Research Highlights

 Unexpected discovery in patients with drug-resistant leukeamia

An international joint effort between FIMM, Faculty of Medicine, University of Helsinki and the HUS Comprehensive Cancer Center, in close collaboration with researchers at Pfizer, led to the discovery of a new opportunity to treat drug-resistant leukeamia with an approved renal cancer drug. The researchers identified a previously unrecognized action of Pfizer’s axitinib as a potent inhibitor of the dominant mutation that confers drug resistance to all well tolerated treatments in patients with certain types of leukeamia. The findings of this international joint effort were published in Nature. Read more.

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119.

Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, Cronin CN, McTigue M, Kallioniemi O, Porkka K, Murray BW, Wennerberg K.

Large-scale meta-analysis discovered ten new genes that tune cholesterol levels

In this large study, published in Nature Genetics, an international research consortium discovered ten new genes underlying blood lipid levels. The work was led by researchers at FIMM and the Faculty of Medicine, University of Helsinki. The DNA of more than 60,000 individuals was examined to discover genetic variants associated with cholesterol levels. In addition to identifying novel risk genes, the researchers were able to pinpoint new genetic risk variants having the most significant effect on cholesterol for most of the already known genomic susceptibility areas. Many of these new risk variants were shown to have a manifold effect on blood cholesterol compared to the previously identified variants. Read more.

The impact of low frequency and rare variants on lipid levels. Nat Genet. 2015 Jun; 47(6):589-97.

Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, Marullo L, Ferreira T, Miraglio B, Timonen S, Kettunen J, Pirinen M, Karjalainen J, Thorleifsson G, Hägg S, Hottenga JJ, Isaacs A, Ladenvall C, Beekman M, Esko T, Ried JS, Nelson CP, Willenborg C, Gustafsson S, Westra HJ, Blades M, de Craen AJ, de Geus EJ, Deelen J, Grallert H, Hamsten A, Havulinna AS, Hengstenberg C, Houwing-Duistermaat JJ, Hyppönen E, Karssen LC, Lehtimäki T, Lyssenko V, Magnusson PK, Mihailov E, Müller-Nurasyid M, Mpindi JP, Pedersen NL, Penninx BW, Perola M, Pers TH, Peters A, Rung J, Smit JH, Steinthorsdottir V, Tobin MD, Tsernikova N, van Leeuwen EM, Viikari JS, Willems SM, Willemsen G, Schunkert H, Erdmann J, Samani NJ, Kaprio J, Lind L, Gieger C, Metspalu A, Slagboom PE, Groop L, van Duijn CM, Eriksson JG, Jula A, Salomaa V, Boomsma DI, Power C, Raitakari OT, Ingelsson E, Järvelin MR, Thorsteinsdottir U, Franke L, Ikonen E, Kallioniemi O, Pietiäinen V, Lindgren CM, Stefansson K, Palotie A, McCarthy MI, Morris AP, Prokopenko I, Ripatti S; ENGAGE Consortium.

From personal genome to personal transcriptome

In a paper published in Science, an international team of researchers reported measuring the cellular effects of genetic variants in unprecedented depth. They documented the impact on gene expression levels of variants that had a high probability of causing proteins to be missing or incomplete (protein-truncating variants, PTVs). Cells have a protective mechanism against truncated proteins called ‘nonsense-mediated decay’, which can degrade abnormal RNA messages before they are translated to proteins. This decay phenomenon, and changes in the content of the RNA message can be detected from RNA sequencing data that the team analysed. By utilizing a statistical package developed by Matti Pirinen, the team was able to compare the expression levels of the two different gene copies and thus make conclusions about the effect of the PTVs on gene expression This work shows how ‘personal transcriptomics’ – measuring gene expression in individuals – could become an important complement to genome analysis in the clinic. Read more.

Effect of predicted protein-truncating genetic variants on the human transcriptome. Science. 2015 May 8; 348(6235):666-9.

Rivas MA, Pirinen M, Conrad DF, Lek M, Tsang EK, Karczewski KJ, Maller JB, Kukurba KR, DeLuca DS, Fromer M, Ferreira PG, Smith KS, Zhang R, Zhao F, Banks E, Poplin R, Ruderfer DM, Purcell SM, Tukiainen T, Minikel EV, Stenson PD, Cooper DN, Huang KH, Sullivan TJ, Nedzel J; GTEx Consortium; Geuvadis Consortium, Bustamante CD, Li JB, Daly MJ, Guigo R, Donnelly P, Ardlie K, Sammeth M, Dermitzakis ET, McCarthy MI, Montgomery SB, Lappalainen T, MacArthur DG.

Assessing allele-specific expression across multiple tissues from RNA-seq read data. Bioinformatics. 2015 Aug 1;31(15):2497-504.

Pirinen M, Lappalainen T, Zaitlen NA; GTEx Consortium, Dermitzakis ET, Donnelly P, McCarthy MI, Rivas MA.

Shared genetic susceptibility for migraine and ischemic stroke

In this large-scale meta-analysis, members of the International Headache Consortium and METASTROKE consortium assessed a shared genetic basis for two neurological disorders, migraine and ischemic stroke. The research team combined the genome-wide data sets on more than 23,000 migraine patients, 12,000 stroke patients and almost 160,000 controls. They were able to demonstrate that several common genetic variants, as well as the overall genetic load influence risk for both migraine and stroke. The findings indicated shared genetic susceptibility, with a particularly strong overlap between migraine without aura and large artery stroke.

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. Neurology. 2015 May 26;84(21):2132-45.

Malik R, Freilinger T, Winsvold BS, Anttila V, Vander Heiden J, Traylor M, de Vries B, Holliday EG, Terwindt GM, Sturm J, Bis JC, Hopewell JC, Ferrari MD, Rannikmae K, Wessman M, Kallela M, Kubisch C, Fornage M, Meschia JF, Lehtimäki T, Sudlow C, Clarke R, Chasman DI, Mitchell BD, Maguire J, Kaprio J, Farrall M, Raitakari OT, Kurth T, Ikram MA, Reiner AP, Longstreth WT Jr, Rothwell PM, Strachan DP, Sharma P, Seshadri S, Quaye L, Cherkas L, Schürks M, Rosand J, Ligthart L, Boncoraglio GB, Davey Smith G, van Duijn CM, Stefansson K, Worrall BB, Nyholt DR, Markus HS, van den Maagdenberg AM, Cotsapas C, Zwart JA, Palotie A; International Headache Genetics Consortium, Dichgans M; For the METASTROKE Collaboration of the International Stroke Genetics Consortium.

Miniaturized, Low-Cost Digital Microscope developed

FIMM’s Research Director Johan Lundin and his group have developed a low-cost, cloud-connected digital microscope. In this publication, they evaluated the performance of the device in the digital assessment of estrogen receptor alpha expression in breast cancer samples. They showed that the estrogen-receptor status of tumours can be accurately quantified with the device. The classification results from the evaluated point-of-care device were comparable to those from conventional computer-assisted or manual scoring.

Quantification of Estrogen Receptor-Alpha Expression in Human Breast Carcinomas With a Miniaturized, Low-Cost Digital Microscope: A Comparison with a High-End Whole Slide-Scanner. PLOS ONE. 2015 Dec 14;10(12):e0144688.

Holmström O, Linder N, Lundin M, Moilanen H, Suutala A, Turkki R, Joensuu H, Isola J, Diwan V, Lundin J.

A prototype of a low-cost, cloud-connected digital microscope MoMic.

Shared biological basis between migraine and coronary artery disease

In another large meta-analysis, a shared genetic risk between migraine and coronary artery disease (CAD) was examined. The results showed that there are shared biological processes that contribute to the risk of both diseases. The commonality was shown to be restricted to migraine without aura. Surprisingly, the impact of the shared genetic variants was in opposite directions indicating that shared genetic risk factors do not explain the comorbidity between the two diseases. Identifying such shared factors is important since it may help researchers to understand the mechanisms underlying both disorders.

Genetic analysis for a shared biological basis between migraine and coronary artery disease. Neurology: Genetics. 2015 1(1), e10.

Winsvold BS, Nelson CP, Malik R, Gormley P, Anttila V, Vander Heiden J, Elliott KS, Jacobsen LM, Palta P, Amin N, de Vries B, Hamalainen E, Freilinger T, Ikram MA, Kessler T, Koiranen M, Ligthart L, McMahon G, Pedersen L M, Willenborg C, Won H-H, Olesen J, Artto V, Assimes T L, Blankenberg S, Boomsma DI, Cherkas L, Davey Smith G, Epstein SE, Erdmann J, Ferrari MD, Gobel H, Hall AS, Jarvelin M-R, Kallela M, Kaprio J, Kathiresan S, Lehtimaki T, McPherson R, Marz W, Nyholt DR, O'Donnell C J, Quaye L, Rader DJ, Raitakari O, Roberts R, Schunkert H, Schurks M, Stewart AFR, Terwindt G M, Thorsteinsdottir U, van den Maagdenberg AMJM, van Duijn C, Wessman M, Kurth T, Kubisch C, Dichgans M, Chasman DI, Cotsapas C, Zwart J-A, Samani N J, Palotie A for the CARDIoGRAM Consortium and the International Headache Genetics Consortium.

Novel genetic variants explaining a third of nicotine metabolite ratio detected

In this study, led by Professor Jaakko Kaprio, the research team utilized a highly heritable biomarker of nicotine metabolism (nicotine metabolite ratio, NMR) in a genome-wide association study of three Finnish cohorts. The aim was to identify novel genetic variants influencing nicotine metabolism rate. Nicotine metabolism rate varies between individuals and affects smoking behaviour and is thus an informative phenotype to study. Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. The researchers were able to detect three variants in or near gene CYP2A6 explaining a strikingly large fraction of variance in NMR. These novel genetic findings deepening the understanding on factors influencing nicotine metabolism are of high importance, since the long-term consequences and action mechanisms of nicotine are of great public health relevance. Read more.

A genome-wide association study of a biomarker of nicotine metabolism. PLoS Genet. 2015 Sep 25;11(9):e1005498.

Loukola A, Buchwald J, Gupta R, Palviainen T, Hällfors J, Tikkanen E, Korhonen T, Ollikainen M, Sarin AP, Ripatti S, Lehtimäki T, Raitakari O, Salomaa V, Rose RJ, Tyndale RF, Kaprio J.

Method revolutionizing the illumination correction for light microscopy

Uneven illumination affects every image acquired by a microscope and can introduce considerable bias to image measurements. In this publication, FiDiPro Fellow Peter Horvath introduces a new illumination-correction method. The method, called corrected intensity distributions using regularized energy minimization (CIDRE), achieves correction quality similar to that of prospective methods but it does not require calibration images. CIDRE is a simple, freely available tool that can help ensure the quality of quantitative microscopy measurements.

CIDRE: an illumination-correction method for optical microscopy. Nat Methods. 2015 May;12(5):404-6.

Smith K, Li Y, Piccinini F, Csucs G, Balazs C, Bevilacqua A, Horvath P.

Research Highlights