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2. Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients

Author

Hathaway, Julie, Heliö, Krista, Saarinen, Inka, Tallila, Jonna, Seppälä, Eija H., Tuupanen, Sari, Turpeinen, Hannu, Kangas-Kontio, Tiia, Schleit, Jennifer, Tommiska, Johanna, Kytölä, Ville, Valori, Miko, Muona, Mikko, Sistonen, Johanna, Gentile, Massimiliano, Salmenperä, Pertteli, Myllykangas, Samuel, Paananen, Jussi, Alastalo, Tero-Pekka, Heliö, Tiina, and Koskenvuo, Juha

Published
2021
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4. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Author

Houlston, Richard S, Cheadle, Jeremy, Dobbins, Sara E, Tenesa, Albert, Jones, Angela M, Howarth, Kimberley, Spain, Sarah L, Broderick, Peter, Domingo, Enric, Farrington, Susan, Prendergast, James GD, Pittman, Alan M, Theodoratou, Evi, Smith, Christopher G, Olver, Bianca, Walther, Axel, Barnetson, Rebecca A, Churchman, Michael, Jaeger, Emma EM, Penegar, Steven, Barclay, Ella, Martin, Lynn, Gorman, Maggie, Mager, Rachel, Johnstone, Elaine, Midgley, Rachel, Niittymäki, Iina, Tuupanen, Sari, Colley, James, Idziaszczyk, Shelley, Thomas, Huw JW, Lucassen, Anneke M, Evans, D Gareth R, Maher, Eamonn R, Maughan, Timothy, Dimas, Antigone, Dermitzakis, Emmanouil, Cazier, Jean-Baptiste, Aaltonen, Lauri A, Pharoah, Paul, Kerr, David J, Carvajal-Carmona, Luis G, Campbell, Harry, Dunlop, Malcolm G, and Tomlinson, Ian PM

Subjects
Prevention, Cancer, Genetics, Colo-Rectal Cancer, Human Genome, Digestive Diseases, Chromosome Mapping, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 3, Colorectal Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Odds Ratio, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Risk Assessment, COGENT Consortium, CORGI Consortium, COIN Collaborative Group, COINB Collaborative Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹⁰ and rs6687758, OR = 1.09, P = 2.27 × 10⁻⁹, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻⁸), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹⁰ and rs7136702, OR = 1.06, P = 4.02 × 10⁻⁸) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹⁰). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

Published
2010

5. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Author

May-Wilson, Sebastian, Sud, Amit, Law, Philip J., Palin, Kimmo, Tuupanen, Sari, Gylfe, Alexandra, Hänninen, Ulrika A., Cajuso, Tatiana, Tanskanen, Tomas, Kondelin, Johanna, Kaasinen, Eevi, Sarin, Antti-Pekka, Eriksson, Johan G., Rissanen, Harri, Knekt, Paul, Pukkala, Eero, Jousilahti, Pekka, Salomaa, Veikko, Ripatti, Samuli, Palotie, Aarno, Renkonen-Sinisalo, Laura, Lepistö, Anna, Böhm, Jan, Mecklin, Jukka-Pekka, Al-Tassan, Nada A., Palles, Claire, Farrington, Susan M., Timofeeva, Maria N., Meyer, Brian F., Wakil, Salma M., Campbell, Harry, Smith, Christopher G., Idziaszczyk, Shelley, Maughan, Timothy S., Fisher, David, Kerr, Rachel, Kerr, David, Passarelli, Michael N., Figueiredo, Jane C., Buchanan, Daniel D., Win, Aung K., Hopper, John L., Jenkins, Mark A., Lindor, Noralane M., Newcomb, Polly A., Gallinger, Steven, Conti, David, Schumacher, Fred, Casey, Graham, Aaltonen, Lauri A., Cheadle, Jeremy P., Tomlinson, Ian P., Dunlop, Malcolm G., and Houlston, Richard S.

Published
2017
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6. Data from Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Author

Alhopuro, Pia, primary, Björklund, Mikael, primary, Sammalkorpi, Heli, primary, Turunen, Mikko, primary, Tuupanen, Sari, primary, Biström, Mia, primary, Niittymäki, Iina, primary, Lehtonen, Heli J., primary, Kivioja, Teemu, primary, Launonen, Virpi, primary, Saharinen, Juha, primary, Nousiainen, Kari, primary, Hautaniemi, Sampsa, primary, Nuorva, Kyösti, primary, Mecklin, Jukka-Pekka, primary, Järvinen, Heikki, primary, Orntoft, Torben, primary, Arango, Diego, primary, Lehtonen, Rainer, primary, Karhu, Auli, primary, Taipale, Jussi, primary, and Aaltonen, Lauri A., primary

Published
2023
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7. Supplementary Data from Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Author

Alhopuro, Pia, primary, Björklund, Mikael, primary, Sammalkorpi, Heli, primary, Turunen, Mikko, primary, Tuupanen, Sari, primary, Biström, Mia, primary, Niittymäki, Iina, primary, Lehtonen, Heli J., primary, Kivioja, Teemu, primary, Launonen, Virpi, primary, Saharinen, Juha, primary, Nousiainen, Kari, primary, Hautaniemi, Sampsa, primary, Nuorva, Kyösti, primary, Mecklin, Jukka-Pekka, primary, Järvinen, Heikki, primary, Orntoft, Torben, primary, Arango, Diego, primary, Lehtonen, Rainer, primary, Karhu, Auli, primary, Taipale, Jussi, primary, and Aaltonen, Lauri A., primary

Published
2023
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8. Supplementary Table 1 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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9. Supplementary Table 3 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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10. Supplementary Table 4 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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11. Supplementary Table 2 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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12. Supplementary Table 5 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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13. Supplementary Table 6 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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14. Supplementary Figures 1-19, supplementary methods and extended literature evaluation of the candidate genes from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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15. Supplementary Table 7 from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., primary, Lundgren, Sofie, primary, Tanskanen, Tomas, primary, Hamberg, Jiri, primary, Aavikko, Mervi, primary, Palin, Kimmo, primary, Ristolainen, Heikki, primary, Katainen, Riku, primary, Kaasinen, Eevi, primary, Taipale, Minna, primary, Taipale, Jussi, primary, Renkonen-Sinisalo, Laura, primary, Järvinen, Heikki, primary, Böhm, Jan, primary, Mecklin, Jukka-Pekka, primary, Vahteristo, Pia, primary, Tuupanen, Sari, primary, Aaltonen, Lauri A., primary, and Pitkänen, Esa, primary

Published
2023
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18. Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Author

Tanskanen, Tomas, van den Berg, Linda, Välimäki, Niko, Aavikko, Mervi, Ness‐Jensen, Eivind, Hveem, Kristian, Wettergren, Yvonne, Bexe Lindskog, Elinor, Tõnisson, Neeme, Metspalu, Andres, Silander, Kaisa, Orlando, Giulia, Law, Philip J., Tuupanen, Sari, Gylfe, Alexandra E., Hänninen, Ulrika A., Cajuso, Tatiana, Kondelin, Johanna, Sarin, Antti‐Pekka, Pukkala, Eero, Jousilahti, Pekka, Salomaa, Veikko, Ripatti, Samuli, Palotie, Aarno, Järvinen, Heikki, Renkonen‐Sinisalo, Laura, Lepistö, Anna, Böhm, Jan, Mecklin, Jukka‐Pekka, Al‐Tassan, Nada A., Palles, Claire, Martin, Lynn, Barclay, Ella, Tenesa, Albert, Farrington, Susan M., Timofeeva, Maria N., Meyer, Brian F., Wakil, Salma M., Campbell, Harry, Smith, Christopher G., Idziaszczyk, Shelley, Maughan, Tim S., Kaplan, Richard, Kerr, Rachel, Kerr, David, Buchanan, Daniel D., Win, Aung K., Hopper, John, Jenkins, Mark A., Newcomb, Polly A., Gallinger, Steve, Conti, David, Schumacher, Fredrick R., Casey, Graham, Cheadle, Jeremy P., Dunlop, Malcolm G., Tomlinson, Ian P., Houlston, Richard S., Palin, Kimmo, and Aaltonen, Lauri A.

Published
2018
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19. Contribution of allelic imbalance to colorectal cancer

Author

Palin, Kimmo, Pitkänen, Esa, Turunen, Mikko, Sahu, Biswajyoti, Pihlajamaa, Päivi, Kivioja, Teemu, Kaasinen, Eevi, Välimäki, Niko, Hänninen, Ulrika A., Cajuso, Tatiana, Aavikko, Mervi, Tuupanen, Sari, Kilpivaara, Outi, van den Berg, Linda, Kondelin, Johanna, Tanskanen, Tomas, Katainen, Riku, Grau, Marta, Rauanheimo, Heli, Plaketti, Roosa-Maria, Taira, Aurora, Sulo, Päivi, Hartonen, Tuomo, Dave, Kashyap, Schmierer, Bernhard, Botla, Sandeep, Sokolova, Maria, Vähärautio, Anna, Gladysz, Kornelia, Ongen, Halit, Dermitzakis, Emmanouil, Bramsen, Jesper Bertram, Ørntoft, Torben Falck, Andersen, Claus Lindbjerg, Ristimäki, Ari, Lepistö, Anna, Renkonen-Sinisalo, Laura, Mecklin, Jukka-Pekka, Taipale, Jussi, and Aaltonen, Lauri A.

Published
2018
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20. Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer

Author

Kondelin, Johanna, Salokas, Kari, Saarinen, Lilli, Ovaska, Kristian, Rauanheimo, Heli, Plaketti, Roosa‐Maria, Hamberg, Jiri, Liu, Xiaonan, Yadav, Leena, Gylfe, Alexandra E, Cajuso, Tatiana, Hänninen, Ulrika A, Palin, Kimmo, Ristolainen, Heikki, Katainen, Riku, Kaasinen, Eevi, Tanskanen, Tomas, Aavikko, Mervi, Taipale, Minna, Taipale, Jussi, Renkonen‐Sinisalo, Laura, Lepistö, Anna, Koskensalo, Selja, Böhm, Jan, Mecklin, Jukka‐Pekka, Ongen, Halit, Dermitzakis, Emmanouil T, Kilpivaara, Outi, Vahteristo, Pia, Turunen, Mikko, Hautaniemi, Sampsa, Tuupanen, Sari, Karhu, Auli, Välimäki, Niko, Varjosalo, Markku, Pitkänen, Esa, and Aaltonen, Lauri A

Published
2018
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23. Characterization of the colorectal cancer–associated enhancer MYC-335 at 8q24: the role of rs67491583

Author

Tuupanen, Sari, Yan, Jian, Turunen, Mikko, Gylfe, Alexandra E., Kaasinen, Eevi, Li, Li, Eng, Charis, Culver, Daniel A., Kalady, Matthew F., Pennison, Michael J., Pasche, Boris, Manne, Upender, de la Chapelle, Albert, Hampel, Heather, Henderson, Brian E., Le Marchand, Loic, Hautaniemi, Sampsa, Askhtorab, Hassan, Smoot, Duane, Sandler, Robert S., Keku, Temitope, Kupfer, Sonia S., Ellis, Nathan A., Haiman, Christopher A., Taipale, Jussi, and Aaltonen, Lauri A.

Published
2012
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25. Unregulated Smooth-Muscle Myosin in Human Intestinal Neoplasia

Author

Alhopuro, Pia, Phichith, Denis, Tuupanen, Sari, Sammalkorpi, Heli, Nybondas, Miranda, Saharinen, Juha, Robinson, James P., Yang, Zhaohui, Chen, Li-Qiong, Orntoft, Torben, Mecklin, Jukka-Pekka, Järvinen, Heikki, Eng, Charis, Moeslein, Gabriela, Shibata, Darryl, Houlston, Richard S., Lucassen, Anneke, Tomlinson, Ian P. M., Launonen, Virpi, Ristimäki, Ari, Arango, Diego, Karhu, Auli, Sweeney, H. Lee, and Aaltonen, Lauri A.

Published
2008
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26. Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients

Author

Tuupanen, Sari, primary, Gall, Kimberly, additional, Sistonen, Johanna, additional, Saarinen, Inka, additional, Kämpjärvi, Kati, additional, Wells, Kirsty, additional, Merkkiniemi, Katja, additional, von Nandelstadh, Pernilla, additional, Sarantaus, Laura, additional, Känsäkoski, Johanna, additional, Mårtenson, Emma, additional, Västinsalo, Hanna, additional, Schleit, Jennifer, additional, Sankila, Eeva-Marja, additional, Kere, Annakarin, additional, Junnila, Heidi, additional, Siivonen, Pauli, additional, Andreevskaya, Margarita, additional, Kytölä, Ville, additional, Muona, Mikko, additional, Salmenperä, Pertteli, additional, Myllykangas, Samuel, additional, Koskenvuo, Juha, additional, and Alastalo, Tero-Pekka, additional

Published
2022
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28. Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer

Author

Cajuso, Tatiana, Hänninen, Ulrika A., Kondelin, Johanna, Gylfe, Alexandra E., Tanskanen, Tomas, Katainen, Riku, Pitkänen, Esa, Ristolainen, Heikki, Kaasinen, Eevi, Taipale, Minna, Taipale, Jussi, Böhm, Jan, Renkonen-Sinisalo, Laura, Mecklin, Jukka-Pekka, Järvinen, Heikki, Tuupanen, Sari, Kilpivaara, Outi, and Vahteristo, Pia

Published
2014
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29. Biallelic NRAP variants are a significant cause of dilated cardiomyopathy

Author

Gall, Kim, primary, Koskenvuo, Juha, additional, Saarinen, Inka, additional, Tommiska, Johanna, additional, Weckstrom, Sini, additional, Seppala, Eija, additional, Tuupanen, Sari, additional, Kangas-Kontio, Tiia, additional, Schleit, Jennifer, additional, Hathaway, Julie, additional, Muona, Mikko, additional, Sistonen, Johanna, additional, Salmenpera, Pertelli, additional, Gentile, Massimiliano, additional, Paananen, Jussi, additional, Alastalo, Tero-Pekka, additional, and Helio, Tiina, additional

Published
2021
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31. Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

Author

Koskenvuo, Juha W., primary, Saarinen, Inka, additional, Ahonen, Saija, additional, Tommiska, Johanna, additional, Weckström, Sini, additional, Seppälä, Eija H., additional, Tuupanen, Sari, additional, Kangas-Kontio, Tiia, additional, Schleit, Jennifer, additional, Heliö, Krista, additional, Hathaway, Julie, additional, Gummesson, Anders, additional, Dahlberg, Pia, additional, Ojala, Tiina H., additional, Vepsäläinen, Ville, additional, Kytölä, Ville, additional, Muona, Mikko, additional, Sistonen, Johanna, additional, Salmenperä, Pertteli, additional, Gentile, Massimiliano, additional, Paananen, Jussi, additional, Myllykangas, Samuel, additional, Alastalo, Tero-Pekka, additional, and Heliö, Tiina, additional

Published
2021
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32. Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals

Author

Dunlop, Malcolm G, Tenesa, Albert, Farrington, Susan M, Ballereau, Stephane, Brewster, David H, Koessler, Thibaud, Pharoah, Paul, Schafmayer, Clemens, Hampe, Jochen, Völzke, Henry, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, von Holst, Susanna, Picelli, Simone, Lindblom, Annika, Jenkins, Mark A, Hopper, John L, Casey, Graham, Duggan, David, Newcomb, Polly A, Abulí, Anna, Bessa, Xavier, Ruiz-Ponte, Clara, Castellví-Bel, Sergi, Niittymäki, Iina, Tuupanen, Sari, Karhu, Auli, Aaltonen, Lauri, Zanke, Brent, Hudson, Tom, Gallinger, Steven, Barclay, Ella, Martin, Lynn, Gorman, Maggie, Carvajal-Carmona, Luis, Walther, Axel, Kerr, David, Lubbe, Steven, Broderick, Peter, Chandler, Ian, Pittman, Alan, Penegar, Steven, Campbell, Harry, Tomlinson, Ian, and Houlston, Richard S

Published
2013
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33. Candidate driver genes in microsatellite-unstable colorectal cancer

Author

Alhopuro, Pia, Sammalkorpi, Heli, Niittymäki, Iina, Biström, Mia, Raitila, Anniina, Saharinen, Juha, Nousiainen, Kari, Lehtonen, Heli J., Heliövaara, Elina, Puhakka, Jani, Tuupanen, Sari, Sousa, Sónia, Seruca, Raquel, Ferreira, Ana M., Hofstra, Robert M. W., Mecklin, Jukka-Pekka, Järvinen, Heikki, Ristimäki, Ari, rntoft, Torben F., Hautaniemi, Sampsa, Arango, Diego, Karhu, Auli, and Aaltonen, Lauri A.

Published
2012
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35. A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants inHGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis

Author

Schiff, Elena R., primary, Daich Varela, Malena, additional, Robson, Anthony G., additional, Pierpoint, Karen, additional, Ba‐Abbad, Rola, additional, Nutan, Savita, additional, Zein, Wadih M., additional, Ullah, Ehsan, additional, Huryn, Laryssa A., additional, Tuupanen, Sari, additional, Mahroo, Omar A., additional, Michaelides, Michel, additional, Burke, Derek, additional, Harvey, Katie, additional, Arno, Gavin, additional, Hufnagel, Robert B., additional, and Webster, Andrew R., additional

Published
2020
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36. Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Author

Pittman, Alan M., Webb, Emily, Carvajal-Carmona, Luis, Howarth, Kimberley, Di Bernardo, Maria Chiara, Broderick, Peter, Spain, Sarah, Walther, Axel, Price, Amy, Sullivan, Kate, Twiss, Philip, Fielding, Sarah, Rowan, Andrew, Jaeger, Emma, Vijayakrishnan, Jayaram, Chandler, Ian, Penegar, Steven, Qureshi, Mobshra, Lubbe, Steven, Domingo, Enric, Kemp, Zoe, Barclay, Ella, Wood, Wendy, Martin, Lynn, Gorman, Maggie, Thomas, Huw, Peto, Julian, Bishop, Timothy, Gray, Richard, Maher, Eamonn R., Lucassen, Anneke, Kerr, David, Evans, Gareth R., van Wezel, Tom, Morreau, Hans, Wijnen, Juul T., Hopper, John L., Southey, Melissa C., Giles, Graham G., Severi, Gianluca, Castellví-Bel, Sergi, Ruiz-Ponte, Clara, Carracedo, Angel, Castells, Antoni, Försti, Asta, Hemminki, Kari, Vodicka, Pavel, Naccarati, Alessio, Lipton, Lara, Ho, Judy W.C., Cheng, K.K., Sham, Pak C., Luk, J., Agúndez, Jose A.G., Ladero, Jose M., de la Hoya, Miguel, Caldés, Trinidad, Niittymäki, Iina, Tuupanen, Sari, Karhu, Auli, Aaltonen, Lauri A., Cazier, Jean-Baptiste, Tomlinson, Ian P.M., and Houlston, Richard S.

Published
2008

39. Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci

Author

Houlston Richard S, Tomlinson Ian PM, Järvinen Heikki, Mecklin Jukka-Pekka, Li Yilong, Tuupanen Sari, Niittymäki Iina, Karhu Auli, and Aaltonen Lauri A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. Methods Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. Results No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. Conclusions The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.

Published
2011
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40. A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.

Author

Schiff, Elena R., Daich Varela, Malena, Robson, Anthony G., Pierpoint, Karen, Ba‐Abbad, Rola, Nutan, Savita, Zein, Wadih M., Ullah, Ehsan, Huryn, Laryssa A., Tuupanen, Sari, Mahroo, Omar A., Michaelides, Michel, Burke, Derek, Harvey, Katie, Arno, Gavin, Hufnagel, Robert B., and Webster, Andrew R.

Published
2020
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41. Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Author

Tanskanen, Tomas, primary, van den Berg, Linda, additional, Välimäki, Niko, additional, Aavikko, Mervi, additional, Ness‐Jensen, Eivind, additional, Hveem, Kristian, additional, Wettergren, Yvonne, additional, Bexe Lindskog, Elinor, additional, Tõnisson, Neeme, additional, Metspalu, Andres, additional, Silander, Kaisa, additional, Orlando, Giulia, additional, Law, Philip J., additional, Tuupanen, Sari, additional, Gylfe, Alexandra E., additional, Hänninen, Ulrika A., additional, Cajuso, Tatiana, additional, Kondelin, Johanna, additional, Sarin, Antti‐Pekka, additional, Pukkala, Eero, additional, Jousilahti, Pekka, additional, Salomaa, Veikko, additional, Ripatti, Samuli, additional, Palotie, Aarno, additional, Järvinen, Heikki, additional, Renkonen‐Sinisalo, Laura, additional, Lepistö, Anna, additional, Böhm, Jan, additional, Mecklin, Jukka‐Pekka, additional, Al‐Tassan, Nada A., additional, Palles, Claire, additional, Martin, Lynn, additional, Barclay, Ella, additional, Tenesa, Albert, additional, Farrington, Susan M., additional, Timofeeva, Maria N., additional, Meyer, Brian F., additional, Wakil, Salma M., additional, Campbell, Harry, additional, Smith, Christopher G., additional, Idziaszczyk, Shelley, additional, Maughan, Tim S., additional, Kaplan, Richard, additional, Kerr, Rachel, additional, Kerr, David, additional, Buchanan, Daniel D., additional, Win, Aung K., additional, Hopper, John, additional, Jenkins, Mark A., additional, Newcomb, Polly A., additional, Gallinger, Steve, additional, Conti, David, additional, Schumacher, Fredrick R., additional, Casey, Graham, additional, Cheadle, Jeremy P., additional, Dunlop, Malcolm G., additional, Tomlinson, Ian P., additional, Houlston, Richard S., additional, Palin, Kimmo, additional, and Aaltonen, Lauri A., additional

Published
2017
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42. Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Author

Kondelin, Johanna, primary, Gylfe, Alexandra E., additional, Lundgren, Sofie, additional, Tanskanen, Tomas, additional, Hamberg, Jiri, additional, Aavikko, Mervi, additional, Palin, Kimmo, additional, Ristolainen, Heikki, additional, Katainen, Riku, additional, Kaasinen, Eevi, additional, Taipale, Minna, additional, Taipale, Jussi, additional, Renkonen-Sinisalo, Laura, additional, Järvinen, Heikki, additional, Böhm, Jan, additional, Mecklin, Jukka-Pekka, additional, Vahteristo, Pia, additional, Tuupanen, Sari, additional, Aaltonen, Lauri A., additional, and Pitkänen, Esa, additional

Published
2017
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43. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Author

Rodriguez‐Broadbent, Henry, primary, Law, Philip J., additional, Sud, Amit, additional, Palin, Kimmo, additional, Tuupanen, Sari, additional, Gylfe, Alexandra, additional, Hänninen, Ulrika A., additional, Cajuso, Tatiana, additional, Tanskanen, Tomas, additional, Kondelin, Johanna, additional, Kaasinen, Eevi, additional, Sarin, Antti‐Pekka, additional, Ripatti, Samuli, additional, Eriksson, Johan G., additional, Rissanen, Harri, additional, Knekt, Paul, additional, Pukkala, Eero, additional, Jousilahti, Pekka, additional, Salomaa, Veikko, additional, Palotie, Aarno, additional, Renkonen‐Sinisalo, Laura, additional, Lepistö, Anna, additional, Böhm, Jan, additional, Mecklin, Jukka‐Pekka, additional, Al‐Tassan, Nada A., additional, Palles, Claire, additional, Martin, Lynn, additional, Barclay, Ella, additional, Farrington, Susan M., additional, Timofeeva, Maria N., additional, Meyer, Brian F., additional, Wakil, Salma M., additional, Campbell, Harry, additional, Smith, Christopher G., additional, Idziaszczyk, Shelley, additional, Maughan, Timothy S., additional, Kaplan, Richard, additional, Kerr, Rachel, additional, Kerr, David, additional, Passarelli, Michael N., additional, Figueiredo, Jane C., additional, Buchanan, Daniel D., additional, Win, Aung K., additional, Hopper, John L., additional, Jenkins, Mark A., additional, Lindor, Noralane M., additional, Newcomb, Polly A., additional, Gallinger, Steven, additional, Conti, David, additional, Schumacher, Fred, additional, Casey, Graham, additional, Aaltonen, Lauri A., additional, Cheadle, Jeremy P., additional, Tomlinson, Ian P., additional, Dunlop, Malcolm G., additional, and Houlston, Richard S., additional

Published
2017
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44. Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Author

University of Helsinki, Research Programs Unit, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, University of Helsinki, Heikki Järvinen / Principal Investigator, University of Helsinki, II kirurgian klinikka, University of Helsinki, Medicum, Orlando, Giulia, Law, Philip J., Palin, Kimmo, Tuupanen, Sari, Gylfe, Alexandra, Hanninen, Ulrika A., Cajuso, Tatiana, Tanskanen, Tomas, Kondelin, Johanna, Kaasinen, Eevi, Sarin, Antti-Pekka, Kaprio, Jaakko, Eriksson, Johan G., Rissanen, Harri, Knekt, Paul, Pukkala, Eero, Jousilahti, Pekka, Salomaa, Veikko, Ripatti, Samuli, Palotie, Aarno, Järvinen, Heikki, Renkonen-Sinisalo, Laura, Lepisto, Anna, Bohm, Jan, Mecklin, Jukka-Pekka, Al-Tassan, Nada A., Palles, Claire, Martin, Lynn, Barclay, Ella, Tenesa, Albert, Farrington, Susan, Timofeeva, Maria N., Meyer, Brian F., Wakil, Salma M., Campbell, Harry, Smith, Christopher G., Idziaszczyk, Shelley, Maughan, Timothy S., Kaplan, Richard, Kerr, Rachel, Kerr, David, Buchanan, Daniel D., Win, Aung Ko, Hopper, John, Jenkins, Mark, Lindor, Noralane M., Newcomb, Polly A., Gallinger, Steve, Conti, David, Schumacher, Fred, Casey, Graham, Taipale, Jussi, Cheadle, Jeremy P., Dunlop, Malcolm G., Tomlinson, Ian P., Aaltonen, Lauri A., Houlston, Richard S., University of Helsinki, Research Programs Unit, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, University of Helsinki, Heikki Järvinen / Principal Investigator, University of Helsinki, II kirurgian klinikka, University of Helsinki, Medicum, Orlando, Giulia, Law, Philip J., Palin, Kimmo, Tuupanen, Sari, Gylfe, Alexandra, Hanninen, Ulrika A., Cajuso, Tatiana, Tanskanen, Tomas, Kondelin, Johanna, Kaasinen, Eevi, Sarin, Antti-Pekka, Kaprio, Jaakko, Eriksson, Johan G., Rissanen, Harri, Knekt, Paul, Pukkala, Eero, Jousilahti, Pekka, Salomaa, Veikko, Ripatti, Samuli, Palotie, Aarno, Järvinen, Heikki, Renkonen-Sinisalo, Laura, Lepisto, Anna, Bohm, Jan, Mecklin, Jukka-Pekka, Al-Tassan, Nada A., Palles, Claire, Martin, Lynn, Barclay, Ella, Tenesa, Albert, Farrington, Susan, Timofeeva, Maria N., Meyer, Brian F., Wakil, Salma M., Campbell, Harry, Smith, Christopher G., Idziaszczyk, Shelley, Maughan, Timothy S., Kaplan, Richard, Kerr, Rachel, Kerr, David, Buchanan, Daniel D., Win, Aung Ko, Hopper, John, Jenkins, Mark, Lindor, Noralane M., Newcomb, Polly A., Gallinger, Steve, Conti, David, Schumacher, Fred, Casey, Graham, Taipale, Jussi, Cheadle, Jeremy P., Dunlop, Malcolm G., Tomlinson, Ian P., Aaltonen, Lauri A., and Houlston, Richard S.

Abstract

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 x 10(-8), odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r(2) = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) <0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Published
2016

45. Exome sequencing reveals frequent inactivating mutations in ARID1A,ARID1B,ARID2, and ARID4A in microsatellite unstable colorectal cancer

Author

Cajuso, Tatiana, Hänninen, Ulrika A., Kondelin, Johanna, Gylfe, Alexandra E., Tanskanen, Tomas, Katainen, Riku, Pitkänen, Esa, Ristolainen, Heikki, Kaasinen, Eevi, Taipale, Minna, Taipale, Jussi, Böhm, Jan, Renkonen-Sinisalo, Laura, Mecklin, Jukka-Pekka, Järvinen, Heikki, Tuupanen, Sari, Kilpivaara, Outi, and Vahteristo, Pia

Published
2014
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46. Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Author

Jarvis, David, primary, Mitchell, Jonathan S, additional, Law, Philip J, additional, Palin, Kimmo, additional, Tuupanen, Sari, additional, Gylfe, Alexandra, additional, Hänninen, Ulrika A, additional, Cajuso, Tatiana, additional, Tanskanen, Tomas, additional, Kondelin, Johanna, additional, Kaasinen, Eevi, additional, Sarin, Antti-Pekka, additional, Kaprio, Jaakko, additional, Eriksson, Johan G, additional, Rissanen, Harri, additional, Knekt, Paul, additional, Pukkala, Eero, additional, Jousilahti, Pekka, additional, Salomaa, Veikko, additional, Ripatti, Samuli, additional, Palotie, Aarno, additional, Järvinen, Heikki, additional, Renkonen-Sinisalo, Laura, additional, Lepistö, Anna, additional, Böhm, Jan, additional, Meklin, Jukka-Pekka, additional, Al-Tassan, Nada A, additional, Palles, Claire, additional, Martin, Lynn, additional, Barclay, Ella, additional, Farrington, Susan M, additional, Timofeeva, Maria N, additional, Meyer, Brian F, additional, Wakil, Salma M, additional, Campbell, Harry, additional, Smith, Christopher G, additional, Idziaszczyk, Shelley, additional, Maughan, Timothy S, additional, Kaplan, Richard, additional, Kerr, Rachel, additional, Kerr, David, additional, Buchanan, Daniel D, additional, Win, Aung K, additional, Hopper, John L, additional, Jenkins, Mark A, additional, Lindor, Noralane M, additional, Newcomb, Polly A, additional, Gallinger, Steve, additional, Conti, David, additional, Schumacher, Fred, additional, Casey, Graham, additional, Taipale, Jussi, additional, Aaltonen, Lauri A, additional, Cheadle, Jeremy P, additional, Dunlop, Malcolm G, additional, Tomlinson, Ian P, additional, and Houlston, Richard S, additional

Published
2016
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47. Variation at 2q35 (PNKDandTMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Author

Orlando, Giulia, primary, Law, Philip J., additional, Palin, Kimmo, additional, Tuupanen, Sari, additional, Gylfe, Alexandra, additional, Hänninen, Ulrika A., additional, Cajuso, Tatiana, additional, Tanskanen, Tomas, additional, Kondelin, Johanna, additional, Kaasinen, Eevi, additional, Sarin, Antti-Pekka, additional, Kaprio, Jaakko, additional, Eriksson, Johan G., additional, Rissanen, Harri, additional, Knekt, Paul, additional, Pukkala, Eero, additional, Jousilahti, Pekka, additional, Salomaa, Veikko, additional, Ripatti, Samuli, additional, Palotie, Aarno, additional, Järvinen, Heikki, additional, Renkonen-Sinisalo, Laura, additional, Lepistö, Anna, additional, Böhm, Jan, additional, Mecklin, Jukka-Pekka, additional, Al-Tassan, Nada A., additional, Palles, Claire, additional, Martin, Lynn, additional, Barclay, Ella, additional, Tenesa, Albert, additional, Farrington, Susan, additional, Timofeeva, Maria N., additional, Meyer, Brian F., additional, Wakil, Salma M., additional, Campbell, Harry, additional, Smith, Christopher G., additional, Idziaszczyk, Shelley, additional, Maughan, Timothy S., additional, Kaplan, Richard, additional, Kerr, Rachel, additional, Kerr, David, additional, Buchanan, Daniel D., additional, Ko Win, Aung, additional, Hopper, John, additional, Jenkins, Mark, additional, Lindor, Noralane M., additional, Newcomb, Polly A., additional, Gallinger, Steve, additional, Conti, David, additional, Schumacher, Fred, additional, Casey, Graham, additional, Taipale, Jussi, additional, Cheadle, Jeremy P., additional, Dunlop, Malcolm G., additional, Tomlinson, Ian P., additional, Aaltonen, Lauri A., additional, and Houlston, Richard S., additional

Published
2016
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49. CTCF/cohesin-binding sites are frequently mutated in cancer

Author

Katainen, Riku, primary, Dave, Kashyap, additional, Pitkänen, Esa, additional, Palin, Kimmo, additional, Kivioja, Teemu, additional, Välimäki, Niko, additional, Gylfe, Alexandra E, additional, Ristolainen, Heikki, additional, Hänninen, Ulrika A, additional, Cajuso, Tatiana, additional, Kondelin, Johanna, additional, Tanskanen, Tomas, additional, Mecklin, Jukka-Pekka, additional, Järvinen, Heikki, additional, Renkonen-Sinisalo, Laura, additional, Lepistö, Anna, additional, Kaasinen, Eevi, additional, Kilpivaara, Outi, additional, Tuupanen, Sari, additional, Enge, Martin, additional, Taipale, Jussi, additional, and Aaltonen, Lauri A, additional

Published
2015
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50. Molecular basis of colorectal cancer predisposition

Author

Tuupanen, Sari, University of Helsinki, Faculty of Medicine, Haartman Institute, Medical Genetics, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, Mannermaa, Arto, Aaltonen, Lauri, and Karhu, Auli

Subjects
digestive system diseases, syöpägenetiikka
Abstract

Colorectal cancer (CRC) is one of the most frequent malignancies in Western countries. Inherited factors have been suggested to be involved in 35% of CRCs. The hereditary CRC syndromes explain only ~6% of all CRCs, indicating that a large proportion of the inherited susceptibility is still unexplained. Much of the remaining genetic predisposition for CRC is probably due to undiscovered low-penetrance variations. This study was conducted to identify germline and somatic changes that contribute to CRC predisposition and tumorigenesis. MLH1 and MSH2, that underlie Hereditary non-polyposis colorectal cancer (HNPCC) are considered to be tumor suppressor genes; the first hit is inherited in the germline and somatic inactivation of the wild type allele is required for tumor initiation. In a recent study, frequent loss of the mutant allele in HNPCC tumors was detected and a new model, arguing against the two-hit hypothesis, was proposed for somatic HNPCC tumorigenesis. We tested this hypothesis by conducting LOH analysis on 25 colorectal HNPCC tumors with a known germline mutation in the MLH1 or MSH2 genes. LOH was detected in 56% of the tumors. All the losses targeted the wild type allele supporting the classical two-hit model for HNPCC tumorigenesis. The variants 3020insC, R702W and G908R in NOD2 predispose to Crohn s disease. Contribution of NOD2 to CRC predisposition has been examined in several case-control series, with conflicting results. We have previously shown that 3020insC does not predispose to CRC in Finnish CRC patients. To expand our previous study the variants R702W and G908R were genotyped in a population-based series of 1042 Finnish CRC patients and 508 healthy controls. Association analyses did not show significant evidence for association of the variants with CRC. Single nucleotide polymorphism (SNP) rs6983267 at chromosome 8q24 was the first CRC susceptibility variant identified through genome-wide association studies. To characterize the role of rs6983267 in CRC predisposition in the Finnish population, we genotyped the SNP in the case-control material of 1042 cases and 1012 controls and showed that G allele of rs6983267 is associated with the increased risk of CRC (OR 1.22; P=0.0018). Examination of allelic imbalance in the tumors heterozygous for rs6983267 revealed that copy number increase affected 22% of the tumors and interestingly, it favored the G allele. By utilizing a computer algorithm, Enhancer Element Locator (EEL), an evolutionary conserved regulatory motif containing rs6983267 was identified. The SNP affected the binding site of TCF4, a transcription factor that mediates Wnt signaling in cells, and has proven to be crucial in colorectal neoplasia. The preferential binding of TCF4 to the risk allele G was showed in vitro and in vivo. The element drove lacZ marker gene expression in mouse embryos in a pattern that is consistent with genes regulated by the Wnt signaling pathway. These results suggest that rs6983267 at 8q24 exerts its effect in CRC predisposition by regulating gene expression. The most obvious target gene for the enhancer element is MYC, residing ~335 kb downstream, however further studies are required to establish the transcriptional target(s) of the predicted enhancer element. Paksusuolisyöpä kuuluu kolmen yleisimmän syövän joukkoon maailmassa. Perintötekijoillä arvellaan olevan vaikutusta noin 35 %:ssa paksusuolisyövistä. Paksusuolisyövälle altistavat, dominantisti periytyvät syndroomat kattavat vain noin 6 % kaikista paksusuolisyöpätapauksista. Näin ollen suuri osa alttiusgeeneistä on vielä tunnistamatta ja tällä hetkellä uskotaan, että niin sanotut alhaisen riskin geenimuutokset voisivat selittää suuren osan perinnöllisestä paksusuolisyöpäalttiudesta. Väitöskirjatutkimukseni tarkoituksena oli tunnistaa uusia paksusuolisyövälle altistavia geenimuutoksia sekä tutkia somaattisia mekanismeja, jotka johtavat kasvaimen syntyyn. Perityvä ei-polypoottinen paksusuolisyöpä (Hereditary non-polyposis colorectal cancer, HNPCC) johtuu ituradan virheistä ns. mismatch repair geeneissä (esim. MLH1 ja MSH2). Kasvaimen syntyminen edellyttää villityypin alleelin somaattista inaktivoimista kohdekudoksessa. Ensimmäisessä osatyössä tutkimme mekanismeja, joilla MLH1- ja MSH2-geenit inaktivoidaan HNPCC-potilaiden kasvaimissa. Osoitimme, että 56 %:ssa kasvaimista villityypin alleeli inaktivoidaan heterotsygotian häviämisen avulla. Emme löytäneet vahvistusta hiljattain esitetylle teorialle, jonka mukaan heterotsygotian häviäminen voisi kohdistua mutanttialleeliin. NOD2-geenissä olevat variaatiot 3020insC, R702W and G908R altistavat Crohnin taudille. Olemme aiemmin osoittaneet, että variaatio 3020insC ei lisää riskiä sairastua paksusuolisyöpään suomalaisessa populaatiossa. Tässä työssä genotyyppasimme variaatiot R702W ja G908R 1042 syöpätapauksen ja 508 terveen väestökontrollien aineistossa. Havaitsimme, että suomalaisilla NOD2-geenin variaatioiden kantajilla ei ole kohonnutta syöpäriskiä. Kromosomissa 8q24 sijaitseva yhden nukleotidin variaatio (Single nucleotide polymorphism, SNP) rs6983267 on ensimmäinen koko genomin kattavien assosiaatioanalyysien tuloksena löytynyt paksusuolisyöpäalttiutta lisäävä SNP. Tutkimme tämän yleisen variaation vaikutusta paksusuolisyöpäriskiin suomalaisessa populaatiossa. Osoitimme, että homotsygooteilla G alleelin kantajilla on noin 1,5 kertaa suurempi syöpäriski kuin T alleelin omaavilla henkilöillä. Selvitimme myös riskialleelin G merkitystä kasvaimen kehityksessä ja havaitsimme, että kasvaimissa riskialleelin sisältävä kromosomi on useammin monistunut kuin villityypin alleelin sisältävä kromosomi. Tutkimme variaation rs6983267 roolia geenien säätelyssä käyttäen hyväksi geenien säätelyelementtejä ennustavaa tietokoneohjelmaa, Enhancer Element Locator (EEL). EEL:n ennustuksen mukaan rs6983267 sijaitsee konservoituneessa säätelyelementissa, jossa se muuttaa Wnt signaloinnissa toimivan transkriptiofaktorin TCF4 sitoutumispaikan. Havaitsimme in vitro ja in vivo kokein, että riskialleeli G lisää TCF4 sitoutumista, joka puolestaan johtaa kohdegeenin lisääntyneeseen ekspressioon. Näytimme myös, että SNP:in sisältävä säätelyelementti toimii kudosspesifisessä kohdegeenin säätelyssä. Tuloksemme osoittavat, että paksusuolisyövälle altistava SNP rs6983267 lisää Wnt signalointia solussa.

Published
2009

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