1p36.31

Neuroblastoma

CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system (Thompson et al., 2003). CHD5 maps to 1p36.3, a region of consistent deletion in neuroblastoma and other tumors (White et al., 2005). CHD5 is one of 23 genes that map to the 800 kb region of consistent deletion on 1p36.3 in an analysis of over 1200 primary neuroblastomas (Okawa et al., 2008). Functional analysis of CHD5 after transfection into neuroblastoma cell lines demonstrates that CHD5 functions as a tumor suppressor gene, suppressing both clonogenicity and tumorigenicity. The promoter was methylated especially between -780 and -450 in neuroblastoma cell lines with 1p36 deletions, but not those with two copies of CHD5. Furthermore, high CHD5 expression is highly correlated with favorable clinical and biological risk features as well as outcome in a panel of 101 primary tumors (Fujita et al., 2008). These data suggest that CHD5 is a bona fide tumor suppressor gene in neuroblastomas. Deletion of 1p36 is associated with loss of CHD5 expression, and the CHD5 promoter is preferentially methylated in lines with 1p36 deletion. Low CHD5 expression is also associated with a worse outcome in neuroblastoma patients. Furthermore, low CHD5 expression is associated with a worse outcome in neuroblastoma patients (Koyama et al., 2012). Most recent protein expression studies showed that CHD5 acted as immunohistochemical marker in NB in 90 primary NTs suggesting a strong association of CHD5 expression with favorable prognostic variables that were tested in a blind set of 32 NB tumors (Garcia et al., 2010). In addition to these observations this brain specific protein has been shown to regulate neural gene expression (Potts et al., 2011). Moreover, CHD5 forms a NuRD complex similar to Mi2β/CHD4, and it presumably acts as chromatin remodeling enzyme in regulating gene expression (Kolla et al., unpublished observations).

Gliomas

CHD5 is one of several genes that maps to the 700 kb region of consistent deletion in 17 glioma cell lines (Law et al., 2005). Loss of CHD5 expression is associated with deletion of 1p36 in a panel of 54 glial tumors (Bagchi et al., 2007). These data are consistent with a role for CHD5 as a tumor suppressor gene in these tumors.

Melanoma

A subset of malignant melanoma families show linkage to 1p36, and CHD5 is a tumor suppressor gene that maps to this region. However, screening of CHD5 for mutations in eight melanoma-prone families linked to 1p36 revealed no deleterious coding or splice site mutations (Ng et al., 2008). Moreover, to understand the role of CHD5 in familial melanoma, studies have shown CHD5 variants in familial cutaneous melanoma that could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. But only one out of 47 families studied has this variant. Thus, it appears to be a rare event and further elaborative studies are required to confirm the role of CHD5 in melanoma pathogenesis (Lang et al., 2011). This suggests that CHD5 is not a major melanoma or subcutaneous melanoma susceptibility gene, at least in the families screened.

Ovarian cancer

Mutation and methylation analysis of CHD5 gene was undertaken in 123 ovarian cancers, whereas no such mutations were identified in 60 primary breast cancers. Somatic heterozygous missense mutations were identified in 3 samples, and promoter methylation was identified in another 3 of 45 samples tested (Gorringe et al., 2008). Recently, correlation of CHD5 with clinicopathological features of the tumor is also shown by quantitative RT-PCR methods. CHD5 is downregulated in a certain number of ovarian cancers and appears to be an adverse predictor candidate of ovarian cancer disease-free and total survival (Wong et al., 2011). These data suggest that CHD5 may play a role as a tumor suppressor gene in a subset of ovarian cancers, but there may be other suppressors on 1p36 as well.

Colorectal cancer

The methylation status of a set of cancer-related genes was studied in 102 colon cancers from Iranian and African-American populations (51 each). The methylation status of the promoters of three genes (CHD5, ICAM5 and GPNMB) was significantly higher in cancers from the African-American population compared to the Iranian patients (Mokarram et al., 2009). This suggests that these genes may play a role in the incidence or aggressiveness of colorectal cancer in this population.

Gastric cancer

The methylation status of the CHD5 promoter was examined in 15 primary gastric cancers and 7 gastric cancer cell lines. CHD5 expression was downregulated in 7/7 cell lines, and methylation of the promoter was found in all 7 lines, and a similar correlation was found in 11/15 primary tumors. Ectopic expression of CHD5 led to significant growth inhibition. These results suggest that CHD5 plays a role as a tumor suppressor gene in gastric cancer, and its expression may be down-regulated epigenetically.

Various cancers (colon cancer, breast cancer, gliomas)

The promoter of all nine current members of the CHD family were analyzed for methylation, and only the CHD5 promoter showed CpG hypermethylation in a subset of primary cancers, especially colon cancer, breast cancer and gliomas (Mulero-Navarro and Esteller, 2008). Thus, epigenetic inactivation of CHD5 expression may contribute to the pathogenesis of various cancers.

Lung cancer

Role of CHD5 in a lung cancer and epigenetic modification as well as its tumor-suppressive capability has been studied by measuring CHD5 mRNA and protein expression in lung cancer cells and tissues. CHD5 expression ranged from low to absent in the lung cancer cell lines and tissues examined correlated the results with CHD5 promoter hypermethylation. Clonogenicity and tumor growth were abrogated in lung cancer cell lines A549 and H1299 upon restoration of CHD5 expression (Zhao et al., 2011). These results suggest that CHD5 serves as a potential tumor suppressor gene in lung cancer that is inactivated via an epigenetic mechanism.

Prostate cancer

Comprehensive genomic survey has been conducted for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancer-related genes using next generation sequencing. Novel somatic point mutations have been shown in CHD5 along with MTOR, BRCA2, and ARHGEF12 (Robbins et al., 2011). This study indicates a deep genomic analysis of advanced metastatic prostate tumors that lead to somatic alterations, possibly contributing to lethal prostate cancer.

Laryngeal squamous cell carcinoma

Tumor suppressive role of CHD5 has been observed in 65 patients with laryngeal squamous cell carcinomas (LSCC) where both CHD5 RNA and protein expressions were significantly lower. These observations were also in correlation with promoter hypermethylation. Interestingly, ectopic expression of CHD5 in laryngeal cancer cells led to significant inhibition of growth and invasiveness (Wang et al., 2011). These data suggest that CHD5 acts as a tumor suppressor gene that is epigenetically downregulated in LSCC.