Molecular Pathology and Genetics of Cancer

Steering Group

Veli-Matti Kosma, MD, PhD, Professor of Pathology, veli-matti.kosma(at)uef.fi

Arto Mannermaa, PhD, Adjunct Professor, arto.mannermaa(at)uef.fi

Ylermi Soini, MD, PhD, Professor of Pathology, ylermi.soini(at)uef.fi

Reijo Sironen, Md, PhD, Senior Researcher, reijo.sironen(at)uef.fi

Project overview

We have two major research entities employing researchers with varying expertise, laboratory personnel and administrative staff. We aim to study the etiology and pathogenesis of malignant diseases with a special emphasis on the histopathologic, molecular pathologic and genetic/genomic factors. Profound collaboration between several research groups at the UEF and Kuopio University Hospital (KUH) as well as with our national and international colleagues is vital for thriving achievements.

Research Topics

1. Cancer Genetics/Genomics and Epigenetics:

  • Important common genetic variants that underlie breast cancer risk, and their effects on risk, individually and in combination.
  • Interaction between genetic loci and known or suspected environmental/lifestyle risk factors.
  • Association between genetic factors, environmental/lifestyle risk factors and cancer risk for certain tumour subtypes, and their effect on clinical outcome.
  • Functional effects of candidate breast cancer risk and clinical outcome affecting genes and gene variants
  • Global histone modification patterns in ER-alpha + and - breast cancer and their effect on clinical outcome.
  • Cell culture models of the data.

2.Interaction between cancer cell and tumour stroma:

  • Regulation of  epitheliomesenchymal transition (EMT) and its involvement in cancer spread and metastasis
  • Involvement of cancer associated fibroblasts and stem cells in tumor spread and involvement of endotheliomesenchymal transition in tumor progression
  • Regulation of mesenchymoepithelial transition (MET) at distant tumor sites
  • Impact of reactive oxygen species on tumor behaviour and the role of nrf2 and keap1 in tumorigenesis, therapy resistance and cancer risk
  • Mechanistic interactions between EMT,  stemness, and oxidative mechanisms which  we believe are highly connected.

Research Group

Jaana Hartikainen, Hanna Tuhkanen, Hanna Peltonen, Kaisa Nieminen, Maria Tengström, Mikko Pelkonen, Marie Tuomarila, Hermanni Ahonen, Anna Jouppila-Mättö, Timo Nykopp, Katri Uimonen

Laboratory personnel

Helena Kemiläinen, Aija Parkkinen, Eija Myöhänen

Funding sources

Finnish Cancer Organisations, Competitive Research Funding of the Northern Savo Hospital District special state subsidy for health research (KUH EVO/VTR-funding), Academy of Finland, UEF strategic funding (Spear Head Projects) and others.

Collaboration

Collaborations within the University:  Collaborations in Kuopio have involved researchers from Medical Biochemistry, Oncology, Surgery, Radiology, Dermatology, Anatomy, Gynecology and Obstetrics, Clinical Microbiology, Otorhinolaryngology and Head and Neck Surgery, Internal Medicine, Pulmonary Section, Urology, Neurosurgery and AIV-Institute. National Collaborations: Researches from Oncology, Pathology, Cancer Genetics, Internal Medicine, pulmonary section and Institute of Dentistry, University of Oulu and Oulu University Hospital as well as researches from Biomedicum, University of Helsinki, Helsinki University Hospital and University of Turku and University of Tampere. International collaboration: Breast Cancer Association Consortium (BCAC, http://ccge.medschl.cam.ac.uk/consortia/bcac/index.html) including 71 research groups. The consortium is lead by Dr. Douglas Easton, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK. Others: University of Naples, Italy; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; The Medical University of Sapporo, Hokkaido, Japan; COGS Breast Cancer Consortium and The Beijing Genome Institute, Shenzhen, China.

Selected Recent Publications

Easton DF, Pooley KA, Dunning AM, Pharoah PD, …, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE, Cox DR, Ponder BA. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007 Jun 28;447(7148):1087-93.

Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, Kallioniemi A, Pylkäs K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007 Mar 15;446(7133):316-9. Epub 2007 Feb 7.

Ahmed S, Thomas G, Ghoussaini M, Healey CS, …Mannermaa A, Kosma VM, Kataja V…, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, Easton DF. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet. 2009 May;41(5):585-90. doi: 10.1038/ng.354. Epub 2009 Mar 29.

Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjäkoski K, Kallioniemi A, Kilpivaara O, Mannermaa A, Kosma VM, Uusitupa M, Eskelinen M, Kataja V, Aittomäki K, von Smitten K, Heikkilä P, Lukas J, Holli K, Bartkova J, Blomqvist C, Bartek J, Nevanlinna H. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet. 2008 Jul;40(7):844-53.

Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, … Mannermaa A, Hartikainen J, Kataja V, Kosma VM, … …,Pharoah PD, Easton DF; Breast Cancer Association Consortium. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007 Mar;39(3):352-8.

Hein R, Flesch-Janys D, Dahmen N, Beckmann L, …, Kataja V, Kosma VM, Mannermaa A, Anton-Culver H, …Couch FJ, Easton DF, Hall P, Chang-Claude J: A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication. Breast Cancer Res Treat 2013 Feb 20. (Epub ahead of print).

Malinen M, Jääskelainen T, Pelkonen M, Heikkinen S, Väisanen S, Kosma V-M, Nieminen K, Mannermaa A, Palvimo JJ: Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors. Mol Cell Endocrinol 365:2:270-276, 2013. IF= 4.192

Auvinen P, Tammi R, Kosma V-M, Sironen R, Soini Y, Mannermaa A, Tumelius R, Uljas E, Tammi M: Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer. Int J Cancer 132:3:531-539, 2013. IF= 5.444

Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y: Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat 2013 Feb 15 (Epub ahead of print). IF= 4.431

Merikallio H, Turpeenniemi-Hujanen T, Pääkkö P, Mäkitaro R, Riitta K, Salo S, Salo T, Harju T, Soini Y: Snail promotes an invasive phenotype in lung carcinoma. Respir Res 13(1):104, 2012. IF= 3.360

Weischer M, Nordestgaard BG, Pharoah P,…Mannermaa A,…Kosma V-M, …Kataja V,…Meyer A, Easton DF, Schmidt MK, Bojesen SE: CHEK2#1100delC heterozygosity in women with breast cancer associated with early death, breast cancer -specific death, and increased risk of a second breast cancer. J Clin Oncol 30:4308-4316, 2012. IF= 18.372

Ghoussaini M, Fletcher O, Michailidou K, Tumbull C,…Mannermaa A, Kataja V, Kosma V-M, Hartikainen JM,…Dunning AM, Rahman N, Peto J, Easton DF: Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44:3: 312-218, 2012. IF= 35.532

Berdel B, Nieminen K, Soini Y, Tendström M, Malinen M, Kosma V-M, Palvimo J, Mannermaa A: Histone demethylase GASC 1- a potential prognostic and predictive marker in invasive breast cancer. BMC Cancer 12:516, 2012. IF= 3.011

Hartikainen JM, Tengström M, Kosma VM, Kinnula VL, Mannermaa A, Soini Y: Genetic polymorphisms and protein expression of NRF2 and sulfiredoxin predict survival outcomes in breast cancer. Cancer Res 72:5537-46, 2012. IF= 7.856

Haiman CA, Chen GK, Vachon CM,…Kosma V-M,…Mannermaa A,...Stram DO, Easton D, Kraft P, Henderson BE, Couch FJ: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet 43:12: 1210-1214, 2011. IF= 35.532

Stevens KN, Vachon CM, Lee AM,…Kosma V-M, ..Mannermaa A,…Nevanlinna H, Wang X, Couch FJ: Common breast cancer susceptibility loci are associated with triple negative breast cancer. Cancer Res 71: 19: 6240-6249, 2011a. IF= 7.856

Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, Milne RL,…Mannermaa A, Kosma V-M, Kauppinen J, Kataja V, Auvinen P, Soini Y, Sironen R,…Easton D, Pharoah P, Sherman ME, Garcia-Closas M: Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the breast cancer association consortium studies. J Natl Cancer Inst 103:3:250-263, 2011. IF= 13.757

Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma V-M: Hyaluronan in human malignancies. Exp Cell Res 317: 383-391, 2011. IF= 3.580

Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, Mannermaa A, Kosma V-M: Transcription factors zeb1, twist and snail1 in breast carcinoma. BMC Cancer 11:73, 2011. IF= 3.011

Jouppila-Mättö A, Närkiö-Mäkelä M, Soini Y, Pukkila M, Sironen R, Tuhkanen H, Mannermaa A, Kosma V-M: Twist and snail 1 expression in pharyngeal squamous cell carcinoma stroma is related to cancer progression. BMC Cancer 11: 350, 2011. IF= 3.011