Abstract
Neoplastic lesions typically express specific carbohydrate antigens on glycolipids, mucins, and other glycoproteins. Such antigens are often under epigenetic control and are subject to reversion and loss upon therapeutic selective pressure. We report here that two of the most common tumor-associated carbohydrate antigens, Tn and sialyl Tn (STn), result from somatic mutations in the gene Cosmc that encodes a molecular chaperone required for formation of the active T-synthase. Diverse neoplastic lesions, including colon cancer and melanoma-derived cells lines, expressed both Tn and STn antigen due to loss-of-function mutations in Cosmc. In addition, two human cervical cancer specimens that showed expression of the Tn/STn antigens were also found to have mutations in Cosmc and loss of heterozygosity for the cross-linked Cosmc locus. This is the first example of somatic mutations in multiple types of cancers that cause global alterations in cell surface carbohydrate antigen expression.
Highlights
Neoplastic transformation of human cells is associated with multiple genetic and epigenetic changes that affect tumor growth, differentiation, and metastatic potential
Expression of the Tn antigen correlates with metastatic potential and poor prognosis www.aacrjournals.org in many cancers [25, 26], including cervical [27, 28], lung adenocarcinomas [29], colorectal carcinomas [30], breast carcinomas [31], and gastric carcinomas [32]
Our studies here show that expression of the Tn and sialyl Tn (STn) antigens in human tumor cell lines and in two cervical cancer specimens results from mutations in Cosmc, leading to a loss of T-synthase activity and consequent inability to modify the Tn precursor
Summary
Neoplastic transformation of human cells is associated with multiple genetic and epigenetic changes that affect tumor growth, differentiation, and metastatic potential. These changes are commonly associated with the expression of tumor-associated carbohydrate antigens (TACA), which have been the targets of multiple studies in attempts to define the molecular basis for their expression [1,2,3,4]. Many of these TACAs have been the focus of potential antitumor vaccines [5].
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