title: Genetic variants in the mTOR pathway and breast cancer risk in African American women.
abstract: The phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28847 single-nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk consortium of 3663 cases [1983 estrogen receptor-positive (ER+) and 1098 ER-negative (ER-)] and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10773 SNPs that were not highly correlated (r (2) < 0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P < 0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 [odds ratio (OR) of each copy of variant allele = 0.77, 95% confidence interval (CI) = 0.65-0.88 for all breast cancer] and BRAF rs114729114 (OR = 1.53, 95% CI = 1.24-1.91 for all breast cancer and OR = 2.03, 95% CI = 1.50-2.76 for ER- tumors). For ER- tumors, intronic SNPs PGF rs11542848 (OR = 1.38, 95% CI = 1.15-1.66) and rs61759375 (OR = 1.34, 95% CI = 1.14-1.57) and MAPK3 rs78564187 (OR = 1.26, 95% CI = 1.11-1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferroni-corrected P < 0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER- than ER+ tumors (OR = 1.18, 95% CI = 1.05-1.31, gene-wide Bonferroni-corrected P = 0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER negativity in African American women.
authors.forename: Ting-Yuan David
authors.initials: TD
authors.lastname: Cheng
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Hong
authors.affiliation: Department of Biostatistics, Boston University School of Public Health , Boston, MA 02118 , USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY 14263 , USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY 14263 , USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.forename: Lara
authors.initials: L
authors.lastname: Sucheston-Campbell
authors.affiliation: Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey , New Brunswick, NJ 08903 , USA.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.affiliation: Slone Epidemiology Center at Boston University , Boston, MA 02215 , USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ruiz-Narváez
authors.affiliation: Slone Epidemiology Center at Boston University , Boston, MA 02215 , USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Haddad
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA and.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine , Los Angeles, CA 90089 , USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA and.
authors.forename: Jeannette T
authors.initials: JT
authors.lastname: Bensen
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA and.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
authors.affiliation: Slone Epidemiology Center at Boston University , Boston, MA 02215 , USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Palmer
authors.affiliation: Slone Epidemiology Center at Boston University , Boston, MA 02215 , USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D002278:Carcinoma in Situ / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D011960:Receptors, Estrogen; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases