Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry.
Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter-patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Two-thousand six hundred and seventy-one women enrolled in the Women's Circle of Health Study were genotyped. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with pARTP≤ 0.10 as significant. Multi-allelic risk scores were created for the ARTP-significant gene(s). Single-SNP and risk score associations were modeled using logistic regression, with false discovery rate (FDR) P-value adjustment. Although single-SNP associations were not significant at pFDR< 0.05, several genes were significant in the ARTP analyses. In AA women, significant ARTP gene-level associations included CDH1 with LN+ (pARTP= 0.10; multi-allelic OR = 1.13, 95%CI 1.07-1.19, pFDR= 0.0003) and SIPA1 with ER- breast cancer (pARTP= 0.10; multi-allelic OR = 1.16, 95%CI 1.02-1.31, pFDR= 0.03). In EA women, MTA2 was associated with overall breast cancer risk (pARTP= 0.004), regardless of ER status, and with LN- disease (pARTP= 0.01). Also significant were SATB1 in ER- (pARTP= 0.03; multi-allelic OR = 1.12, 95%CI 1.05-1.20, pFDR= 0.003) and KISS1 in LN- (pARTP= 0.10; multi-allelic OR = 1.18, 95%CI 1.08-1.29, pFDR= 0.002) analyses. Among LN+ cases, significant ARTP associations were observed for SNAI1, CD82, NME1, and CTNNB1 (multi-allelic OR = 1.09, 95%CI 1.04-1.14, pFDR= 0.001). Our findings suggest that variants in several metastasis genes may affect breast cancer risk by LN or ER status, although verification in larger studies is required. © 2016 Wiley Periodicals, Inc.
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.|Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.
Michelle R
MR
Roberts
Division of Pharmacy Practice and Science, The Ohio State University, Columbus, Ohio.
Lara E
LE
Sucheston-Campbell
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Gary R
GR
Zirpoli
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
Michael
M
Higgins
Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.
Jo L
JL
Freudenheim
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Elisa V
EV
Bandera
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
Christine B
CB
Ambrosone
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
Song
S
Yao
D000328:Adult; D000368:Aged; D044383:Black People / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism*; D044465:White People / Q000235:genetics*; D055815:Young Adult; D001741:Black or African American
D011960:Receptors, Estrogen
African-American; breast neoplasms; estrogen receptor; lymph nodes; single nucleotide polymorphism