Naslov
In silico methods for assessing potential functional impact of human breast cancer gene BRCA2 sequence variants found in 5' untranslated region

Autori
Ozretić, Petar ; Levačić Cvok, Mirela ; Musani, Vesna ; Sabol, Maja ; Car, Diana ; Levanat, Sonja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Proceedings of the Abstracts of The 16th World Congress on Advances in Oncology, and 14th International Symposium on Molecular Medicine / Spandidos, Demetrios A. - Atena : Spandidos Publications, 2011, S33-S33

Skup
16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine 6-8 October, 2011, Hotel Rodos Palace, Rhodes, Greece

Mjesto i datum
Rodos, Grčka, 06.10.2011. - 08.10.2011

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
breast cancer; BRCA2; 5' UTR; secondary structure; prediction

Sažetak
BRCA1 and BRCA2 are major hereditary breast/ovarian cancer predisposing genes and their mutations increase the risk of developing breast and/or ovarian cancer. Genetic testing of those two genes is commonly performed but almost half of found genetic alterations are declared as variants of unknown clinical significance. Interpretation of those unclassified variants is major concern for risk assessment in genetic counseling. In silico methods present fast and cheap alternative for assessing the preliminary clinical significance. Most tools primarily predict the effect of variants found in protein coding regions or exon/intron boundaries. Our intention was to find proper computational method for assessing functional impact of variants found in 5' untranslated region (5' UTR) of mRNA. As the functioning of UTRs depends both on nucleotide sequence and secondary structure, our major premise is that harmful UTR variants would disrupt the RNA substructures requisite for post-transcriptional regulation of protein translation. Using general secondary structure predicting software, consensus BRCA2 5’ UTR secondary structure was built based on wild type sequences from four different species. Consensus structure was used since it is more likely that evolutionary conserved substructures are functionally important. The effect of SNPs was explored by folding human BRCA2 5’ UTR including one of each variant, using consensus structure as a constraint. If constrained folding resulted in structure very different from the consensus one, this particular SNP could have functional impact. Among 13 BRCA2 5' UTR SNPs found in public databases, variants c.-26G>A, c.-26G>C, c.-26G>T and c.-12T>C most notably disturbed consensus structure by creating substructures with higher minimum free energy, thus less stable. As previously demonstrated for c.-26G>A (Gochhait et al, 2007), other three variants could also unstabilize the loop at the vicinity of the translation start site and thereby increase the efficiency of translation and the expression of BRCA2 protein. Accordingly, we suggested these three SNPs as potentially clinically significant. Computational screening for 5’ UTR variants with eventual structural and functional significance is a valuable tool for narrowing a list of candidates for further experimental molecular characterization.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA