title: Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population.
abstract: BACKGROUND
  Breast cancer (BC) is the most prevalent cancer in women and a major public health problem in Morocco. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. Therefore, we investigated the potential association of several functional germline variants in the genes commonly mutated in sporadic breast cancer.
  
  
  METHODS
  In this case-control study, we examined 36 single nucleotide polymorphisms (SNPs) in 13 genes (APOBEC3A, APOBEC3B, ARID1B, ATR, MAP3K1, MLL2, MLL3, NCOR1, RUNX1, SF3B1, SMAD4, TBX3, TTN), which were located in the core promoter, 5'-and 3'UTR or which were nonsynonymous SNPs to assess their potential association with inherited predisposition to breast cancer development. Additionally, we identified a ~29.5-kb deletion polymorphism between APOBEC3A and APOBEC3B and explored possible associations with BC. A total of 226 Moroccan breast cancer cases and 200 matched healthy controls were included in this study.
  
  
  RESULTS
  The analysis showed that12 SNPs in 8 driver genes, 4 SNPs in APOBEC3B gene and 1 SNP in APOBEC3A gene were associated with BC risk and/or clinical outcome at P ≤ 0.05 level. RUNX1_rs8130963 (odds ratio (OR) = 2.25; 95 % CI 1.42-3.56; P = 0.0005; dominant model), TBX3_rs8853 (OR = 2.04; 95 % CI 1.38-3.01; P = 0.0003; dominant model), TBX3_rs1061651 (OR= 2.14; 95 % CI1.43-3.18; P = 0.0002; dominant model), TTN_rs12465459 (OR = 2.02; 95 % confidence interval 1.33-3.07; P = 0.0009; dominant model), were the most significantly associated SNPs with BC risk. A strong association with clinical outcome were detected for the genes SMAD4 _rs3819122 with tumor size (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009) and TTN_rs2244492 with estrogen receptor (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009).
  
  
  CONCLUSIONS
  Our results suggest that genetic variations in driver and APOBEC3 genes were associated with the risk of BC and may have impact on clinical outcome. However, the reported association between the deletion polymorphism and BC risk was not confirmed in the Moroccan population. These preliminary findings require replication in larger studies.
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. maroufchaymaa@gmail.com.|Laboratory of Genetics and Molecular Pathology-Medical School of Casablanca, Casablanca, Morocco. maroufchaymaa@gmail.com.|University Hassan II Ain Chock, Center Of Doctoral Sciences "In Health Sciences", Casablanca, Morocco. maroufchaymaa@gmail.com.
authors.forename: Chaymaa
authors.initials: C
authors.lastname: Marouf
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. s.goehler@dkfz-heidelberg.de.
authors.forename: Stella
authors.initials: S
authors.lastname: Göhler
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.inacio@dkfz-heidelberg.de.
authors.forename: Miguel Inacio Da Silva
authors.initials: MI
authors.lastname: Filho
authors.affiliation: Department of Oncology, Littoral Clinic, Casablanca, Morocco. o.hajji@cliniquelelittoral.ma.
authors.forename: Omar
authors.initials: O
authors.lastname: Hajji
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. k.hemminki@dkfz-heidelberg.de.|Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden. k.hemminki@dkfz-heidelberg.de.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Laboratory of Genetics and Molecular Pathology-Medical School of Casablanca, Casablanca, Morocco. nadifisel@yahoo.com.|University Hassan II Ain Chock, Center Of Doctoral Sciences "In Health Sciences", Casablanca, Morocco. nadifisel@yahoo.com.
authors.forename: Sellama
authors.initials: S
authors.lastname: Nadifi
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.foersti@dkfz-heidelberg.de.|Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden. a.foersti@dkfz-heidelberg.de.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009018:Morocco / Q000453:epidemiology; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D011506:Proteins / Q000235:genetics*; D012306:Risk; D017384:Sequence Deletion
chemical_list: D014408:Biomarkers, Tumor; D011506:Proteins; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase