The search for additional major susceptibility genes for familial melanoma has remained elusive. Currently two genes (CDKN2A
) have been identified and together account for ≤ 40% of all CMM families. Thus, a majority of CMM families do not have a defined CMM susceptibility gene. Linkage analysis of CDKN2A, CDK4
mutation negative families identified a susceptibility locus at 1p22 [12
], however, no candidate gene has been identified. Prior linkage studies identified a subset of CMM/DN families with simultaneous linkage to 9p21 and 1p36 [15
]. Loss of heterozygosity at 1p36 was originally found in neuroblastoma [23
] and has subsequently been reported in many types of human tumors [24
] suggesting the presence of a tumor suppressor gene(s) in this region. Somatic deletion of the 1p36 locus occurs in a wide range of solid and lymphoid tumors [24
] and has been observed in nodular, metastatic and superficial spreading melanomas [16
]. Therefore the loss of a common tumor suppressor gene or a combination of several genes in this region may predispose to tumor development or contribute to tumor progression [24
was identified as a candidate tumor suppressor gene [18
] by the use of Cre-loxP site-specific recombinant technology to generate a region of gain or loss of mouse chromosome 4 corresponding to the human 1p36 locus. Bagchi et al
] was able to demonstrate that mouse cells with an extra copy of chromosome 4 corresponding to human 1p36 exhibited enhance cellular senescence. The observed cellular senescence was rescued by RNAi-mediated knockdown of p53. Mouse cells deficient in Chd5
due to loss of one copy by Cre-loxP-mediated recombination expressed decreased levels of p53, p16 and p19. Subsequent experiments showed that cellular proliferation can be restored by depletion of p19 suggesting that Chd5
regulated p53 expression and that cell growth was directed through chromatin remodeling and control of gene expression at the CDKN2A
Among the eight CMM/DN families screened for CHD5 mutations in this study, only one family (AH) was found to have a missense coding change. However, upon in depth mutation analysis of family AH with additional affected and unaffected family members, the I1117M variant was found to be inherited from the unaffected mother. Family AH consists of six CMM/DN affected individuals. The CMM/DN phenotype is inherited through the paternal side of the family. Neither the affected father nor additional affected individuals carried the I1117M variant. This finding strongly suggests that the I1117M variant is not associated with the CMM/DN phenotype. Sequence analysis of the remaining intronic SNPs and synonymous cSNPs found in the screening panel (Table ) among additional affected and unaffected individuals from their respective CMM/DN kindreds revealed that none of these variants showed complete co-segregation with the CMM/DN phenotype. Taken together, these results did not support CHD5 as a melanoma susceptibility gene in these eight families.
Limitations of this study include small sample size. Also we did not possess a source of mRNA to study CHD5 expression in tumor or compare melanocyte expression of CHD5 between affected individuals and controls. To our knowledge, the eight families screened represent all the known CMM families linked to 1p36. We limited our CHD5 mutation screen to the coding regions and flanking splice sites, thus changes to promoter, enhancer and micro-RNA binding sites may have been missed. We caution that our findings pertain only to the eight families screened in this study and should not be generalized to other CMM families.