , S & Ristimaki , A 2017 , ' Multiple components of PKA and TGF-beta pathways are mutated in pseudomyxoma peritonei ' , PLoS One , vol. 12 , no. 4 , 0174898 . https://doi.org/10.1371/journal.pone.0174898

Title: Multiple components of PKA and TGF-beta pathways are mutated in pseudomyxoma peritonei
Author: Saarinen, Lilli; Nummela, Pirjo; Thiel, Alexandra; Lehtonen, Rainer; Järvinen, Petrus; Järvinen, Heikki; Aaltonen, Lauri A.; Lepisto, Anna; Hautaniemi, Sampsa; Ristimaki, Ari
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, Heikki Järvinen / Principal Investigator
University of Helsinki, University of Helsinki
University of Helsinki, II kirurgian klinikka
University of Helsinki, Research Programs Unit
University of Helsinki, Department of Pathology
Date: 2017-04-20
Language: eng
Number of pages: 16
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/196937
Abstract: Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma mainly restricted to the peritoneal cavity and most commonly originating from the appendix. The genetic background of PMP is poorly understood and no targeted treatments are currently available for this fatal disease. While RAS signaling pathway is affected in most if not all PMP cases and over half of them also have a mutation in the GNAS gene, other genetic alterations and affected pathways are, to a large degree, poorly known. In this study, we sequenced whole coding genome of nine PMP tumors and paired normal tissues in order to identify additional, commonly mutated genes and signaling pathways affected in PMP. These exome sequencing results were validated with an ultra-deep amplicon sequencing method, leading to 14 validated variants. The validated results contain seven genes that contribute to the protein kinase A (PKA) pathway. PKA pathway, which also contains GNAS, is a major player of overproduction of mucin, which is the characteristic feature of PMP. In addition to PKA pathway, we identified mutations in six genes that belong to the transforming growth factor beta (TGF-beta) pathway, which is a key regulator of cell proliferation. Since either GNAS mutation or an alternative mutation in the PKA pathway was identified in 8/9 patients, inhibition of the PKA pathway might reduce mucin production in most of the PMP patients and potentially suppress disease progression.
Subject: APPENDICEAL MUCINOUS NEOPLASMS
PROTEIN-KINASE
SOMATIC MUTATIONS
CARNEY COMPLEX
HUMAN CANCER
SEQUENCE
ORIGIN
IDENTIFICATION
GENOME
GRADE
3111 Biomedicine
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