Common genetic variants in sex hormone pathway genes and papillary thyroid cancer risk.
BACKGROUND
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.


METHODS
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.


RESULTS
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.


CONCLUSIONS
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-7238, USA. schonfes@mail.nih.gov
Sara J
SJ
Schonfeld
Gila
G
Neta
Erich M
EM
Sturgis
Ruth M
RM
Pfeiffer
Amy A
AA
Hutchinson
Li
L
Xu
William
W
Wheeler
Pascal
P
Guénel
Preetha
P
Rajaraman
Florent
F
de Vathaire
Elaine
E
Ron
Margaret A
MA
Tucker
Stephen J
SJ
Chanock
Alice J
AJ
Sigurdson
Alina V
AV
Brenner
D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics; D002277:Carcinoma; D002291:Carcinoma, Papillary; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D012739:Gonadal Steroid Hormones / Q000235:genetics*; D006062:Gonadotropins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011388:Prolactin / Q000235:genetics; D012306:Risk; D012737:Sex Factors; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D011388:Prolactin; D001141:Aromatase; C561410:CYP19A1 protein, human