title: Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome).
abstract: Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
authors.affiliation: Familial Cancer Laboratory, Queensland Institute of Medical Research, Herston, QLD 4006, Australia.
authors.forename: Aedan
authors.initials: A
authors.lastname: Roberts
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: Darin
authors.initials: D
authors.lastname: Taverna
authors.forename: Diane
authors.initials: D
authors.lastname: McKeone
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Walters
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Young
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Michael
authors.initials: M
authors.lastname: Gattas
authors.forename: Elise
authors.initials: E
authors.lastname: Pelzer
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Jill
authors.initials: J
authors.lastname: George
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Suthers
authors.forename: Kerry
authors.initials: K
authors.lastname: Phillips
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Sonja
authors.initials: S
authors.lastname: Woodall
authors.forename: Julie
authors.initials: J
authors.lastname: Arnold
authors.forename: Kathy
authors.initials: K
authors.lastname: Tucker
authors.forename: Amanda
authors.initials: A
authors.lastname: Muir
authors.forename: Musa
authors.initials: M
authors.lastname: Drini
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Polly
authors.initials: P
authors.lastname: Newcomb
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Erika
authors.initials: E
authors.lastname: Pavluk
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D013577:Syndrome