title: Clinical significance of frequent somatic mutations detected by high-throughput targeted sequencing in archived colorectal cancer samples.
abstract: Colorectal cancer (CRC) is a heterogeneous disease with different molecular characteristics associated with many variables such as the sites from which the tumors originate or the presence or absence of chromosomal instability. Identification of such variables, particularly mutational hotspots, often carries a significant diagnostic and/or prognostic value that could ultimately affect the therapeutic outcome.
  
  
  
  High-throughput mutational analysis of 99 CRC formalin-fixed and paraffin-embedded (FFPE) cases was performed using the Cancer Hotspots Panel (CHP) v2 on the Ion Torrent™ platform. Correlation with survival and other Clinicopathological parameters was performed using Fisher's exact test and Kaplan-Meier curve analysis.
  
  
  
  Targeted sequencing lead to the identification of frequent mutations in TP53 (65 %), APC (36 %), KRAS (35 %), PIK3CA (19 %), PTEN (13 %), EGFR (11 %), SMAD4 (11 %), and FBXW7 (7 %). Other genes harbored mutations at lower frequency. EGFR mutations were relatively frequent and significantly associated with young age of onset (p = 0.028). Additionally, EGFR or PIK3CA mutations were a marker for poor disease-specific survival in our cohort (p = 0.009 and p = 0.032, respectively). Interestingly, KRAS or PIK3CA mutations were significantly associated with poor disease-specific survival in cases with wild-type TP53 (p = 0.001 and p = 0.02, respectively).
  
  
  
  Frequent EGFR mutations in this cohort as well as the differential prognostic potential of KRAS and PIK3CA in the presence or absence of detectable TP53 mutations may serve as novel prognostic tools for CRC in patients from the Kingdom of Saudi Arabia. Such findings could help in the clinical decision-making regarding therapeutic intervention for individual patients and provide better diagnosis or prognosis in this locality.
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia. adallol@kau.edu.sa.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. adallol@kau.edu.sa.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dallol
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Abdelbaset
authors.initials: A
authors.lastname: Buhmeida
authors.affiliation: Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Scientific Chair for Colorectal Cancer, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mahmoud Shaheen
authors.initials: MS
authors.lastname: Al-Ahwal
authors.affiliation: Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Jaudah
authors.initials: J
authors.lastname: Al-Maghrabi
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Department of Obstetrics and Gynecology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Osama
authors.initials: O
authors.lastname: Bajouh
authors.affiliation: Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Shadi
authors.initials: S
authors.lastname: Al-Khayyat
authors.affiliation: Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Rania
authors.initials: R
authors.lastname: Alam
authors.affiliation: Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Atlal
authors.initials: A
authors.lastname: Abusanad
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Rola
authors.initials: R
authors.lastname: Turki
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Aisha
authors.initials: A
authors.lastname: Elaimi
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Hani A
authors.initials: HA
authors.lastname: Alhadrami
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abuzenadah
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.
authors.forename: Huda
authors.initials: H
authors.lastname: Banni
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Al-Qahtani
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D011379:Prognosis; D016016:Proportional Hazards Models; D014015:Tissue Banks
keywords: Colon cancer; Hotspots; Mutational hotspots; Next-generation sequencing; Somatic