title: Multiplicity and molecular heterogeneity of colorectal carcinomas in individuals with serrated polyposis.
abstract: Serrated polyposis (SP) is a clinically defined syndrome characterized by the occurrence of multiple serrated polyps in the large intestine. Individuals with SP and their relatives are at increased risk of colorectal carcinoma (CRC). We aimed to determine the pathologic and molecular profiles of CRCs in individuals fulfilling World Health Organization criteria for SP. A total of 45 CRCs were obtained from 38 individuals with SP (27 female and 11 male patients; median age at CRC diagnosis, 58.5 y) attending genetics clinics. Tumor samples were pathologically reviewed, screened for somatic BRAF and KRAS mutations, and analyzed immunohistochemically for mismatch repair protein (MMR) expression. Tumors were spread throughout the large intestine, with 64% located in the proximal colon. Mutations in BRAF and KRAS and immunohistochemical evidence of MMR deficiency were found in 46%, 5%, and 38%, respectively. Nearly half of CRCs were BRAF/KRAS wild type, and these were associated with distal location (63%) and MMR proficiency (84%). Overexpression of p53 and/or evidence of β-catenin activation were identified in 13 CRCs. Ten patients (26%) had synchronous or metachronous CRCs. In conclusion, the majority of CRCs arising in individuals with SP do not harbor molecular hallmarks of serrated pathway CRCs but show a diverse range of molecular profiles. The high proportion of multiple CRCs suggests that individuals with SP would benefit from frequent colonoscopic surveillance and from a consideration of a more extensive colectomy at the time of CRC diagnosis.
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Bancroft Centre, Herston, Qld, Australia. c.rosty@uq.edu.au
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Pearson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Kevin
authors.initials: K
authors.lastname: Sweet
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Kathy
authors.initials: K
authors.lastname: Tucker
authors.forename: Sian
authors.initials: S
authors.lastname: Greening
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gattas
authors.forename: Sonja
authors.initials: S
authors.lastname: Woodall
authors.forename: Julie
authors.initials: J
authors.lastname: Arnold
authors.forename: Neal I
authors.initials: NI
authors.lastname: Walker
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D003111:Colonic Polyps / Q000150:complications* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D055815:Young Adult