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Increased Cancer Risks in Myotonic Dystrophy

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Increased Cancer Risks in Myotonic Dystrophy ORIGINAL ARTICLE Increased Cancer Risks in Myotonic Dystrophy Aung Ko Win, MBBS, MPH; Promilla G. Perattur, MBBS; Jose S. Pulido, MD, MS, MPH, MBA; Christine M. Pulido; and Noralane M. Lindor, MD Abstract Objective: To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified. Patients and Methods: A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method. Results: A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; Pϭ.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; PϽ.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; Pϭ.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; Pϭ.05). The estimated cumu- lative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma. Conclusion: Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers. © 2012 Mayo Foundation for Medical Education and Research Ⅲ Mayo Clin Proc. 2012;87(2):130-135 yotonic dystrophy (dystrophia myo- thyroid, thyroid, and pituitary glands; and cancers tonica) is initially a clinically defined dis- of the stomach, colon, testis, ovary, kidney, larynx, From the Centre for Molec- order and is commonly characterized by and thyroid. Tumors were first diagnosed, on aver- M 17 ular, Environmental, Genetic myotonia, progressive muscle weakness, and onset age, in patients 44 years of age. To our knowledge, and Analytic Epidemiology, of cataracts at a young age.1 Molecular genetic stud- risks of cancers in patients with myotonic dystrophy The University of Mel- ies have identified 2 types of myotonic dystrophy have not been quantified. bourne, Parkville, Victoria, Australia (A.K.W.); and the (summarized in Table 1): myotonic dystrophy type Department of Medical Ge- 1 (Online Mendelian Inheritance in Man [OMIM] netics (P.G.P., N.M.L.) and 160900), which is caused by an unstable CTG tri- PATIENTS AND METHODS Department of Ophthalmol- nucleotide repeat expansion in the 3= untranslated ogy (J.S.P., C.M.P.), Mayo Identification of Patients region of the DMPK gene,2-6 and myotonic dystro- Clinic, Rochester, MN. The electronic medical records of Mayo Clinic in phy type 2 (OMIM 602668), which is caused by an Rochester, MN, from January 1, l993, through May unstable CCTG tetranucleotide repeat expansion in 28, 2010, were text-word searched for the term intron 1 of the CNBP (ZNF9) gene.7-9 Approxi- myotonic dystrophy, identifying 1687 unique medical mately 1 in 8000 people have myotonic dystro- 10 records. The medical records were then abstracted phy, and the prevalence appears to differ in vari- individually to confirm a diagnosis of myotonic dys- 11-16 ous geographic and ethnic populations. The trophy. A total of 307 patients had a confirmed di- proportions of myotonic dystrophy type 1 and type agnosis based on (1) a positive genetic test result in 2 are unknown, but myotonic dystrophy type 1 has that individual (expansion mutation within DMPK been reported to be more common than type 2 in or CNBP), (2) a positive gene test result in a blood 10 most populations. relative plus a clinical picture of myotonic dystro- There have been several studies and case reports phy in the patient even if a gene test was not per- on both benign and malignant neoplasms in patients formed, or (3) a clinical diagnosis alone established with myotonic dystrophy. Pilomatricomas are the by consultation with a neurologist plus relevant lab- most commonly reported neoplasms. A variety of oratory findings. We were not able to determine other neoplasms have been described, including from this chart review how many unique families thymoma; basal cell carcinomas; insulinomas; leu- were represented by these 307 patients. Most pa- kemia; lymphoma; spinal hemangioblastoma; max- tients had a comprehensive consultation in one or illary jaw odontoma; adenomas of the parotid, para- more departments, and all patients completed a 130 Mayo Clin Proc. Ⅲ February 2012;87(2):130-135 Ⅲ doi:10.1016/j.mayocp.2011.09.005 Ⅲ © 2012 Mayo Foundation for Medical Education and Research www.mayoclinicproceedings.org INCREASED CANCER RISKS IN MYOTONIC DYSTROPHY TABLE 1. Comparison of Clinical and Genetic Features of Myotonic Dystrophy Type 1 and Type 2 Type 1 Type 2 Synonyms DM1, Steinert disease DM2, proximal myotonic myopathy (PROMM), Ricker syndrome Causative gene DMPK CNBP (ZNF9) Chromosomal location 19q13.3 3q21 Mutation Unstable trinucleotide (CTG) expansion in Unstable tetranucleotide (CCTG) expansion in 3= untranslated region of messenger intron 1 (75-11,000; mean, 5000 repeats) in RNA that is expressed in tissues of CNBP affected individuals Inheritance Autosomal dominant Autosomal dominant Myotonia ϩϩ Muscle weakness ϩϩ Cataracts ϩϩ Muscle/joint pain/stiffness - ϩ Muscle atrophy ϩϩ/- Calf hypertrophy - ϩ/- Cardiac arrhythmias ϩϩ/- Elevated serum creatine kinase level ϩϩ Hypoimmunoglobulinemia ϩϩ/- Tremors - ϩ/- Late change in cognition ϩϩ/- Hypersomnia ϩϩ/- Mental retardation ϩ/- - Insulin resistance/diabetes ϩϩ/- Male hypogonadism ϩϩ/- Frontal baldness ϩϩ/- medical history intake form. This study was ap- be 1 year before the last known age. Kaplan-Meier proved by the Mayo Clinic Institutional Review failure function was used to estimate cumulative risk Board, and patients gave consent for use of their (penetrance) at ages 50 and 70 years. All reported medical records for research. statistical tests were 2-sided, and PϽ.05 was consid- ered statistically significant. All statistical analyses were performed using Stata 11.2 (StataCorp LP, Statistical Analyses College Station, TX). Observation time for each patient started at birth and ended at the age at first diagnosis of cancer or last contact or death, whichever occurred first. Can- RESULTS cer-specific standardized incidence ratios (SIRs) The study comprised 307 patients with myotonic were calculated by dividing the observed numbers dystrophy (54% female) who were identified from of cancers by the expected numbers. Ninety-five medical records of Mayo Clinic in Rochester, MN, percent confidence intervals (CIs) were calculated and were included regardless of cancer status or by exact methods, assuming Poisson distribution of family history of cancer. Of all patients with myo- observed cases. The expected numbers of cancers tonic dystrophy in this study, 118 were type 1 (74 were calculated by multiplying the age- and sex- were verified by genetic test in our records) and 86 specific incidence for the US general population were type 2 (45 were verified by genetic test in our with the corresponding observation time in the records). The remainder of these groups were as- study cohort. We obtained age- and sex-specific US signed on the basis of genetic tests conducted else- cancer incidences in 1998-2002 from the Surveil- where and cited in the medical record or known to lance, Epidemiology, and End Results (SEER) 14 be positive in a blood relative. For 103 patients, no registries.18 For patients with missing ages at cancer genetic testing was reported to have been done in diagnoses (nϭ5; 3 nonmelanoma skin cancers and 2 the patient or in any affected relative, but the clinical prostate cancers), age at diagnosis was assumed to diagnosis was well established (Table 2). Mayo Clin Proc. Ⅲ February 2012;87(2):130-135 Ⅲ doi:10.1016/j.mayocp.2011.09.005 131 www.mayoclinicproceedings.org MAYO CLINIC PROCEEDINGS years. The estimated cumulative risk for choroidal ؍ TABLE 2. Baseline Characteristics of Patients With Myotonic Dystrophy (N 307) melanoma was 1.00% (95% CI, 0.25%-3.92%) at Characteristic No. (%) of patients age 50 years. Sex The incidence of testicular and prostate cancers was increased but did not reach statistical signifi- Male 142 (46) cance: testicular cancer SIR, 5.09, 95% CI, 0.62- Female 165 (54) 18.38, Pϭ.06; and prostate cancer SIR, 2.21, 95% Race CI, 0.95-4.35, Pϭ.05. We also observed 9 nonmela- White 239 (78) noma skin cancers (8 basal cell carcinomas and 1 Other 5 (2) squamous cell carcinoma) at median age at diagno- Unknown 63 (21) sis of 57 years. Because there are no referent inci- Type of myotonic dystrophy dences of nonmelanoma skin cancers for the general 1 118 (38) population (eg, SEER data), we are unable to esti- mate SIR to state whether this is excessive. Of the 2 86 (28) nonmelanoma skin cancers, 3 were observed in pa- Unknown 103 (34) tients with myotonic dystrophy type 1 and 6 in pa- Diagnosis with electromyography tients with type 2. There was no statistical evidence Yes 123 (40) of an increased risk of brain, breast, colorectal, No 1 (Ͻ1) lung, renal, bladder, endometrial, or ovarian can- Unknown 183 (60) cers; lymphoma; leukemia; or multiple myeloma Genetic testing (Table 3). Yes 165 (54) No 19 (6) DISCUSSION Unknown 123 (40) In this analysis of medical records of 307 individuals Cancer diagnosis with myotonic dystrophy seen one or more times as At least 1 41 (13) patients at Mayo Clinic, we have demonstrated an Never 266 (87) increased risk of thyroid cancer and choroidal mel- Age at last contact (y), mean (SD) 49.3 (16.7) anoma compared with the incidence of these tumors Age at symptom presentation (y), mean (SD) 39.6 (15.0) in the US general population.
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