A recent study corroborated increased susceptibility to cancer in DM1, for women in particular, and linked the elevated risk to depressed levels of a tumor suppressor microRNA (miRNA). The association between DM1 and increased risk of certain types of cancer was first recognized in 1965. Recent studies have validated these initial findings and suggested that cancer risks in DM1 were greater in women, but the causative mechanisms remained unknown.
Dr. Adolfo López de Munain (Donostia University Hospital, San Sebastián, Spain) and colleagues have now corroborated gender differences in susceptibility to cancer and identified potential molecular mechanisms behind the cancer risk in DM1. In a publication in Neurology, Dr. López de Munain’s team quantified cancer risk in a well-characterized cohort of 424 patients with DM1, representing > 18,000 patient years of data, and explored the potential molecular links between DM1 and cancer prevalence.
All patients in the study had molecular confirmation of DM1 and substantial longitudinal phenotypic data available. The observed numbers of cancers in the DM1 cohort were compared against the numbers that would be expected, as calculated from the Basque region’s overall prevalence numbers, in order to determine standardized cancer incidence ratios. The investigators also performed gene expression analyses as a first step to understand molecular mechanisms behind the cancer prevalence data.
When compared to a general, geographically controlled population, DM1 patients showed a 2-fold increased risk of developing cancer. Mean age of malignant cancer detection in the DM1 cohort was 47 years. Gastrointestinal, genitourinary, skin and thyroid were the most frequent sites for malignant tumors. Increased risk was stronger in women with DM1.
In the overall DM1 population evaluated in this study, cancer represented the third leading cause of death, after respiratory and circulatory diseases. Analyses of molecular factors that may differentiate the at-risk DM1 population included CTG repeat length and genome-wide expression analysis of blood leukocytes using Affymetrix microarrays. The authors did not find a correlation between expanded CTG repeat length and cancer risk. Genome wide expression analysis did show differential expression of several genes that were previously linked to cancer (e.g., PDK4, DAPK1, CASP5, and PLA2G7).
Moreover, female patients with DM1 displayed significant down-regulation of the miRNA-200c/141 tumor suppressor family, while levels of this miRNA were elevated in men with DM1. Prior studies, in non-DM cohorts, have shown an association between declines in miRNA-200c and tumor progression/poor prognosis. Although further studies will be needed to mechanistically link changes in the DM1 transcriptome to increased cancer risk, the data from the San Sebastián group supports a compelling hypothesis linking reduction in tumor suppressor genes to cancer risk in women with DM1. The gender-specific differences in susceptibility to cancer, and the linkage to reduced levels of miRNA-200c, are particularly compelling findings for validation in independent DM1 cohorts and further mechanistic analyses.
Publication: "Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation." Fernández-Torrón R, García-Puga M, Emparanza JI, Maneiro M, Cobo AM, Poza JJ, Espinal JB, Zulaica M, Ruiz I, Martorell L, Otaegui D, Matheu A, López de Munain A. Neurology. 2016 Aug 24. pii: 10.1212/WNL.0000000000003124. [Epub ahead of print]