title: Serrated polyposis associated with a family history of colorectal cancer and/or polyps: The preferential location of polyps in the colon and rectum defines two molecular entities.
abstract: Serrated polyposis (SPP) is characterized by the development of multiple serrated polyps and an increased predisposition to colorectal cancer (CRC). In the present study, we aimed to characterize, at a clinical and molecular level, a cohort of SPP patients with or without a family history of SPP and/or polyps/CRC (SPP-FHP/CRC). Sixty-two lesions from 12 patients with SPP-FHP/CRC and 6 patients with sporadic SPP were included. The patients with SPP-FHP/CRC presented with an older mean age at diagnosis (p=0.027) and a more heterogeneous histological pattern of lesions (p=0.032) than the patients with sporadic SPP. We identified two molecular forms of SPP-FHP/CRC, according to the preferential location of the lesions: proximal/whole-colon or distal colon. Mismatch repair (MMR) gene methylation [mutS homolog 6 (MSH6)/mutS homolog 3 (MSH3)] or loss of heterozygosity (LOH) of D2S123 (flanking MSH6) were detected exclusively in the former (p=3.0x10-7), in most early lesions. Proximal/whole‑colon SPP-FHP/CRC presented a higher frequency of O-6-methylguanine-DNA methyltransferase (MGMT) methylation/LOH, microsatellite instability (MSI) and Wnt mutations (19/29 vs. 7/17; 16/23 vs. 1/14, p=2.2x10-4; 15/26 vs. 2/15, p=0.006; 14/26 vs. 4/20, p=0.02) but a lower frequency of B-raf proto-oncogene, serine/threonine kinase (BRAF) mutations (7/30 vs. 12/20, p=0.0089) than the distal form. CRC was more frequent in cases of Kirsten rat sarcoma viral oncogene homolog (KRAS)-associated proximal/whole-colon SPP-FHP/CRC than in the remaining cases (4/4 vs. 1/8, p=0.01). Thus, SPP-FHP/CRC appears to be a specific entity, presenting two forms, proximal/whole-colon and distal, which differ in the underlying tumor initiation pathways. Early MGMT and MMR gene deficiency in the former may underlie an inherited susceptibility to genotoxic stress.
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Silva
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Albuquerque
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Lage
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fontes
authors.affiliation: Pathology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Vitoriano
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Filipe
authors.affiliation: Familial Cancer Risk Clinic, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Rodrigues
authors.affiliation: Molecular Pathobiology Research Unit (UIPM), Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Moita
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Ferreira
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Sousa
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Claro
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Nobre Leitão
authors.affiliation: Pathology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Chaves
authors.affiliation: Gastroenterology Service, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E. (IPOLFG, EPE), Lisbon, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Dias Pereira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012007:Rectum / Q000378:metabolism / Q000473:pathology*; D017422:Sequence Analysis, DNA / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C117307:KRAS protein, human; C000715470:MAS1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D045643:DNA Repair Enzymes