title: Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors.
abstract: Some patients happen to have a colorectal cancer with microsatellite instability (MSI), but without any alteration in Mismatch Repair (MMR) system (germline mutation/promoter methylation). We aimed to identify the mechanism of inactivation of MMR genes in those cases. We studied 18 patients with MSI CCR and loss of expression of a MMR protein. DNA was extracted from tumoral and normal colonic material. We studied the 3 main MMR genes in tumors, by sequencing and large rearrangement analysis, and looked for mosaicism. Seven patients lost expression of MLH1, we found 1 mutation in the tumor for 3 patients and 2 mutations in one. Eight patients lost expression of MSH2: we found 1 mutation in 2 patients and 2 mutations in four. In the 5 cases with 2 hits, MSI was due to double somatic hits (n = 3), mosaicism (n = 1) and missed germline mutation (n = 1). Mosaicism was confirmed by HRM analysis, and by finding a germline mutation in one patient's son. We could explain MSI in the tumors of 5 patients (27.8 %). Their follow up and family's surveillance could be adjusted, as the sporadic cases don't require intensive surveillance. We describe the first case of somatic mosaicism after de novo mutation in MSH2.
authors.affiliation: Department of Digestive Surgery, Hôpital Saint Antoine (AP-HP), Paris VI University, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sourrouille
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.forename: Jeremie H
authors.initials: JH
authors.lastname: Lefevre
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Colas
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.forename: Armelle
authors.initials: A
authors.lastname: Bardier-Dupas
authors.forename: Yann
authors.initials: Y
authors.lastname: Parc
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
mesh_terms: D000328:Adult; D000368:Aged; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009030:Mosaicism; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D055815:Young Adult
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein