TY - JOUR
T1 - Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
AU - Møller, Pål
AU - Seppälä, Toni T.
AU - Ahadova, Aysel
AU - Crosbie, Emma J.
AU - Holinski-Feder, Elke
AU - Scott, Rodney
AU - Haupt, Saskia
AU - Möslein, Gabriela
AU - Winship, Ingrid
AU - Broeke, Sanne W.Bajwa ten
AU - Kohut, Kelly E.
AU - Ryan, Neil
AU - Bauerfeind, Peter
AU - Thomas, Laura E.
AU - Evans, D. Gareth
AU - Aretz, Stefan
AU - Sijmons, Rolf H.
AU - Half, Elizabeth
AU - Heinimann, Karl
AU - Horisberger, Karoline
AU - Monahan, Kevin
AU - Engel, Christoph
AU - Cavestro, Giulia Martina
AU - Fruscio, Robert
AU - Abu-Freha, Naim
AU - Zohar, Levi
AU - Laghi, Luigi
AU - Bertario, Lucio
AU - Bonanni, Bernardo
AU - Tibiletti, Maria Grazia
AU - Lino-Silva, Leonardo S.
AU - Vaccaro, Carlos
AU - Valle, Adriana Della
AU - Rossi, Benedito Mauro
AU - da Silva, Leandro Apolinário
AU - de Oliveira Nascimento, Ivana Lucia
AU - Rossi, Norma Teresa
AU - Dębniak, Tadeusz
AU - Mecklin, Jukka Pekka
AU - Bernstein, Inge
AU - Lindblom, Annika
AU - Sunde, Lone
AU - Nakken, Sigve
AU - Heuveline, Vincent
AU - Burn, John
AU - Hovig, Eivind
AU - Kloor, Matthias
AU - Sampson, Julian R.
AU - Dominguez-Valentin, Mev
N1 - Funding Information:
PM, EH and MD-V received a grant from The Norwegian Cancer Society, Contract 194751–2017. TTS received grants from 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 (IS-BRC-1215–20007), IS-BRC-1215–20007. JRS received grant support previously from Health and Care Research Wales for the Wales Gene Park.
Publisher Copyright:
© 2023, BioMed Central.
PY - 2023/10
Y1 - 2023/10
N2 - The 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.
AB - The 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.
U2 - 10.1186/s13053-023-00263-3
DO - 10.1186/s13053-023-00263-3
M3 - Review Article
AN - SCOPUS:85173795794
SN - 1731-2302
VL - 21
JO - HEREDITARY CANCER IN CLINICAL PRACTICE
JF - HEREDITARY CANCER IN CLINICAL PRACTICE
M1 - 19
ER -
