Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients.
We examined the influence that rare variants and low-frequency polymorphisms in the cancer candidate gene CCND1 have on the development of multiple intestinal adenomas and the early onset of colorectal cancer. Individuals with <100 multiple polyps and patients with colorectal cancer diagnosed before 50 years of age were recruited in UK, and screened for sequence changes in the coding and regulatory regions of CCND1. A set of about 800 UK control individuals was genotyped for the variants discovered in the cases. Variants in the promoter, intron-exon boundaries and untranslated regions of the CCND1 gene had higher frequencies in cases than in controls. Five of these variants were typed in a set of French multiple adenoma and early-onset patients, who also showed higher allele frequencies than UK controls. When pooled together, variants with frequencies lower than 1% conferred an increased risk of disease that was significant in the multiple adenoma group (odds ratio (OR) 2.2; 95% confidence interval, 1.1-4.4; P = 0.03). Most variants had a putative functional effect when assessed in silico. We conclude that rare variants of CCND1 are risk factors for colorectal cancer, with considerably larger effects than common polymorphisms, and as such should be systematically evaluated in susceptibility studies.
Department of Clinical Pharmacology, University of Oxford, Headington, Oxford, UK.
Carolina
C
Bonilla
Jérémie H
JH
Lefèvre
Bruce
B
Winney
Elaine
E
Johnstone
Susan
S
Tonks
Chrystelle
C
Colas
Tammy
T
Day
Katarzyna
K
Hutnik
Abdelhamid
A
Boumertit
Rachel
R
Midgley
David
D
Kerr
Yann
Y
Parc
Walter F
WF
Bodmer
D000236:Adenoma / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D006113:United Kingdom / Q000453:epidemiology
D019938:Cyclin D1