Research

INTERNATIONAL LYNCH SYNDROME RESEARCH

Inherited MMR deficiency, i.e. Lynch syndrome, gives rise to a broad spectrum of tumors, especially colorectal and endometrial cancers, but also ovarian, gastric, urinary, small bowel, brain and bile duct/gallbladder cancers. The history of international Lynch syndrome research can be traced back to 1895 and the discovery of a family cancer syndrome. The disease was characterized by Henry T. Lynch in 1966 and came to be known as Hereditary NonPolyposis Colorectal Cancer (HNPCC), which in honour of Dr. Lynch’s findings, was later termed Lynch syndrome. The molecular genetics era began in 1993 when a germline MMR gene mutation was identified as a cause of LS. Currently Lynch syndrome research is being actively carried out worldwide, with an approach that focuses on obtaining a deeper understanding of the molecular mechanism behind LS, enabling preventive diagnosis and personalized medical care.

RESOURCES

International Society for Gastrointestinal Hereditary Tumors (InSiGHT) is an international multidisciplinary, scientific organization with the mission to improve the quality of care of patients and their families with any condition resulting in hereditary gastrointestinal tumors. The inventors, scientific advisors, key collaborators, and LS CancerDiag Ltd employees have actively participated in the activities of InSiGHT.

Finnish HNPCC is a group formed by leading Finnish Lynch syndrome researchers. The group is actively involved in several projects on the MMR mechanism and LS in collaboration with Central University Hospitals in Finland.

International Agency for Cancer Research (IARC) is the specialized cancer agency of the World Health Organization. The objective of the IARC is to promote international collaboration in cancer research to adopt preventive measures and reduce cancer mortality.

ACADEMIC RESEARCH ROOT OF DIAGMMR

The DiagMMR innovation is based on more than 20 years of academic research at the University of Helsinki, where the functional MMR assay research and development has resulted in 7 PhDs and 30 original peer-reviewed publications in the 2000’s. DiagMMR is an advanced application of an in vitro MMR assay used for the functional characterization of MMR gene mutations.

ORIGINAL ARTICLES

Kansikas M, Vähätalo L, Kantelinen J, Kasela M, Putula J, Døhlen A, Paloviita P, Kärkkäinen E, Lahti N, Arnez P, Kilpinen S, Alcala-Repo B, Pylvänäinen K, Pöyhönen M, Peltomäki P, Järvinen HJ, Seppälä TT, Renkonen-Sinisalo L, Lepistö A, Mecklin JP, Nyström M; Tumor-independent detection of inherited mismatch repair deficiency for the diagnosis of Lynch syndrome with high specificity and sensitivity. Cancer Res Commun 3: 361–370, 2023.

Peltomäki P, Nyström M, Mecklin JP, Seppälä TT. Lynch Syndrome Genetics and Clinical Implications. Gastroenterology 164: 783-799, 2023.

Kasela M, Nyström M, Kansikas M. PMS2 expression decrease causes severe problems in mismatch repair. Hum Mutat 40: 904- 907, 2019.

Tricarico R, Kasela M, Mareni C, Thompson BA, Drouet A, Staderini L, Gorelli G, Crucianelli F, Ingrosso V, Kantelinen J, Papi L, De Angioletti M, Berardi M, Gaildrat P., Soukarieh O, Turchetti D, Martins A, Spurdle AB, Nyström M, Genuardi, M. & InSiGHT Variant Interpretation Committee. Assessment of the InSiGHT interpretation criteria for the clinical classification of 24 MLH1 and MSH2 gene variants. Hum Mutat 38: 64-77, 2016

Kansikas M, Kasela M, Kantelinen J, Nyström M. Assessing how reduced expression levels of the mismatch repair genes MLH1, MSH2, and MSH6 affect repair efficiency. Hum Mutat 35:1123-1127, 2014.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, Martins A, Moller P, Morak M, Nystrom M, Peltomaki P, Pineda M, Qi M, Ramesar R, Rasmussen LJ, Royer-Pokora B, Scott RJ, Sijmons R, Tavtigian SV, Tops CM, Weber T, Wijnen J, Woods MO, Macrae F, Genuardi M. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46: 107-15, 2014.

Kantelinen J, Kansikas M, Candelin S, Hampel H, Smith B, Holm L, Kariola R, Nyström M. Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients. Hum Mutat 33: 1294-1301, 2012.

Kantelinen J, Hansen TVO, Kansikas M, Nylandsted Krogh L, Korhonen MK, Ollila S, Nyström M, Gerdes A-M, Kariola R. A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance – functional analysis reveals the pathogenic one. Fam Cancer 10: 515-520, 2011.

Kansikas M, Kariola R, Nyström M. Verification of the Three Step Model in Assessing the Pathogenicity of Mismatch Repair Gene Variants. Hum Mutat 32: 107-115, 2011.

Ollila, S, Dermadi Bebek D, Jiricny J, Nyström M. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat 29: 1355-1363, 2008.

Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes A-M, Peltomäki P, Mangold E, de la Chapelle A, Greenblatt M, Nyström M. Pathogenicity of MSH2 Missense Mutations is Typically Associated with Impaired Repair Capability of the Mutated Protein. Gastroenterology 131: 1408-1417, 2006.

Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lönnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes A-M, Peltomäki P, Kohonen-Corish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, and Nyström M. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 129: 537-549, 2005.

Kariola R, Hampel H, Frankel WL, Raevaara TE, de la Chapelle A, and Nyström-Lahti M. MSH6 missense mutations are often associated with no or low cancer susceptibility. Brit J Cancer 91: 1287-1292, 2004.

Kariola R, Otway R, Lönnqvist KE, Raevaara TE, Macrae F, Vos YJ, Kohonen-Corish M, Hofstra RMW, Nyström-Lahti M. Two mismatch repair gene mutations found in a colon cancer patient – which one is pathogenic? Hum Genet 112: 105-109, 2003.

Kariola R, Raevaara TE, Lönnqvist KE, Nyström-Lahti M. Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome. Hum Mol Genet 11: 1303-1310, 2002.

Nyström-Lahti M, Perrera C, Räschle M, Panyushkina-Seiler E, Marra G, Curci A, Quaresima B, Costanzo F, D’Urso M, Venuta S, Jiricny J. Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes, Chromosomes & Cancer 33: 160-167, 2002.

Schweizer P, Moisio A-L, Kuismanen SA, Truninger K, Vierumäki R, Salovaara R, Arola J, Butzow R, Jiricny J, Peltomäki P, Nyström-Lahti M. Lack of MSH2 and MSH6 characterizes endometrial but not colon carsinomas in hereditary nonpolyposis colorectal cancer. Cancer Res 61: 2813-2815, 2001.

Nyström-Lahti M, Wu Y, Moisio A-L, Hofstra RMW, Osinga J, Mecklin J-P, Järvinen HJJ, Leisti J, Buys CHCM, de la Chapelle A, Peltomäki P: DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 5:763-769, 1996.

Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M, Guan X-Y, Zhang J, Meltzer PS, Yu J-W, Kao F-T, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin J-P, Järvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B: Mutations of a MutS homolog in hereditary non-polyposis colorectal cancer. Cell 75: 1215-1225, 1993.