title: Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations.
abstract: BACKGROUND
  Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.
  
  
  METHODS
  We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival.
  
  
  RESULTS
  CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481).
  
  
  CONCLUSIONS
  TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.
authors.affiliation: Department of Human Cancer Genomic Research, MBC 98-16,Research Centre at KFNCCC, King Faisal Specialist Hospital and Research Centre,PO Box 3354, Riyadh 11211,Kingdom of Saudi Arabia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.forename: Sarita E
authors.initials: SE
authors.lastname: Prabhakaran
authors.forename: Jehad
authors.initials: J
authors.lastname: Abubaker
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Qadri
authors.forename: Thara
authors.initials: T
authors.lastname: George
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Sanea
authors.forename: Alaa
authors.initials: A
authors.lastname: Abduljabbar
authors.forename: Luai H
authors.initials: LH
authors.lastname: Ashari
authors.forename: Samar
authors.initials: S
authors.lastname: Alhomoud
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D008877:Middle East; D011379:Prognosis; D053218:Receptors, Death Domain / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D053218:Receptors, Death Domain