Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.
In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, Rockville, MA 20852, USA.hylandpl@mail.nih.gov
Paula L
PL
Hyland
Neal D
ND
Freedman
Nan
N
Hu
Ze-Zhong
ZZ
Tang
Lemin
L
Wang
Chaoyu
C
Wang
Ti
T
Ding
Jin-Hu
JH
Fan
You-Lin
YL
Qiao
Asieh
A
Golozar
William
W
Wheeler
Kai
K
Yu
Jeff
J
Yuenger
Laurie
L
Burdett
Stephen J
SJ
Chanock
Sanford M
SM
Dawsey
Margaret A
MA
Tucker
Alisa M
AM
Goldstein
Christian C
CC
Abnet
Philip R
PR
Taylor
D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002681:China; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015994:Incidence; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism
D012739:Gonadal Steroid Hormones