Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study.
BACKGROUND
RNASEL is thought to be a susceptibility gene for hereditary prostate cancer and encodes the endoribonuclease RNase L, which has a role in apoptosis and is a candidate tumour-suppressor protein. A common sequence variation in RNASEL, Arg462Gln, has been associated with hereditary and sporadic prostate cancer, and the Gln variant has about three-fold reduced RNase activity in vitro. In view of the association between the age of onset of hereditary non-polyposis colorectal cancer and functionally different variants of P53, which play a key part in the apoptotic pathway, we aimed to assess whether the Arg462Gln variation of RNASEL affects the age of onset of hereditary non-polyposis colorectal cancer.


METHODS
We screened 251 patients with hereditary non-polyposis colorectal cancer who were unrelated, had pathogenic germline mutations in MSH2 (n=141) or MLH1 (n=110), and had colorectal carcinoma as the first tumour, for variation at codon 462 of RNASEL and compared them with 439 healthy controls.


RESULTS
The median age of onset was 40 years (range 17-75) for patients with an Arg/Arg genotype at codon 462, 37 years (13-69) for patients with an Arg/Gln genotype, and 34 years (20-49) for those with a Gln/Gln genotype (p=0.0198). Only the RNASEL genotype had a significant effect on age of onset (p=0.0062) in an additive mode of inheritance. Pair-wise comparisons between genotype groups showed that the two homozygous groups (ie, Arg/Arg vs Gln/Gln) differed significantly in age of disease onset (mean age difference 4.8 years [SD 1.7], p=0.0044).


CONCLUSIONS
A sequence variation in the prostate-cancer-susceptibility gene RNASEL has a role in a different, unassociated malignant disease. Genotypes at RNASEL codon 462 are associated with age of onset of hereditary non-polyposis colorectal cancer in a dose-dependent way, and might have a role in preventive strategies for this disease.
Krüger
Stefan
S
Department of Surgical Research, Dresden University of Technology, Dresden, Germany. Stefan.Krueger@mailbox.tu-dresden.de
Silber
Ann-Sophie
AS
Engel
Christoph
C
Görgens
Heike
H
Mangold
Elisabeth
E
Pagenstecher
Constanze
C
Holinski-Feder
Elke
E
von Knebel Doeberitz
Magnus
M
Moeslein
Gabriela
G
Dietmaier
Wolfgang
W
Stemmler
Susanne
S
Friedl
Waltraut
W
Rüschoff
Josef
J
Schackert
Hans K
HK
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017209:Apoptosis; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology*; D004722:Endoribonucleases / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics
D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease