Hlutverk RNA smásameinda og sviperfða í brjóstakrabbameini hjá áhættuhópum - verkefni lokið

Fréttatilkynning verkefnisstjóra

16.3.2018

Í rannsókninni var beitt nýrri nálgun á mjög vel skilgreint rannsóknaþýði. Gerð var in situ tölvuleit í skrám um allar þekktar miRNA sameindir. Nokkur miRNA gen fundust á svæðum sem sýna CGH breytileika eða “mögnun” í brjóstaæxlisvef. Þessi gen voru skoðuð m.t.t. methýlunar og tjáningar. Í framhaldi var meðal annars sýnt var fram á yfirtjáningu miR21 smásameindar í brjóstaæxlisvef og vísbendingar um tengsl við sjúkdómshorfur. Sýnt var fram á yfirtjáningu og mismunandi methýlun annarrar RNA smásameindar, miR-190b, í estrogen viðtaka (ER) jákvæðum æxlum, bæði í lumA og LumB æxlisgerðum.

Við höfðum áður sýnt fram á að horfur BRCA2 999del5 arfbera sem greinast með brjóstakrabbamein eru verri í þeim sem hafa ER⁺ viðtaka í æxlisvef, sérstaklega þeim sem hafa lumB æxlisgerð. Nánari greining á metýlun í æxlisvef og eðlilegum brjóstavef sýndi að yfirtjáningu mátti rekja til hypo-metýlunar á stjórnröð miR-190b gensins. Munur á sjúkdómsframvindu reyndist vera milli undirhópa, þannig að hypomethýlun (minnkuð metýlun) á miR-190b stjórnröð (og þá aukin tjáning) tengdist betri horfum í lumA hópnum, en öfugt í einstaklingum með lumB æxlisgerð þar sem aukin methýlun tengist betri horfum en hypomethýlun mjög slæmum. Þessar niðurstöður eru athyglisverðar þar sem lumB æxlisgerðin tengist einmitt mjög slæmum sjúkdómshorfum í brjóstakrabbameini. Í þessu tilfelli virðist miR-190b vinna sem eins konar oncoMIR, þ.e. leiða til illvígrar æxlisframvindu. Mikilvægt er að hægt verði að fylgja þessu eftir með frekari rannsóknum.

English:
The main aim of the project was to identify potential microRNAs that might play a role in the development of high risk breast cancer, such as cancers in carriers of mutations in the BRCA1 or BRCA2 genes. This was to be examined in relation to copy number variation and epigenetic gene inactivation in tumor tissue and, last but not least, with respect to potential clinical relevance. The study was novel and exploratory, focusing on our well-defined cancer cohort. The first steps were to do in silico analyses on all known miRNAs and map to areas of breast cancer associated copy number (CGH) variation. Then to analyse miRNA locations with respect to whole genome methylation patterns in breast tumors.  Promoter regions for all 1852 known human miRNAs were mapped onto whole genome methylation data on breast tumors from BRCA2 mutation carriers and non-carriers, making use of samples from our well-defined patients cohort. Analyses showed miR-21 overexpression in breast tumors from BRCA2 carriers and non-carriers, with tendency for higher expression in the BRCA2 group. RNA isolation from fresh frozen tumor tissue samples was carried out to further substantiate our previous findings, demonstrating upregulation of miR-21 in breast tumors in BRCA2 999del5 carriers. Previous studies had suggested overexpression in miR-190b in estrogen receptor positive, ER⁺, compared to ER^- breast tumors and this led us to further investigations in our Icelandic cohort. We observed higher methylation in normal breast tissue and ER^- tumor samples, compared to ER⁺ tumor samples, both lumA and LumB subtypes, and that miR-190b methylation status is negatively correlated to its expression, both in tumors and normal breast tissue .

We had previously shown that BRCA2 999del mutation carriers with ER⁺ breast tumors have worse survival than those with ER^- tumors, and that this is even more pronounced for the lumB subtype. Our expression and methylation analyses showed poorer survival in relation to high methylation status in patients of subtype lumA, but the opposite was seen for patients of subtype lumB, where high methylation status is associated with improved survival. Thus miR-190b hypomethylation is protective in individuals with lumA breast cancers, but the opposite is seen in individuals with lumB breast cancer. This is of interest as the lumB tumor subtype is associated with poor breast cancer survival. The results suggest that miR-190b could act as an oncoMir in this subtype. Findings that need to be followed up by further studies. 

Heiti verkefnis: Hlutverk RNA smásameinda og sviperfða í brjóstakrabbameini hjá áhættuhópum / The role of microRNAs and epigenetics in high-risk breast cancer
Verkefnisstjóri: Jórunn Erla Eyfeld, Háskóla Íslands
Tegund styrks: Verkefnisstyrkur
Styrktímabil: 2014-2016
Fjárhæð styrks: 30 millj. kr. alls
Tilvísunarnúmer Rannís:  141395