Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.

<h4>Background</h4>Coding region microsatellite instability (MSI) results in loss of gene products and promotion of microsatellite-unstable (MSI-H) carcinogenesis. Recent studies have indicated that MSI within 3'-untranslated regions (3'UTRs) may post-transcriptionally dysregul...

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Autores principales:	Bogdan C Paun, Yulan Cheng, Barbara A Leggett, Joanne Young, Stephen J Meltzer, Yuriko Mori
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/576e470d9b5e4cc4bd997916c221ac2c
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spelling	oai:doaj.org-article:576e470d9b5e4cc4bd997916c221ac2c2021-11-25T06:28:22ZScreening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.1932-620310.1371/journal.pone.0007715https://doaj.org/article/576e470d9b5e4cc4bd997916c221ac2c2009-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19888451/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Coding region microsatellite instability (MSI) results in loss of gene products and promotion of microsatellite-unstable (MSI-H) carcinogenesis. Recent studies have indicated that MSI within 3'-untranslated regions (3'UTRs) may post-transcriptionally dysregulate gene products. Within this context, we conducted a broad mutational survey of 42 short 3'UTR microsatellites (MSs) in 45 MSI-H colorectal tumors and their corresponding normal colonic mucosae.<h4>Methodology/principal findings</h4>In order to estimate the overall susceptibility of MSs to MSI in MSI-H tumors, the observed MSI frequency of each MS was correlated with its length, interspecies sequence conservation level, and distance from some genetic elements (i.e., stop codon, polyA signal, and microRNA binding sites). All MSs were stable in normal colonic mucosae. The MSI frequency at each MS in MSI-H tumors was independent of sequence conservation level and distance from other genetic elements. In contrast, MS length correlated significantly with MSI frequency in MSI-H tumors (r=0.86, p=7.2x10(-13)). 3'UTR MSs demonstrated MSI frequencies in MSI-H tumors higher than the 99% upper limit predicted by MS length for RB1-inducible coiled-coil 1(RB1CC1, mutation frequency 68.4%), NUAK family SNF1-like kinase 1(NUAK1, 31.0%), and Rtf1, Paf1/RNA polymerase II complex component, homolog (RTF1, 25.0%). An in silico prediction of RNA structure alterations was conducted for these MSI events to gauge their likelihood of affecting post-transcriptional regulation. RB1CC1 mutant was predicted to lose a microRNA-accessible loop structure at a putative binding site for the tumor-suppressive microRNA, miR-138. In contrast, the predicted 3'UTR structural change was minimal for NUAK1- and RTF1 mutants. Notably, real-time quantitative RT-PCR analysis revealed significant RB1CC1 mRNA overexpression vs. normal colonic mucosae in MSI-H cancers manifesting RB1CC1 3'UTR MSI (9.0-fold; p = 3.6x10(-4)).<h4>Conclusions</h4>This mutational survey of well-characterized short 3'UTR MSs confirms that MSI incidence in MSI-H colorectal tumors correlates with MS length, but not with sequence conservation level or distance from other genetic elements. This study also identifies RB1CC1 as a novel target of frequent mutation and aberrant upregulation in MSI-H colorectal tumors. The predicted loss of a microRNA-accessible structure in mutant RB1CC1 RNA fits the hypothesis that 3'UTR MSI involves in aberrant RB1CC1 posttranscriptional upregulation. Further direct assessments are indicated to investigate this possibility.Bogdan C PaunYulan ChengBarbara A LeggettJoanne YoungStephen J MeltzerYuriko MoriPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 11, p e7715 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bogdan C Paun Yulan Cheng Barbara A Leggett Joanne Young Stephen J Meltzer Yuriko Mori Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
description	<h4>Background</h4>Coding region microsatellite instability (MSI) results in loss of gene products and promotion of microsatellite-unstable (MSI-H) carcinogenesis. Recent studies have indicated that MSI within 3'-untranslated regions (3'UTRs) may post-transcriptionally dysregulate gene products. Within this context, we conducted a broad mutational survey of 42 short 3'UTR microsatellites (MSs) in 45 MSI-H colorectal tumors and their corresponding normal colonic mucosae.<h4>Methodology/principal findings</h4>In order to estimate the overall susceptibility of MSs to MSI in MSI-H tumors, the observed MSI frequency of each MS was correlated with its length, interspecies sequence conservation level, and distance from some genetic elements (i.e., stop codon, polyA signal, and microRNA binding sites). All MSs were stable in normal colonic mucosae. The MSI frequency at each MS in MSI-H tumors was independent of sequence conservation level and distance from other genetic elements. In contrast, MS length correlated significantly with MSI frequency in MSI-H tumors (r=0.86, p=7.2x10(-13)). 3'UTR MSs demonstrated MSI frequencies in MSI-H tumors higher than the 99% upper limit predicted by MS length for RB1-inducible coiled-coil 1(RB1CC1, mutation frequency 68.4%), NUAK family SNF1-like kinase 1(NUAK1, 31.0%), and Rtf1, Paf1/RNA polymerase II complex component, homolog (RTF1, 25.0%). An in silico prediction of RNA structure alterations was conducted for these MSI events to gauge their likelihood of affecting post-transcriptional regulation. RB1CC1 mutant was predicted to lose a microRNA-accessible loop structure at a putative binding site for the tumor-suppressive microRNA, miR-138. In contrast, the predicted 3'UTR structural change was minimal for NUAK1- and RTF1 mutants. Notably, real-time quantitative RT-PCR analysis revealed significant RB1CC1 mRNA overexpression vs. normal colonic mucosae in MSI-H cancers manifesting RB1CC1 3'UTR MSI (9.0-fold; p = 3.6x10(-4)).<h4>Conclusions</h4>This mutational survey of well-characterized short 3'UTR MSs confirms that MSI incidence in MSI-H colorectal tumors correlates with MS length, but not with sequence conservation level or distance from other genetic elements. This study also identifies RB1CC1 as a novel target of frequent mutation and aberrant upregulation in MSI-H colorectal tumors. The predicted loss of a microRNA-accessible structure in mutant RB1CC1 RNA fits the hypothesis that 3'UTR MSI involves in aberrant RB1CC1 posttranscriptional upregulation. Further direct assessments are indicated to investigate this possibility.
format	article
author	Bogdan C Paun Yulan Cheng Barbara A Leggett Joanne Young Stephen J Meltzer Yuriko Mori
author_facet	Bogdan C Paun Yulan Cheng Barbara A Leggett Joanne Young Stephen J Meltzer Yuriko Mori
author_sort	Bogdan C Paun
title	Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
title_short	Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
title_full	Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
title_fullStr	Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
title_full_unstemmed	Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.
title_sort	screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the rb1-inducible coiled-coil 1 gene in colon tumors.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/576e470d9b5e4cc4bd997916c221ac2c
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Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.

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