Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium.
BACKGROUND
We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.


METHODS
Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.


RESULTS
The five polymorphisms were not associated with ovarian carcinoma overall (P(trend) > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; P(heterogeneity) = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).


CONCLUSIONS
TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.


CONCLUSIONS
Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology.
Kelemen
Linda E
LE
Department of Population Health Research, Alberta Health Services-Cancer Care, 1331 29th Street Northwest, Calgary, Alberta T2N4N2, Canada. lkelemen@post.harvard.edu
Goodman
Marc T
MT
McGuire
Valerie
V
Rossing
Mary Anne
MA
Webb
Penelope M
PM
Köbel
Martin
M
Anton-Culver
Hoda
H
Beesley
Jonathan
J
Berchuck
Andrew
A
Brar
Sony
S
Carney
Michael E
ME
Chang-Claude
Jenny
J
Chenevix-Trench
Georgia
G
Cramer
Daniel W
DW
Cunningham
Julie M
JM
Dicioccio
Richard A
RA
Doherty
Jennifer A
JA
Easton
Douglas F
DF
Fredericksen
Zachary S
ZS
Fridley
Brooke L
BL
Gates
Margaret A
MA
Gayther
Simon A
SA
Gentry-Maharaj
Aleksandra
A
Høgdall
Estrid
E
Kjaer
Susanne Krüger
SK
Lurie
Galina
G
Menon
Usha
U
Moorman
Patricia G
PG
Moysich
Kirsten
K
Ness
Roberta B
RB
Palmieri
Rachel T
RT
Pearce
Celeste L
CL
Pharoah
Paul D P
PD
Ramus
Susan J
SJ
Song
Honglin
H
Stram
Daniel O
DO
Tworoger
Shelley S
SS
Van Den Berg
David
D
Vierkant
Robert A
RA
Wang-Gohrke
Shan
S
Whittemore
Alice S
AS
Wilkens
Lynne R
LR
Wu
Anna H
AH
Schildkraut
Joellen M
JM
Sellers
Thomas A
TA
Goode
Ellen L
EL
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000235:genetics; D016022:Case-Control Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D013940:Thymidylate Synthase; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase