Hypothesis: neoplasms in myotonic dystrophy

Abstract

Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.

Fig. 1

Wnt signaling and regulation of β-catenin in tumorigenesis. In the presence of Wnt signaling, or after mutations of APC, axin, or β-catenin, the phosphorylation and degradation of β-catenin are blocked. This leads to the accumulation of β-catenin in the nucleus, where it binds to TCF4 and promotes transcriptional activation of target genes including c-Myc and cyclin D1. The transcriptional co-activator complex CREBBP/p300 interacts with β-catenin and synergistically activates β-catenin/TCF4 transcriptional activation. In the absence of Wnt signaling, the cytoplasmic degradation complex of APC, GSK3β, CKI, and β-catenin forms leading to the phosphorylation of β-catenin, ultimately leading to its ubiquitination and its degradation in the proteasome. Somatic β-catenin mutations have been seen in pilomatricomas as well as other tumors associated with DM. Germline APC mutations result in Gardner syndrome. Germline CREBBP and p300 mutations result in Rubinstein-Taybi syndrome. We believe that the association between DM and pilomatricomas, as well as the other tumors that have been reported in these patients involves the upregulation of β-catenin via the Wnt signaling pathway, possibly via the actions of CUGBP or MBNL