title: Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival.
abstract: Lymph node metastases and tumor characteristics predict breast cancer prognosis but correlate imperfectly with likelihood of metastatic relapse. Discovery of genetic polymorphisms affecting metastasis may improve identification of patients requiring aggressive adjuvant therapy to prevent recurrence. We investigated associations between several variants in the BRMS1 and SIPA1 metastasis-modifying genes and lymph node metastases, tumor subtype and grade, recurrence, disease-free survival, and overall survival. This cross-sectional and prospective prognostic analysis included 859 patients who received surgery for incident breast cancer at Roswell Park Cancer Institute, participated in the DataBank and BioRepository shared resource, and had DNA, clinical, and pathology data available for analysis. Genotyping for BRMS1 (rs11537993, rs3116068, and rs1052566) and SIPA1 (rs75894763, rs746429, rs3741378, and rs2306364) polymorphisms was performed using Sequenom(®) iPLEX Gold and Taqman(®) real-time PCR assays. Logistic and Cox proportional hazards regressions were used to estimate odds ratios (OR) and hazard ratios (HR), respectively. BRMS1 rs1052566 heterozygous individuals were more likely to have node-positive tumors (OR = 1.58, 95 % CI 1.13-2.23), although there was no dose-response relationship, and those with at least one variant allele were less likely to have the luminal B subtype (AG + AA: OR = 0.59, 95 % CI 0.36-0.98). BRMS1 rs3116068 was associated with increased likelihood of having the luminal B and the HER2-enriched tumor subtype (P trend = 0.03). Two SIPA1 SNPs, rs746429 and rs2306364, were associated with decreased risk of triple-negative tumors (P trend = 0.04 and 0.07, respectively). Presence of 8 or more risk alleles was associated with an increased likelihood of having a node-positive tumor (OR = 2.14, 95 % CI 1.18-3.36, P trend = 0.002). There were no significant associations with survival. Polymorphisms in metastasis-associated genes may be related to tumor characteristics and lymph node metastasis, but not survival. Future evaluation of metastasis-modifying gene variants is necessary to better understand the biology of metastasis.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. michelle.roberts@roswellpark.org
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Roberts
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Hong
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Edge
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higgins
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D003430:Cross-Sectional Studies; D018572:Disease-Free Survival; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012097:Repressor Proteins
chemical_list: C410024:BRMS1 protein, human; D020690:GTPase-Activating Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C490403:SIPA1 protein, human