ORIGINAL CONTRIBUTION Cancer Risk Among Patients With Myotonic Muscular Dystrophy Shahinaz M. Gadalla, MD, PhD Context Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisys- Marie Lund, MD tem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Ruth M. Pfeiffer, PhD Case reports have suggested that MMD patients may be at increased risk of malig- nancy, putative risks that have never been quantified. Sanne Gørtz, MSc Objective To quantitatively evaluate cancer risk in patients with MMD, overall and Christine M. Mueller, DO by sex and age. Richard T. Moxley III, MD Design, Setting, and Participants We identified 1658 patients with an MMD dis- Sigurdur Y. Kristinsson, MD, PhD charge diagnosis in the Swedish Hospital Discharge Register or Danish National Pa- tient Registry between 1977 and 2008. We linked these patients to their correspond- Magnus Bjo¨rkholm, MD, PhD ing cancer registry. Patients were followed up from date of first MMD-related inpatient Fatma M. Shebl, MD, PhD or outpatient contact to first cancer diagnosis, death, emigration, or completion of can- cer registration. James E. Hilbert, MS Main Outcome Measures Risks of all cancers combined and by anatomic site, strati- Ola Landgren, MD, PhD fied by sex and age. Jan Wohlfahrt, DMSc Results One hundred four patients with an inpatient or outpatient discharge diag- Mads Melbye, MD, DMSc nosis of MMD developed cancer during postdischarge follow-up. This corresponds to Mark H. Greene, MD an observed cancer rate of 73.4 per 10 000 person-years in MMD vs an expected rate of 36.9 per 10 000 person-years in the general Swedish and Danish populations com- YOTONIC MUSCULAR DYS- bined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we ob- trophy (MMD) is an au- served significant excess risks of cancers of the endometrium (n=11; observed rate, tosomal-dominant, mul- 16.1/10 000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n=7; observed rate, 4.9/10 000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n=7; observed rate, 10.3/ tisystem disorder 10 000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n=10; observed rate, Mcomprising 2 subtypes.1 Type 1 MMD 7.1/10 000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women (Online Mendelian Inheritance in Man and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; [OMIM] 160900) is caused by unstable 95% CI, 1.3-2.5, respectively; P=.81 for heterogeneity; observed rates, 64.5 and 47.7 trinucleotide (CTG) repeat expansion in per 10 000 person-years in women and men, respectively). The same pattern of can- the 3Ј untranslated region of the dystro- cer excess was observed first in the Swedish and then in the Danish cohorts, which phia myotonica-protein kinase (DMPK) were studied sequentially and initially analyzed independently. gene2-4; type 2 MMD (OMIM 602668) is Conclusion Patients with MMD identified from the Swedish and Danish patient reg- a tetra-nucleotide (CCTG) repeat ex- istries were at increased risk of cancer both overall and for selected anatomic sites. pansion in intron 1 of the zinc finger 9 JAMA. 2011;306(22):2480-2486 www.jama.com (ZNF9) gene.5,6 It is the most common adult muscle dystrophy, with an esti- diac conduction defects, insulin ment, and premature cataract.1 Both mated prevalence of 1 in 8000.7 Type 1 resistance, testicular atrophy, respira- MMD subtypes result from interactions MMD displays a more severe pheno- tory insufficiency, cognitive impair- between CUG or CCUG repeat RNA and type that can present at any age (me- dian, 20-30 years)1 and result in prema- Author Affiliations: Clinical Genetics Branch (Drs of Neurology, Neuromuscular Disease Center, Uni- ture death (at 50-65 years of age).8,9 Both Gadalla, Mueller, and Greene), Biostatistics Branch (Dr versity of Rochester Medical Center, Rochester, New Pfeiffer), Infections and Immunoepidemiology Branch York (Dr Moxley and Mr Hilbert); and Division of He- subtypes share myotonia and progres- (Dr Shebl), Division of Cancer Epidemiology and Ge- matology, Department of Medicine, Karolinska Uni- sive skeletal muscle weakness and wast- netics, Medical Oncology Branch (Dr Landgren), Cen- versity Hospital Solna and Karolinska Institutet, Stock- ter for Cancer Research, Cancer Prevention Fellow- holm, Sweden (Drs Kristinsson and Bjo¨ rkholm). ing. Other manifestations include car- ship Program (Dr Gadalla), National Cancer Institute, Corresponding Author: Mark H. Greene, MD, Clini- National Institutes of Health, Bethesda, Maryland; Di- cal Genetics Branch, Division of Cancer Epidemiol- vision of Epidemiology, Department of Epidemiology ogy and Genetics, National Cancer Institute, 6120 Ex- See also Patient Page. Research, Statens Serum Institut, Denmark (Drs Lund, ecutive Blvd, EPS/7023, Rockville, MD 20892 (greenem Wohlfahrt, and Melbye and Ms Gørtz); Department @mail.nih.gov). 2480 JAMA, December 14, 2011—Vol 306, No. 22 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 CANCER RISK AND MYOTONIC MUSCULAR DYSTROPHY regulatory binding proteins, mainly the Figure. Selection of Swedish and Danish Myotonic Muscular Dystrophy Patients for Inclusion muscle-blind-like (MBNL) protein fam- in the Current Study ily,10 which lead to abnormal regula- tion of pre–messenger RNA alternative Swedish Hospital Discharge Register Danish National Patient Registry 1987-2004 (inpatient 1977-2008 and outpatient 1995-2008) splicing.11 Depletion of MBNL1 in MMD has been implicated in the develop- 768 Patients with MMD discharge 1049 Patients with MMD discharge diagnosis diagnosis ment of myotonia, premature cata- 12 13,14 ract, and skin cancer. 40 Excluded 33 Excluded (died before 36 Died before start of start of follow-up) Case reports have suggested that follow-up MMD patients may be at increased risk 4 Had incomplete data of benign and malignant tumors. Pi- 728 Assessed for cancer diagnoses 1016 Assessed for cancer diagnoses lomatricoma, a rare benign calcifying cutaneous neoplasm derived from hair 59 Excluded (had cancer 27 Excluded (had cancer before start of follow-up) matrix cells, is the most commonly re- before start of follow-up) ported. Additionally, multiple skin basal 669 Included in analysis 989 Included in analysis cell carcinomas have been suggested as an MDD phenotypic variant.14-17 We Follow-up began at the date of the first myotonic muscular dystrophy (MMD)–related contact. Whereas the Swedish cohort did not capture data for patients who remained outpatients, the Danish Patient Registry cov- have previously reviewed this litera- ered all hospital admissions and outpatient visits from 1977 and 1995, respectively. ture, described neoplasms reported by participants enrolled in the National Registry of Myotonic Dystrophy and Fa- tional identification numbers, we linked the National Institutes of Health Of- cioscapulohumeral Muscular Dystro- MMD patients to the Cancer Registry. fice of Human Subjects Research be- phy and Family Members, and dis- The Swedish MMD cohort did not cap- cause all analyses were performed using cussed possible molecular reasons for ture data for patients who were man- deidentified data. a hypothetical cancer predisposi- aged exclusively as outpatients. When tion.13 analyses in Swedish MMD patients sug- Cancer Ascertainment To further explore whether the MMD gested a possible excess cancer risk, we The Swedish and Danish cancer regis- phenotype includes cancer risk, we con- sought to replicate our findings in a tries have identified all incident can- ducted a population-based linkage separate, independent population (the cers detected in Sweden and Denmark study of MMD patients using the na- Danish cohort). since 1958 and 1943, respectively. Reg- tionwide Swedish and Danish regis- The Danish National Patient Regis- istry completeness and diagnostic ac- tries. Our data provide the first objec- try covers all hospital admissions and curacy exceeded 95% in several vali- tive, quantitative evidence to suggest outpatient visits since 1977 and 1995, dation studies.21-24 For this study, cancer that the MMD syndrome includes can- respectively. All Danish registry diag- sites were identified using ICD-7 and cer susceptibility. noses are coded according to the ICD ICD-10 codes from Sweden and Den- revision 8 (1969-1993) and revision 10 mark, respectively. To ensure compa- METHODS (from 1994).20 Each individual’s unique rability between reported cancer sites, Within the Swedish Hospital Dis- civil registration number was used to we used a slightly modified version of charge Register, which began in 1964 link the patients to the Danish Cancer the NORDCAN cancer dictionary,25 and reached 100% nationwide hospi- Registry. After excluding registrants which was designed by the Associa- talization coverage in 1987, we identi- with prior cancer and those who died tion of the Nordic Cancer Registries and fied all patients with an MMD dis- prior to follow-up initiation, we iden- the International Agency for Research charge diagnosis (ICD-9 code 359C, tified 989 inpatients or outpatients dis- on Cancer to formalize Nordic coun- ICD-10 code G711) between January charged with an MMD diagnosis be- tries’ data harmonization. Amend- 1987 and December 2004 (n=768) tween 1977 and 2008 (ICD-8 codes ments to the cancer codes were made (FIGURE). Diagnoses were coded using 330.90, 330.91; ICD-10 code G711) for cancers of the brain (only malig- the International Classification of Dis- (Figure). nant tumors were included), as well as eases (ICD) revision 7 (1964-1968), re- Access to the Swedish and Danish lymphoma and leukemia, to accommo- vision 8 (1969-1986), revision 9 (1987- registry data was approved by the Karo- date differing coding schemes over time 1995), and revision 10 (after 1995).18,19 linska Institutional Review Board and in Denmark and Sweden, respec- We excluded 99 patients from analy- the Danish Data Protection Agency, re- tively.