Loss of imprinting of the insulin-like growth factor 2 gene and risk of colorectal cancer

Abstract

The insulin-like growth factor 2 (IGF2) gene is the first gene discovered to be imprinted and expressed exclusively from the paternal allele in both humans and mice. Similarly, IGF2 is the first imprinted gene displaying loss of imprinting (LOI) in human cancers. LOI of IGF2 results in activation of the normally silent maternal allele, with increased IGF2 expression and possible increased cancer risk. LOI occurs in colonic cancer tissues, matched normal tissues, and peripheral blood lymphocytes. Human studies have found a significant, independent, positive association between LOI of IGF2 and personal and family history of colorectal neoplasia. Furthermore, animal studies using a murine model of LOI of IGF2 support an increase in intestinal neoplasia risk and abnormal colonic mucosal differentiation. LOI of IGF2 appears to be associated with a human colorectal cancer phenotype involving younger age at diagnosis, more advanced disease, right-side colonic location, and poorly differentiated or mucinous carcinoma.