title: Familial colorectal cancer type X syndrome: two distinct molecular entities?
abstract: In a fraction of families fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer, colorectal cancers are microsatellite stable and DNA mismatch repair gene (MMR) mutations are not found. These families were designated as familial colorectal cancer type X (FCCTX). We aimed to characterise a group of FCCTX families defined by the Amsterdam criteria and MSS tumours at clinical and molecular level. Twenty-four tumours from 15 FCCTX families were analysed for loss of known tumour suppressor gene (TSG) loci (APC, TP53, SMAD4 and DCC), MGMT and MMR genes promoter methylation, and also APC and KRAS somatic mutations. FCCTX families presented specific clinical features: absence of endometrial tumours, high adenoma/carcinoma ratio (1.91) and prevalence of rectal cancers (13/27, 48%). New molecular features were found: the majority of FCCTX tumours (13/18; 72%) presented TSG loss. TSG loss positive tumours presented frequent APC and KRAS somatic mutations and MGMT methylation [10/13 (77%), 7/13 (54%) and 6/11 (54%), respectively]. In TSG loss negative tumours (5/18; 28%), the same molecular events were found in 2/5 (40%), 2/5 (40%) and 1/3 (33%) tumours, respectively. Transition mutations in KRAS were more frequent among MGMT methylated tumours than in unmethylated [5/8 (63%) vs. 1/10 (10%), P = 0.03]. Although sharing similar clinical features, at least two different molecular entities should exist among FCCTX families, one whose tumours present frequent TSG loss, APC and KRAS somatic mutations, and MGMT promoter methylation, and a second, lesser predominant, with no evidence of TSG loss and rarely presenting promoter methylation.
authors.affiliation: Centro de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Francisco
authors.forename: Cristina
authors.initials: C
authors.lastname: Albuquerque
authors.forename: Pedro
authors.initials: P
authors.lastname: Lage
authors.forename: Hélio
authors.initials: H
authors.lastname: Belo
authors.forename: Inês
authors.initials: I
authors.lastname: Vitoriano
authors.forename: Bruno
authors.initials: B
authors.lastname: Filipe
authors.forename: Isabel
authors.initials: I
authors.lastname: Claro
authors.forename: Sara
authors.initials: S
authors.lastname: Ferreira
authors.forename: Paula
authors.initials: P
authors.lastname: Rodrigues
authors.forename: Paula
authors.initials: P
authors.lastname: Chaves
authors.forename: Carlos Nobre
authors.initials: CN
authors.lastname: Leitão
authors.forename: António Dias
authors.initials: AD
authors.lastname: Pereira
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000145:classification / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000145:classification / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011174:Portugal; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D009687:Nuclear Proteins