Author:
Møller Pal,Seppälä Toni T.,Ahadova Aysel,Crosbie Emma J.,Holinski-Feder Elke,Scott Rodney,Haupt Saskia,Möslein Gabriela,Winship Ingrid,Broeke Sanne W. Bajwa-ten,Kohut Kelly E.,Ryan Neil,Bauerfeind Peter,Thomas Laura E.,Evans D. Gareth,Aretz Stefan,Sijmons Rolf H.,Half Elizabeth,Heinimann Karl,Horisberger Karoline,Monahan Kevin,Engel Christoph,Cavestro Giulia Martina,Fruscio Robert,Abu-Freha Naim,Zohar Levi,Laghi Luigi,Bertario Lucio,Bonanni Bernardo,Tibiletti Maria Grazia,Lino-Silva Leonardo S.,Vaccaro Carlos,Valle Adriana Della,Rossi Benedito Mauro,da Silva Leandro Apolinário,de Oliveira Nascimento Ivana Lucia,Rossi Norma Teresa,Dębniak Tadeusz,Mecklin Jukka-Pekka,Bernstein Inge,Lindblom Annika,Sunde Lone,Nakken Sigve,Heuveline Vincent,Burn John,Hovig Eivind,Kloor Matthias,Sampson Julian R.,Dominguez-Valentin Mev,
Abstract
AbstractThe recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
Funder
The Norwegian Cancer Society
Cancer Society Finland, Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Relander Foundation and the Academy of Finland.
EJC and DGE are funded by the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre
JRS received grant support previously from Health and Care Research Wales for the Wales Gene Park
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Oncology