Abstract 1237: Cancer risk in myotonic dystrophy type I: First evidence of a role for disease severity

Background. Myotonic Dystrophy type 1 (DM1) is the first inherited nucleotide repeat disorder found to increase cancer susceptibility. The molecular mechanism underlying DM-related carcinogenesis is unknown. We hypothesized that cancer risk in DM1 is modified by disease severity. In this study, we evaluated the effect of age at DM1 diagnosis, a known proxy for disease severity, on the association between DM1 and cancer. Methods. Utilizing the United Kingdom Clinical Practice Research Datalink from 1988-2016, we identified 927 DM1-affected and 13,085 DM1-free individuals, matched on birth year, gender, clinic, and registration year. Follow-up started at the later of age at DM1 diagnosis/selection, practice registration, or study start date (January 1, 1988). We used Cox regression models to compare the risks of organ-specific cancers for DM1 patients and their matched cohort. Analyses were further stratified by age at DM1 diagnosis (0-10 years: congenital/childhood; 11-40 years: classic; and >40 years: late-onset) to assess effect modification. The baseline hazards were stratified on the matched sets, and models were adjusted for average number of primary care visits per year. Results. Of the 927 DM1 patients, 41 (4%) developed cancer, compared with 708 (5%) of the 13,085 DM1-free cohort (mean age at cancer= 56 versus 61, respectively). No cancers were observed in patients with congenital/childhood DM1 versus 1% of DM1-free subjects (p=0.6). Patients with classic DM1 were at elevated risk of cancers overall (HR=1.8; 95%CI=1.1-2.9); 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) accounted for the excess. In late-onset DM1 patients, a reduced risk was observed (HR=0.5; 95%CI=0.3-0.9), possibly driven by hematological malignancies (DM1=0 cases, DM1-free=54 cases; p=0.02). Conclusions. Our results suggest that excess cancer risk in DM1 patients occurs mainly in those with the classic form, driven by previously-reported DM1 site-specific cancers. The lack of cancers in congenital/childhood DM1 patients is likely due to competing mortality (mean age at death=38 years). The significant difference in cancer risk between classic and late-onset DM1 patients provides the first evidence that more severe disease increases DM1-related cancer susceptibility. Validation is warranted; if confirmed, these novel findings may guide clinical management and scientific planning for investigatin