RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.

The Middle East (ME) is an important crossroad where modern humans migrated 'out of Africa' and spread into Europe and Asia. After the initial peopling and long-term isolation leading to well-differentiated populations, the ME also had a crucial role in subsequent human migrations among Africa, Europe and Asia; thus, recent population admixture has been common in the ME. On the other hand, consanguinity, a well-known practice in the ME, often reduces genetic diversity and works in opposition to admixture. Here, we explored the degree to which admixture and consanguinity jointly affected genetic diversity in ME populations. Genome-wide single-nucleotide polymorphism data were generated in two representative ME populations (Arabian and Iranian), with comparisons made with populations worldwide. Our results revealed an overall higher genetic diversity in both ME populations relative to other non-African populations. We identified a much larger number of long runs of homozygosity in ME populations than in any other populations, which was most likely attributed to high levels of consanguineous marriages that significantly decreased both individual and population heterozygosity. Additionally, we were able to distinguish African, European and Asian ancestries in ME populations and quantify the impact of admixture and consanguinity with statistical approaches. Interestingly, genomic regions with significantly excessive ancestry from individual source populations are functionally enriched in olfactory pathways, which were suspected to be under natural selection. Our findings suggest that genetic admixture, consanguinity and natural selection have collectively shaped the genetic diversity of ME populations, which has important implications in both evolutionary studies and medical practices.

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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)

The imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways through which ONC201/CHOP crosstalk is regulated in ONC201-treated nonmetastatic and metastatic cancer cell lines (Dukes' type B colorectal adenocarcinoma nonmetastatic SW480 and metastatic LS-174T cells, respectively). Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry, gene expression was assessed by Affymetrix microarray, signaling pathway perturbations were assessed in silico, and key regulatory proteins were validated by Western blotting. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment; Gene Ontology analysis of differentially expressed genes showed that cellular responsiveness to ONC201 treatment also differed substantially. In both ONC201-treated cell lines, CHOP expression was upregulated; however, its upstream regulatory mechanisms were perturbed. Although, PERK, ATF6 and IRE1 ER-stress pathways upregulated CHOP in both cell types, the Bak/Bax pathway regulated CHOP only LS-174T cells. Additionally, CHOP RNA splicing profiles varied between cell lines; these were further modified by ONC201 treatment. In conclusion, we delineated the signaling mechanisms by which CHOP expression is regulated in ONC201-treated non-metastatic and metastatic colorectal cell lines. The observed differences could be related to cellular plasticity and metabolic reprogramming, nevertheless, detailed mechanistic studies are required for further validations.