Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2, allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F18%3A00077971" target="_blank" >RIV/00209805:_____/18:00077971 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/65269705:_____/18:00068819

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23390" target="_blank" >https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23390</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/humu.23390" target="_blank" >10.1002/humu.23390</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2, allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

Popis výsledku v původním jazyce

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programswas evaluated. Aberrant splicingwas confirmed for 12 alterations. In silico prediction toolswere helpful to determine for which variantscDNAanalysis iswarranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5&apos; breakpoint in intron 4; 3&apos; breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G &gt; C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

Název v anglickém jazyce

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2, allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

Popis výsledku anglicky

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programswas evaluated. Aberrant splicingwas confirmed for 12 alterations. In silico prediction toolswere helpful to determine for which variantscDNAanalysis iswarranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5&apos; breakpoint in intron 4; 3&apos; breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G &gt; C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LO1413" target="_blank" >LO1413: RECAMO2020</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Human mutation

ISSN

1059-7794

e-ISSN

—

Svazek periodika

39

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

515-526

Kód UT WoS článku

000426727800005

EID výsledku v databázi Scopus

2-s2.0-85043236315