title: The association of tumor microsatellite instability phenotype with family history of colorectal cancer.
abstract: Family history is a strong predictor of colorectal cancer risk; however, a diagnosis of colorectal cancer among first-degree relatives has not been systematically investigated as a function of the colorectal cancer molecular subtypes related to tumor microsatellite instability (MSI) status. We investigated whether the observable familial colorectal cancer risks differed according to tumor MSI subtypes, stratified as MSI-High (>30% instability), MSI-Low (<30% instability), and MSS (no instability). Data from 3,143 population-based colorectal cancer cases from five institutions were assessed for family history according to the Amsterdam criteria and the Bethesda guidelines, age at diagnosis, sex, tumor location, and MSI status. The distribution of patient characteristics by MSI status was compared using polytomous logistic regression. Overall, 2.8% colorectal cancer cases met the Amsterdam criteria and 37% met the Bethesda guidelines. There were 14% MSI-High, 13% MSI-Low, and 73% MSS colorectal cancers. MSI-High (P<0.0001) and MSI-Low tumors (P=0.01) were more proximally located than MSS tumors. MSI-High tumors were more common among females (P<0.001). The highest proportion of MSI-High tumors occurred in cases<40 years of age whereas the age-dependent distribution of MSI-Low tumors was unchanged. MSI-High tumors showed a statistically significant association with increasing numbers of first-degree relatives with colorectal cancer (P=0.002); this association disappeared, however, when MSI-High cases meeting Amsterdam criteria were removed from the analysis. MSI-Low tumors did not show a similar association with family history of colorectal cancer. Familial risk associated with MSI-High tumors is primarily driven by the Amsterdam-criteria patients. MSI-Low tumors may represent a distinct subtype of colorectal cancer with respect to certain epidemiologic variables studied here.
authors.affiliation: Department of Pathology and Lab Medicine, Mount Sinai Hospital, and Samuel Lunenfeld Research Institute, University of Toronto, 60 Murray Street, Box 30, Toronto, M5T 3L9, Ontario, Canada. bapat@lunenfeld.ca
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: John
authors.initials: J
authors.lastname: Baron
authors.forename: Kim
authors.initials: K
authors.lastname: Siegmund
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.forename: Mark
authors.initials: M
authors.lastname: Jenkins
authors.forename: John
authors.initials: J
authors.lastname: Grove
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Dennis
authors.initials: D
authors.lastname: Ahnen
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D018570:Risk Assessment