Gallar í DNA viðgerð og lyfjasvörun í brjóst- og eggjastokkakrabbameini - verkefni lokið

Fréttatilkynning verkefnisstjóra

19.3.2019

Kímlínustökkbreytingar í BRCA1 og BRCA2 auka mjög áhættuna á myndun krabbameina í brjósti og eggjastokkum. Bæði genin taka þátt í DNA viðgerð og undirstrika því mikilvægi DNA viðgerðarferla í krabbameinum. Í hluta krabbameina þar sem um litla eða enga fjölskyldusögu er að ræða hefur komið í ljós að tjáingu BRCA1 er stjórnað með sviperfðum (epigenetics) þar sem stýrilsvæði gensins er methýlerað sem undirstrikar mikilvægi sviperfða í krabbameinum. Í þessu verkefni rannsökuðum við methýleringar á stýrilsvæðum DNA viðgerðargena. Niðurstöður okkar benda til að stýrilsvæði BRCA1 sé methylerað í 3% brjóstakrabbameina á Íslandi og að þeir sjúklingar sem hafi stýrilsvæðið methylerað vegni betur eftir frumudrepandi lyfjameðferð. Þetta eru svipaðar niðurstöður og sjást hjá sjúklingum sem bera kímlínubreytinga í BRCA1 en í báðum tilfellum er BRCA1 próteinið ekki tjáð. Auk BRCA1, sýnum við fram á að tjáning ALKHB3 sem tekur þátt í viðgerð á alkýleruðum DNA skemmdum er líka stjórnað af sviperfðum sem hefur áhrif til hins verra á horfur sjúklinga með brjóstakrabbamein.

DNA repair defects and drug response in breast and ovarian cancer

Breast Breast cancer is the most common cancer among women and ranks among the leading causes of cancer related deaths. Ovarian cancer, although not as common as breast cancer, tends to be more aggressive as they are often diagnosed at late stages. Germline mutations in BRCA1 and BRCA2 greatly increase the risk for developing breast and ovarian cancer. Both genes are involved in DNA repair, highlighting the importance of DNA repair processes in cancer. In a subset of sporadic cases, epigenetic gene silencing of BRCA1 has been found, underscoring the role of epigenetic regulation in cancer. We analyzed promoter methylation of known DNA repair genes and our results show that BRCA1 is promoter methylated in 3.0% of breast cancer cases. Importantly, patients with BRCA1 promoter hypermethylation receiving chemotherapeutic drug treatment show highly improved breast cancer specific survival compared with controls. Therefore, BRCA1 promoter hypermethylation is predictive of improved disease outcome in patients receiving chemotherapeutic drug treatment. Our results support the use of markers indicative of BRCAness in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA damaging agents. In addition to BRCA1, we show that ALKBH3 involved in DNA alkylation damage repair is epigenetically regulated and statistically significantly associated with reduced survival.

List of project´s output:

Published papers:

Stefansson OA, Hermanowicz S, van der Horst J, Hilmarsdottir H, Staszczak Z, Jonasson JG, Tryggvadottir L, Gudjonsson T, Sigursson S. CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer. (2017) BMC Cancer, 17, 3453-3458.

Manuscripts in review/submitted

Stefansson OA, Hilmarsdottir H, Olafsdottir K, Tryggvadottir L, Sverrisdottir A, Jonasson JG, Eyfjord JE, Sigurdsson S. BRCA1 promoter methylation status in 1031 primary breast cancers predicts favorable response to chemotherapy. Being reviewed by the Journal of the National Cancer Institute.

Pique L, Martinez de Paz A, Pineyro D, Martinez-Cardús A, Llinas-Arias P, Setien F, Sigurdsson ST, Jonasson JG, Villanueva A, Vidal A, Davalos V, Esteller M. Epigenetic Inactivation of the splicing RNA binding protein CELF2 in human breast cancer. Submitted to Oncogene

Graduated students:

Jasper van der Horst – MS thesis defended in December 2018. Thesis title: Epigenetic modifications of DNA repair genes in breast cancer.

Stefan Þór Hermanowicz – Ph.D. thesis will be defended in May 2019. Thesis title: The Epigenetic Silencing of ALKBH3 and the Epitranscriptomic Regulation of DNA Repair.

Presentations:

Numerous presentations – including:

American Association for Cancer Research (AACR) Annual Meeting – Chicago US, April 14-18, 2018. Title: BRCA1 promoter methylation analyzed in 1032 primary breast cancers predicts favorable response to chemotherapy independently of p53 mutations. http://cancerres.aacrjournals.org/content/78/13_Supplement/3307

From Epigenome towards Epitranscriptome in Cell Fate Choice – EMBO Workshop – Capri Itali, October 14-17, 2018. Title: The epitranscriptomic regulation of RNF168 by ALKHB3.

Protein Signaling – Copenhagen Bioscience Conferences – Copenhagen Denmark, September 30 – October 4, 2018. Title: Uncovering the regulatory role of RNF168 RNA demethylation in DNA double strand break signaling.

Heiti verkefnis: Gallar í DNA viðgerð og lyfjasvörun í brjóst- og eggjastokkakrabbameini/ DNA repair defects and drug response in breast and ovarian cancer
Verkefnisstjóri: Stefán Sigurðsson, Háskóla Íslands
Tegund styrks: Verkefnisstyrkur
Styrktímabil: 2015-2017
Fjárhæð styrks: 36 millj. kr. alls