Much effort in cancer research has focused on the tiny part of our genome that 
codes for mRNA. However, it has recently been recognized that microRNAs also 
contribute decisively to tumorigenesis. Studies have also shown that epigenetic 
silencing by CpG island hypermethylation of microRNAs with tumor suppressor 
activities is a common feature of human cancer. The importance of other classes 
of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed 
ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also 
gaining recognition. Thus, we wondered whether there were other ncRNAs 
undergoing CpG island hypermethylation-associated inactivation in cancer cells. 
We focused on the small nucleolar RNAs (snoRNAs), a subset of ncRNA with a wide 
variety of cellular functions, such as chemical modification of RNA, pre-RNA 
processing and control of alternative splicing. By data mining snoRNA databases 
and the scientific literature, we selected 49 snoRNAs that had a CpG island 
within ≤ 2 Kb or that were processed from a host gene with a 5'-CpG island. 
Bisulfite genomic sequencing of multiple clones in normal colon mucosa and the 
colorectal cancer cell line HCT-116 showed that 46 snoRNAs were equally 
methylated in the two samples: completely unmethylated (n = 26) or fully 
methylated (n = 20). Most interestingly, the host gene-associated 5'-CpG islands 
of the snoRNAs SNORD123, U70C and ACA59B were hypermethylated in the cancer 
cells but not in the corresponding normal tissue. CpG island hypermethylation 
was associated with the transcriptional silencing of the respective snoRNAs. 
Results of a DNA methylation microarray platform in a comprehensive collection 
of normal tissues, cancer cell lines and primary malignancies demonstrated that 
the observed hypermethylation of snoRNAs was a common feature of various tumor 
types, particularly in leukemias. Overall, our findings indicate the existence 
of a new subclass of ncRNAs, snoRNAs, that are targeted by epigenetic 
inactivation in human cancer.