Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers.
BACKGROUND
Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk.


METHODS
We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses.


RESULTS
Suggestive pathway-based associations were observed for the overall epigenetic (P-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value(GENE )< 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues.


CONCLUSIONS
Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.
Division of Cancer Epidemiology and Genetics, and.
Hyuna
H
Sung
Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Howard H
HH
Yang
Division of Cancer Epidemiology and Genetics, and.
Han
H
Zhang
Division of Cancer Epidemiology and Genetics, and.
Qi
Q
Yang
Division of Cancer Epidemiology and Genetics, and.
Nan
N
Hu
Shanxi Cancer Hospital, Taiyuan, People's Republic of China.
Ze-Zhong
ZZ
Tang
Division of Cancer Epidemiology and Genetics, and.
Hua
H
Su
Division of Cancer Epidemiology and Genetics, and.
Lemin
L
Wang
Division of Cancer Epidemiology and Genetics, and.
Chaoyu
C
Wang
Shanxi Cancer Hospital, Taiyuan, People's Republic of China.
Ti
T
Ding
Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Jin-Hu
JH
Fan
Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
You-Lin
YL
Qiao
Information Management Services, Silver Spring, MD, USA and.
William
W
Wheeler
Information Management Services, Silver Spring, MD, USA and.
Carol
C
Giffen
Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick Inc., Frederick, MD, USA.
Laurie
L
Burdett
Division of Cancer Epidemiology and Genetics, and Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick Inc., Frederick, MD, USA.
Zhaoming
Z
Wang
Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Maxwell P
MP
Lee
Division of Cancer Epidemiology and Genetics, and.
Stephen J
SJ
Chanock
Division of Cancer Epidemiology and Genetics, and.
Sanford M
SM
Dawsey
Division of Cancer Epidemiology and Genetics, and.
Neal D
ND
Freedman
Division of Cancer Epidemiology and Genetics, and.
Christian C
CC
Abnet
Division of Cancer Epidemiology and Genetics, and.
Alisa M
AM
Goldstein
Division of Cancer Epidemiology and Genetics, and.
Kai
K
Yu
Division of Cancer Epidemiology and Genetics, and.
Philip R
PR
Taylor
Division of Cancer Epidemiology and Genetics, and hylandpl@mail.nih.gov.
Paula L
PL
Hyland
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D044466:Asian People / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics*
DNA methylation; Epigenetics; SNP; chromatin remodelling; gastric cancer; gastric cardia; gastric non-cardia; gene-based; microRNA; oesophageal squamous cell carcinoma; pathway-based