Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.
OBJECTIVE
Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers.


METHODS
We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk.


RESULTS
A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers.


CONCLUSIONS
We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.
Wijnen
Juul T
JT
Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
Brohet
Richard M
RM
van Eijk
Ronald
R
Jagmohan-Changur
Shanty
S
Middeldorp
Anneke
A
Tops
Carli M
CM
van Puijenbroek
Mario
M
Ausems
Margreet G E M
MG
Gómez García
Encarna
E
Hes
Frederik J
FJ
Hoogerbrugge
Nicoline
N
Menko
Fred H
FH
van Os
Theo A M
TA
Sijmons
Rolf H
RH
Verhoef
Senno
S
Wagner
Anja
A
Nagengast
Fokko M
FM
Kleibeuker
Jan H
JH
Devilee
Peter
P
Morreau
Hans
H
Goldgar
David
D
Tomlinson
Ian P
IP
Houlston
Richard S
RS
van Wezel
Tom
T
Vasen
Hans F A
HF
D000328:Adult; D000368:Aged; D002880:Chromosomes, Human, Pair 11; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000209:etiology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide