TY - JOUR
T1 - Reduced FHIT Expression Is Associated with Mismatch Repair Deficient and High CpG Island Methylator Phenotype Colorectal Cancer
AU - Al-Temaimi, Rabeah Abbas
AU - Jacob, Sindhu
AU - Al-Ali, Waleed
AU - Thomas, Diana Ann
AU - Al-Mulla, Fahd
PY - 2013/6/1
Y1 - 2013/6/1
N2 - Colorectal cancer (CRC) is a heterogeneous disease and a major contributor to world cancer mortality rates. Molecular subtypes of CRC have become standards for CRC classification and have established prognostic potential. Here, we attempt to corroborate and provide further insight pertinent to the fragile histidine triad (FHIT) gene in microsatellite instable (MSI), microsatellite stable (MSS), and CpG island methylator phenotype (CIMP) CRC subtypes. We employed array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA) techniques to survey genomic aberrations in FHIT gene and their effects on FHIT protein expression using immunohistochemistry (IHC) in a CRC cohort. We further studied FHIT protein expression by IHC in a larger CRC cohort defined for its mismatch repair (MMR) protein expression and genomic methylation profiles. Our results show FHIT genomic deletions centered in exons 4 and 5 in most of MSI-CRC samples. Moreover, we confirmed the significant association of FHIT protein expression diminution (p=0.035) with MSI-CRC. In the larger cohort, reduced FHIT protein expression was significantly associated with CIMP-high subtype of CRC (p=0.009) and loss of PMS2 protein expression (p=0.017). We conclude that FHIT expression may be a valuable marker for CRC subtyping, and its diagnostic, prognostic, and therapeutic potential should be perused.
AB - Colorectal cancer (CRC) is a heterogeneous disease and a major contributor to world cancer mortality rates. Molecular subtypes of CRC have become standards for CRC classification and have established prognostic potential. Here, we attempt to corroborate and provide further insight pertinent to the fragile histidine triad (FHIT) gene in microsatellite instable (MSI), microsatellite stable (MSS), and CpG island methylator phenotype (CIMP) CRC subtypes. We employed array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA) techniques to survey genomic aberrations in FHIT gene and their effects on FHIT protein expression using immunohistochemistry (IHC) in a CRC cohort. We further studied FHIT protein expression by IHC in a larger CRC cohort defined for its mismatch repair (MMR) protein expression and genomic methylation profiles. Our results show FHIT genomic deletions centered in exons 4 and 5 in most of MSI-CRC samples. Moreover, we confirmed the significant association of FHIT protein expression diminution (p=0.035) with MSI-CRC. In the larger cohort, reduced FHIT protein expression was significantly associated with CIMP-high subtype of CRC (p=0.009) and loss of PMS2 protein expression (p=0.017). We conclude that FHIT expression may be a valuable marker for CRC subtyping, and its diagnostic, prognostic, and therapeutic potential should be perused.
KW - aCGH
KW - colorectal cancer
KW - CpG island methylator phenotype
KW - fragile histidine triad gene
KW - microsatellite instability
UR - http://www.scopus.com/inward/record.url?scp=84886792305&partnerID=8YFLogxK
U2 - 10.1369/0022155413497367
DO - 10.1369/0022155413497367
M3 - Article
C2 - 23797051
AN - SCOPUS:84886792305
VL - 61
SP - 627
EP - 638
JO - Journal of Histochemistry and Cytochemistry
JF - Journal of Histochemistry and Cytochemistry
SN - 0022-1554
IS - 9
ER -