Neoplasms and Factors Associated with Their Development in Patients Diagnosed with Myotonic Dystrophy Type I

Abstract

Background. Recent epidemiological studies have provided evidence that myotonic dystrophy type I (DM1) patients are at excess risk of cancer, but inconsistencies in reported cancer sites exist. The risk of benign tumors and contributing factors to tumor development in these patients remain unknown. Methods. From the United Kingdom Clinical Practice Research Datalink, we identified a cohort of 927 DM1-affected and a matched cohort of 13,085 DM1-free individuals. We used Cox proportional hazards regression models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of tumor risks (benign or malignant), overall and by anatomic site, comparing DM1 patients and their matched DM1-free cohort. Cancer risk analyses were stratified by disease severity into: congenital/childhood (age-at-DM1-diagnosis: 0-10 years), classic (11-40 years), and late-onset (>40 years). We also assessed the association between benign tumors and subsequent cancers in each cohort, and the associations between tumor risk and sex, as well as selected disease-related phenotypes (cataracts, thyroid disease, and type 2 diabetes) in DM1. Results. Elevated cancer risk was restricted to patients with classic DM1, driven by cancers of the thyroid (HR=15.9, 95%CI=2.4-103.6), uterus (HR=26.8, 95%CI=2.3-309.3), and cutaneous melanoma (HR=6.0, 95%CI=1.2-28.8). DM1 patients, regardless of their disease severity, were at excess risk of benign skin tumors (HR=1.5, 95%CI=1.1-1.9), uterine fibroids and polyps (HR=4.7, 95%CI=2.2-9.9), colorectal/anal polyps (HR=2.7, 95%CI=1.1-6.9), and benign tumors of the nervous system (HR=9.9, 95%CI=2.9-28.8). Having these benign neoplasms was associated with a significantly increased cancer risk only in patients with classic DM1 (HR=3.34, 95%CI=1.14-9.83). In DM1, cancer was not associated with sex, thyroid disease, diabetes, or cataracts; female patients and those with cataracts were more likely to develop benign tumors. Conclusions. Our study shows that DM1 patients are at increased risk of tumors (both benign and malignant), with the skin, uterus, endocrine, and lower digestive systems as possible targets for tumorigenesis, but only cancer risk was modified by disease severity. Our results also suggest that cancers in DM1 may have a distinct underlying biologic mechanism from the phenotypes under study. If confirmed, these findings may guide future investigations of DM1-tumorigenesis and inform the clinical management of these patients.