title: Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent.
abstract: OBJECTIVE
  Amphiregulin (AREG) and epiregulin (EREG) are important ligands to the epithelial growth factor receptor, which is involved in the regulation of progression and stemness in gastric cancer (GC). This study investigated whether frequent single nucleotide polymorphisms (SNPs) in genes of AREG and EREG are associated with recurrence-free survival and overall survival in patients with locally advanced GC.
  
  
  METHODS
  SNPs with a minor allele frequency of at least 10% were analyzed using direct DNA sequencing in two independent study populations.
  
  
  RESULTS
  The minor allele of AREG rs1615111 was associated with a significantly higher 3-year recurrence rate and lower 3-year survival rate [hazard ratio (HR)=2.21 and 2.35, respectively] compared with patients homozygous for the dominant allele G. The value for overall survival could be validated with a HR of 2.54 (P=0.018) in an independent cohort. Patients homozygous for the minor allele A of EREG rs12641042 had a significantly higher 3-year survival rate than patients with allele C (HR 0.48; P=0.034), but significance was lost in multivariable analysis (P=0.066). The value of rs12641042 could not be validated (P=0.98). Exploratory multivariable subgroup analysis showed the strongest prognostic value for rs1615111 in tumors with a diffuse histology (Pfor interaction=0.004).
  
  
  CONCLUSIONS
  AREG rs1615111, located in the AREG genomic region, can significantly define different prognostic cohorts in locally advanced GC. This value is most evident in GC patients with diffuse histology, which might be relevant as none of the trials testing epithelial growth factor receptor inhibitors has been enriched for diffuse histology or a molecularly defined population.
authors.affiliation: aSharon Carpenter Laboratory, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California bMemorial Sloan Kettering Cancer Center, New York, New York, USA cDepartment of Gastroenterology Center, Cancer Institute Hospital, Tokyo Departments of dGastroenterology eSurgery, School of Medicine, Kitasato University, Sagamihara, Japan fDepartment of Hematology and Oncology, University Hospital Grosshadern, University of Munich, Munich, Germany.
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Mizutomo
authors.initials: M
authors.lastname: Azuma
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamauchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.forename: Nico B
authors.initials: NB
authors.lastname: Volz
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Barzi
authors.forename: Anthony B
authors.initials: AB
authors.lastname: El Khoueiry
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000368:Aged; D066258:Amphiregulin; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D066255:EGF Family of Proteins / Q000235:genetics*; D066260:Epiregulin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D013274:Stomach Neoplasms / Q000378:metabolism / Q000601:surgery*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D014408:Biomarkers, Tumor; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin