title: Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer.
abstract: OBJECTIVE
  Next Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations.
  
  
  OBJECTIVE
  To identify variants in 15 CRC-associated genes in patients of Iranian descent.
  
  
  RESULTS
  There were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%).
  
  
  METHODS
  CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established.
  
  
  CONCLUSIONS
  These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashktorab
authors.affiliation: Current address: Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Pooneh
authors.initials: P
authors.lastname: Mokarram
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Hamed
authors.initials: H
authors.lastname: Azimi
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Hasti
authors.initials: H
authors.lastname: Olumi
authors.affiliation: Hithru LLC, Silver Spring, MD, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.affiliation: Department of Pathology, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Brim
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D019295:Computational Biology; D030541:Databases, Genetic; D059472:Exome; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D007492:Iran; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D059467:Transcriptome; D000073359:Exome Sequencing / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor
keywords: Caucasian; Iranian; Shirazi; colon; targeted exome sequencing