Colorectal cancer – update on immunohistochemistry and molecular morphology
Colorectal cancer (CRC) is a leading cause of cancer deaths, and it develops as a consequence of various genetic and epigenetic alterations. Molecular background of CRC has an effect on patient prognosis and treatment response, emphasizing the need for diagnostic tests that can identify these different molecular subtypes. Transcriptomic analyses have identified distinct molecular subtypes of colorectal, some of which can be identified by immunohistochemical analysis. Lynch syndrome, the most common form of hereditary CRC, is caused by inactivating mutations involving DNA mismatch repair (MMR) genes. This leads to microsatellite instability (MSI) and increased risk for cancer development especially in the colorectum and the endometrium. Initial testing of tumor tissues for the presence of MMR gene deficiency is standard practice with immunohistochemistry and/or PCR-based microsatellite instability analysis. The ultimate diagnosis of Lynch syndrome requires documentation of mutation within one of the four MMR genes (MLH1, PMS2, MSH2 and MSH6) or EPCAM, currently achieved by next generation sequencing analysis of the germline DNA. MSI may also be used as a biomarker for PD1/PD-L1 blockade. In this case, MSI usually arises more commonly from a somatic hypermethylation of the MLH1 promoter. The result is a cancer with a several fold increase in mutation rate, associated with poor histological differentiation, an intense lymphocytic infiltrate and an improved prognosis. In addition to MMR gene products, BRAF V600E mutation can be analyzed by immunohistochemistry, which has high diagnostic accuracy when compared to DNA mutation analysis. Identification of BRAF V600E mutation in a MSI-H CRC tissue practically rules out Lynch syndrome and thus can be used as a screening test to exclude individuals from the germ line testing. Furthermore, immunohistochemistry is used in differential diagnostics of poorly differentiated carcinomas of the colorectum, in identification of tumor budding and potentially also in testing CRC patients who may benefit from anti-HER2 treatment.
- Ålgars A, Sundström J, Lintunen M, Jokilehto T, Kytölä S, Kaare M, Vainionpää R, Orpana A, Österlund P, Ristimäki A, Carpen O, Ristamäki R. EGFR gene copy number predicts response to anti-EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. Int J Cancer. 2017 Feb 15;140(4):922-929.
- Taipale K, Liikanen I, Juhila J, Turkki R, Tähtinen S, Kankainen M, Vassilev L, Ristimäki A, Koski A, Kanerva A, Diaconu I, Cerullo V, Vähä-Koskela M, Oksanen M, Linder N, Joensuu T, Lundin J, Hemminki A. Chronic Activation of Innate Immunity Correlates With Poor Prognosis in Cancer Patients Treated With Oncolytic Adenovirus. Mol Ther. 2016 Feb;24(1):175-83.
- Thiel A, Moza M, Kytölä S, Orpana A, Jahkola T, Hernberg M, Virolainen S, Ristimäki A. Prospective immunohistochemical analysis of BRAF V600E mutation in melanoma. Hum Pathol. 2015 Feb;46(2):169-75.
- Nummela P, Saarinen L, Thiel A, Järvinen P, Lehtonen R, Lepistö A, Järvinen H, Aaltonen LA, Hautaniemi S, Ristimäki A. Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry. Int J Cancer. 2015 Mar 1;136(5):E282-9.
- Thiel A, Heinonen M, Kantonen J, Gylling A, Lahtinen L, Korhonen M, Kytölä S, Mecklin JP, Orpana A, Peltomäki P, Ristimäki A. BRAF mutation in sporadic colorectal cancer and Lynch syndrome. Virchows Arch. 2013 Nov;463(5):613-21.
- Thiel A, Narko K, Heinonen M, Hemmes A, Tomasetto C, Rio MC, Haglund C, Mäkelä TP, Ristimäki A. Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice. Int J Cancer. 2012 Sep 1;131(5):1032-41
Ari Ristimäki, MD/PhD, Professor of Molecular Pathology, Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
1.1. 2016 onwards: Professor of Molecular Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
1.8. 2010 onwards: Head of Gastrointestinal Pathology and Coordinator of Molecular Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland.
1.1. 2007 onwards: Principal Investigator, Genome-Scale Biology Research Programs Unit, University of Helsinki, Helsinki, Finland.
Research experience and previous professor appointments:
Professor Ari Ristimäki has published 148 original articles and 35 reviews, editorials and book chapters. He also has supervised nine doctoral dissertations.
Professor of Clinical (Surgical/Histological) Pathology, Faculty of Medicine, University of Helsinki, Finland, 1.8.2009-31.12.2015.
Professor of (Surgical/Histological) Pathology, Faculty of Medicine, University of Oulu, Finland, 1.1.2009-31.7.2010.
European Helicobacter Study Group, board member, 2008 onwards.
United European Gastroenterelogy (UEG), committee member, Future trends committee, 2010-4.
Nordic immunohistochemical quality control (NordiQC), core group member, 2011-6.
European Network of Gastrointestinal Pathology, steering committee member, 2012-6.
Advisory Board on Biotechnology (Ministry of Social Affairs and Health), Chair of the health issue group, 2011-2016
The Finnish Medical Society Duodecim, vice Chair of the board, 2016-9.
Helsinki University Hospital board of research funding, 2014 onwards and Chair 2016 onwards.
HUS Biobank scientific/ethical advisory board, vice Chair, 2016 onwards.
2005: Specialist in surgical pathology, University of Helsinki, Helsinki, Finland.
1997: Docent (senior lecturer) of Cell Biology, University of Helsinki, Helsinki, Finland.
1992-5: Postdoctoral Fellow, Department of Molecular Biology, Holland Laboratory, American Red Cross, MD, USA (Fogarty Fellow), 1992-5.
1991: Doctor of Medicine (MD/PhD), University of Helsinki, Helsinki, Finland.
1990: Licentiate of Medicine (MD), University of Helsinki, Helsinki, Finland.
1982 Matriculation, Martinlaakso High School, Vantaa, Finland.
1980 Matriculation, Petaluma High School, Petaluma, CA, USA.