title: Pharmacogenetics driving personalized medicine: analysis of genetic polymorphisms related to breast cancer medications in Italian isolated populations.
abstract: BACKGROUND
  Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way.
  
  
  METHODS
  A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher's exact test.
  
  
  RESULTS
  Statistical analyses revealed that 13 out of the 41 (32 %) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy.
  
  
  CONCLUSIONS
  All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. massimiliano.cocca@burlo.trieste.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cocca
authors.affiliation: Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar. dbedognetti@sidra.org.
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.affiliation: IRCCS Burlo Garofolo, Trieste, Italy. martina.labianca@burlo.trieste.it.
authors.forename: Martina
authors.initials: M
authors.lastname: La Bianca
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. pgasparini@sidra.org.|Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar. pgasparini@sidra.org.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. giorgia.girotto@burlo.trieste.it.|Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar. giorgia.girotto@burlo.trieste.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Girotto
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005843:Geography; D006801:Humans; D007558:Italy; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D012307:Risk Factors