Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.
Pal MøllerToni T SeppäläAysel AhadovaEmma J CrosbieElke Holinski-FederRodney ScottSaskia HauptGabriela MösleinIngrid WinshipSanne W Bajwa-Ten BroekeKelly E KohutNeil RyanPeter BauerfeindLaura E ThomasD Gareth EvansStefan AretzRolf H SijmonsElizabeth HalfKarl HeinimannKaroline HorisbergerKevin MonahanChristoph EngelGiulia Martina CavestroRobert FruscioNaim Abu-FrehaLevi ZoharLuigi LaghiLucio BertarioBernardo BonanniMaria Grazia TibilettiLeonardo S Lino-SilvaCarlos VaccaroAdriana Della ValleBenedito Mauro RossiLeandro Apolinário da SilvaIvana Lucia de Oliveira NascimentoNorma Teresa RossiTadeusz DębniakJukka-Pekka MecklinInge BernsteinAnnika LindblomLone SundeSigve NakkenVincent HeuvelineJohn BurnEivind HovigMatthias KloorJulian R SampsonMev Dominguez-Valentinnull nullPublished in: Hereditary cancer in clinical practice (2023)
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.
Keyphrases
- papillary thyroid
- early onset
- squamous cell
- genome wide
- copy number
- childhood cancer
- public health
- low dose
- late onset
- genome wide identification
- type diabetes
- young adults
- gene expression
- cardiovascular disease
- induced apoptosis
- cell death
- antiplatelet therapy
- acute coronary syndrome
- dna methylation
- transcription factor
- neural network