Reduced FHIT Expression Is Associated with Mismatch Repair Deficient and High CpG Island Methylator Phenotype Colorectal Cancer

Abstract

SummaryColorectal 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. ( J Histochem Cytochem 61:627-638, 2013)

Combined Effects Methylation of FHIT, RASSF1A and RARβ Genes on Non-Small Cell Lung Cancer in the Chinese Population

“…Methylation is major epigenetic modification in mammal, and changes in methylation patterns play a key role in tumor genesis with humans (Virmani et al, 2000;Dumitrescu et al, 2012;Fiolka et al, 2013). In particular, the promoter CpG island hypermethylation is closely related between inactivation and silencing, resulting in tumor suppressor loss of gene expression and X-chromosome inactivationmay, and affect development of carcinogenesis (Ki et al, 2008;Fiolka et al, 2013;Al-Temaimi et al, 2013). The aberrant promoter region methylation of tumor suppressor genes is associated with mechanism for carcinogenesis (Grote et al, 2006;Neyaz et al, 2008;Dumitrescu et al, 2012).…”

“…Although the aberrant promoter region methylation was a common epigenetic event with lung cancer, combined detection of these genes may vastly improve the positive detection rate of tumors or prognostic judgment Dumitrescu et al, 2012;Vo et al, 2013;Al-Temaimi et al, 2013;Zuo et al, 2013). Several studies showed separately that methylation of CpG islands of FHIT, RASSF1A and RARβ genes has a significant role in the process of lung cancer (range, 20-90%, depending on tumor type), this figure identified the these genes as the most commonly modified gene in human cancers (Ki et al, 2008;Neyaz et al, 2008;Jeong et al, 2013;Liu et al, 2013;Al-Temaimi et al, 2013;Zuo et al, 2013). however, there are only a few studies reporting hypermethylation of combined FHIT, RASSF1A and RARβ genes together in cancers, especially in non-small cell lung cancer (Li et al, 2012;Zuo et al, 2013;Mengxi et al, 2013;Ko et al, 2013).…”

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

“…Several studies have demonstrated an association between FHIT hypermethylation and an increased risk of non-small-cell lung carcinoma (NSCLC) (13), breast cancer (14,15), cervical cancer (16), hepatocellular carcinoma (17) and thyroid carcinoma (18). Furthermore, downregulation of FHIT expression has been observed in acute lymphoblastic leukemia (ALL) (19), gastric cancer (20), colon adenocarcinoma (21), nasopharyngeal carcinoma (22) and colorectal cancer (23).…”

Protein expression of Fragile Histidine Triad and cyclooxgenase-2 in serrated neoplasia of the colorectum

“…FHIT performs a role in the development and progression of CRC (9,13), and its expression is associated with deficient mismatch repair (MMR) in advanced human CRCs (14)(15)(16). In addition, low FHIT protein expression is also associated with CIMP-high CRCs (17). However, relatively few studies have been published on the early serrated tumorigenic pathway.…”