Cancer Risk Among Patients with Myotonic Muscular Dystrophy

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 cancer 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, comprisingM 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 (median, 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).

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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 regulation 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. Furthermore, we included sub- sis: 59 had cancer before or during the spectively. Informed consent was analyses of rectal and anal cancers in first MMD hospitalization, 36 died dur- waived because we had no contact with recognition of their etiologic differing the first hospitalization, and 4 had study participants. An institutional re- ences. Nonmelanoma skin cancers were incomplete data. Using the Swedish na- view board waiver was obtained from not considered in the current analyses

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first MMD-related inpatient discharge contributing 4724 and 9446 person- Table 1. Characteristics of the Swedish and Danish Myotonic Muscular Dystrophy diagnosis, or date of first outpatient con- years of observation, respectively. In Cohorts tact, to the first cancer diagnosis, death, Sweden, the median age at first MMD No. (%) emigration, or the end of complete can- discharge diagnosis (inpatient only) was cer registration (Sweden: December 31, 46 years vs 38 years in Denmark (41 Sweden Denmark (n = 669) (n = 989) 2004; Denmark: December 31, 2008). years for inpatients and 37 years for out- Sex The observed and expected cancer rates patients). In both countries, approxi- Male 331 (49.5) 530 (53.6) for MMD patients were calculated by mately half were men, 40% died dur- Female 338 (50.5) 459 (46.4) dividing the observed and expected ing follow-up, and 6% developed cancer Age at first MMD numbers of cancers by the person- (TABLE 1). discharge diagnosis Median 46 (0-86) 38 (0-85) years of follow-up. During 14 170 person-years of fol- (range), y In a subgroup analysis using the Dan- low-up, 104 MMD patients developed 0-14 71 (10.6) 130 (13.1) ish database, we calculated SIRs for all cancer compared with 52.3 expected 15-29 86 (12.9) 188 (19.0) cancers combined, stratified by type of cases, corresponding to an observed 30-44 168 (25.1) 304 (30.7) hospital contact (inpatient vs outpa- cancer rate of 73.4 per 10 000 person- 45-59 244 (36.5) 267 (27.0) tient) as a proxy for disease severity, hy- years in MMD patients vs an expected Ն60 100 (14.9) 100 (10.1) pothesizing that patients who were hos- rate of 36.9 per 10 000 person-years. Calendar year at first pitalized represented a more severe Compared with expected case num- MMD discharge diagnosis MMD phenotype. Patients who were bers based on cancer rates in the gen- 1977-1981 0 156 (15.8) first identified from the outpatient reg- eral population, MMD patients had an 1982-1986 0 112 (11.3) istry and later hospitalized (n=125) increased overall cancer risk (SIR, 2.0; 1987-1991 261 (39.0) 96 (9.7) contributed person-years of follow-up 95% CI, 1.6-2.4). Most notably, we ob- 1992-1996 171 (25.6) 143 (14.5) to the outpatient group until the first served significant excesses of endome- 1997-2001 157 (23.5) 196 (19.8) hospitalization date and subsequently trial cancer (n=11; observed rate, 16.1/ a 2002-2006 80 (12.0) 204 (20.6) contributed person-years to the inpa- 10 000 person-years; SIR, 7.6; 95% CI, 2007-2008 0 82 (8.3) tient group. Of note, 331 of 456 Dan- 4.0-13.2), brain cancer (n=7; ob- Had cancer during 43 (6.4) 61 (6.2) follow-up ish MMD patients (72.6%) first ascer- served rate, 4.9/10 000 person-years; Age, median 57 (24-85) 56 (27-87) tained in the outpatient setting were SIR, 5.3; 95% CI, 2.3-10.4), ovarian can- (range), y never hospitalized during follow-up. cer (n=7; observed rate=10.3/10 000 Died during follow-up 255 (38.1) 387 (39.1) We evaluated the risk of each can- person-years; SIR, 5.2; 95% CI, 2.3- Age, median 59 (0-89) 58 (0-93) cer site and considered an association 10.2), and colon cancer (n=10; ob- (range), y to be statistically significant at P=.05. served rate, 7.1/10 000 person-years; Abbreviation: MMD, myotonic muscular dystrophy. aThrough 2004 for the Swedish data. In the “Results” and “Comment” sec- SIR, 2.9; 95% CI, 1.5-5.1). Our data also tions, we focused primarily on associa- suggested possible excesses of eye can- tions with P values less than .01 to mini- cer (n=2; observed rate, 1.4/10 000 per- because of differing registration prac- mize testing-related false discovery. Mid son-years; SIR, 12.0; 95% CI, 2.0- tices between the 2 countries.24 P tests and confidence intervals were 39.6), other female genital organ cancer used throughout, defined by the mean (n=2; observed rate, 2.9/10 000 person- Statistical Analysis value of the Poisson distribution that years; SIR, 9.6; 95% CI, 1.6-31.8), thy- We calculated standardized incidence makes the probability the test statistic roid cancer (n=3; observed rate, 2.1/ ratios (SIRs) for all cancers combined is less than its observed value plus half 10 000 person-years; SIR, 7.1; 95% CI, and by anatomic site, stratified by sex the probability of its observed value 1.8-19.3), and pancreatic cancer (n=4; and age (Ͻ50 and Ն50 years). Each SIR equal to 0.975 (upper limit) and 0.025 observed rate, 2.8/10 000 person- was calculated by dividing the num- (lower limit).26 Subgroup interactions years; SIR, 3.2; 95% CI, 1.0-7.6) ber of observed cancers in MMD pa- were tested using conditional exact tests (TABLE 2). Close similarity in overall tients by the expected number of can- with mid P values. Because the site- and site-specific cancer excess was ob- cers. Expected cancer numbers were specific SIRs did not differ statistically served in both Swedish and Danish calculated by applying country-, age-, in the 2 national cohorts, the data were MMD patients (eTable 1). sex-, and calendar time–specific popu- combined for presentation. (See eTable After excluding genital organ can- lation incidence rates from each can- 1, available at http://www.jama.com, for cers (uterus, cervix, ovary and fallo- cer registry to the person-years ob- country-specific data). pian tubes, vulva, vagina, prostate, tes- served among its subset of MMD cases. tis, penis, scrotum, and unspecified To prevent survival bias from affect- RESULTS parts), no statistically significant sex dif- ing cancer risk estimates, MMD pa- The study included 1658 MMD pa- ference was observed in overall cancer tients were followed up from date of tients (Sweden=669; Denmark=989), risk (SIR, 1.9; 95% CI, 1.4-2.5 in women

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vs SIR, 1.8; 95% CI, 1.3-2.5 in men; failure), cardiovascular problems overall cancer risk was primarily due to P=.81 for heterogeneity; observed rates, (n=27), and eye diseases (n=22, 55% malignancies of the endometrium, brain, 64.5 and 47.7/10 000 person-years in of whom had cataract). ovary, and colon. women and men, respectively). How- Case reports have suggested a strong ever, the data suggested possible sex- COMMENT association between MMD and pilo- specific differences for cancers of the Our study is the first to our knowledge matricoma, a rare benign skin neo- rectum and lung (TABLE 3), findings to quantify cancer risk in patients with plasm (which is not registered in the that did not reach statistical signifi- MMD. In this large population-based Swedish Cancer Registry and is incom- cance. study, we observed an excess cancer risk pletely registered in the Danish Cancer In age-stratified analyses (Ͻ50 vs compared with the general population, Registry) and also included reports of a Ն50 years), no statistically significant first among Swedish MMD patients and number of rare malignancies.13 Pub- difference was observed in overall can- then among the replication cohort of lished case reports tend to present un- cer risk (SIR, 2.2; 95% CI, 1.4-3.2 and Danish patients. Because of the close usual cases and therefore cannot pro- SIR, 1.9; 95% CI, 1.6-2.4, respec- similarity in the results, we combined the vide conclusive evidence of a genuine tively; P=.58 for heterogeneity; ob- findings from these 2 cohorts to im- association. This methodological short- served rates, 25.7 and 165.6/10 000 per- prove statistical power. The elevated coming led to the current study, which son-years in the younger and older groups, respectively). However, we did observe a significantly higher excess risk Table 2. Standardized Incidence Ratios of Cancers in 14 170 Person-Years of Swedish and of endometrial cancer among women Danish Patients With Myotonic Muscular Dystrophy by Anatomic Site a younger than 50 years (n=5; observed Anatomic Site No. Diagnosed Expected No. SIR (95% CI) P Value rate, 11.1/10 000 person-years; SIR, All sites except nonmelanoma skin 104 52.28 2.0 (1.6-2.4) Ͻ.001 35.6; 95% CI, 13.0-78.9) vs women 50 Pharynx 1 0.55 1.8 (0.1-9.1) .52 years and older (n=6; observed rate, Esophagus 2 0.59 3.4 (0.6-11.2) .14 25.8/10 000 person-years; SIR, 4.6; 95% Colon 10 3.47 2.9 (1.5-5.1) .004 CI, 1.9-9.5; P=.003 for heterogeneity) Rectum and anus 5 2.47 2.0 (0.7-4.5) .15 (TABLE 4). Rectum 5 2.30 2.2 (0.8-4.8) .11 In a subgroup analysis among Dan- Anus 0 0.17 0 ish patients by type of hospital con- Liver 2 0.48 4.2 (0.7-13.8) .10 tact, our data suggested that inpa- Pancreas 4 1.27 3.2 (1.0-7.6) .05 tients were at higher relative risk of Nose, sinuses 1 0.11 9.0 (0.5-44.4) .11 developing cancers than outpatients. Lung 10 5.98 1.7 (0.8-3.0) .12 The difference, however, did not reach Melanoma (skin) 6 2.58 2.3 (0.9-4.8) .06 statistical significance (SIR, 2.0; 95% CI, Breast 11 9.40 1.2 (0.6-2.0) .58 1.5-2.6, vs SIR, 1.1; 0.5-2.0, respec- Cervix 1 1.15 0.9 (0.0-4.3) .99 tively; P=.08 for heterogeneity). Endometrium 11 1.45 7.6 (4.0-13.2) Ͻ.001 In 3 additional analyses based on the Ovary, tube, broad ligament 7 1.36 5.2 (2.3-10.2) Ͻ.001 Danish cohort, we found the overall re- Other female genital organs 2 0.21 9.6 (1.6-31.8) .02 sults to remain the same when start- Prostate 3 4.20 0.7 (0.2-1.9) .61 ing follow-up 5 years after the first Testis 1 0.73 1.4 (0.1-6.8) .68 MMD discharge diagnosis (SIR, 2.04; Kidney 2 1.21 1.7 (0.3-5.5) .46 95% CI, 1.49-2.72), when restricting the Other urinary organs 1 2.62 0.4 (0.0-1.9) .34 analysis to those with MMD as their Eyeb 2 0.17 12.0 (2.0-39.6) .01 main diagnosis (n=702; SIR, 1.8; 95% Central nervous system 7 1.60 4.4 (1.9-8.7) .002 CI, 1.4-2.4), and when considering Brainc 7 1.33 5.3 (2.3-10.4) Ͻ.001 those inpatients with no diagnoses other Thyroid gland 3 0.42 7.1 (1.8-19.3) .01 than MMD at the first MMD admit- Acute leukemia 1 0.50 2.0 (0.1-9.8) .49 tance (n=255; SIR, 1.9; 95% CI, 1.3- Non-Hodgkin lymphoma 3 1.67 1.8 (0.5-4.9) .32 2.8). Among 287 MMD patients who Other sitesd 8 2.56 3.1 (1.4-5.9) .006 had a main discharge diagnosis other Abbreviation: SIR, standardized incidence ratio. than MMD, a family history of congen- aSites with no cases: lip, tongue, mouth, salivary glands, stomach, small intestine, gallbladder, larynx, pleura, bone, soft tissues, other parts of the uterus, male genital organs, Hodgkin lymphoma, multiple myeloma, and chronic leukemia. ital or specified condition (n=34) was bOne case was mixed epithelioid spindle cell melanoma, and the second was malignant but unknown histology. cThree cases were astrocytoma, 1 glioblastoma, 1 astroblastoma, 1 oligodendroglioma, and 1 malignant but unknown the most commonly reported diagno- histology. sis, followed by respiratory problems dOther sites included cancers of the parathyroid (n=2), cancer in another unspecific/unknown primary site (n=5), and neoplasm of the retroperitoneum (n=1). (n=33, 33% of whom had respiratory

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provides strong evidence that MMD that the type 1 MMD gene product— terminant of cancer risk in this con- may in fact be a cancer susceptibility DMPK (OMIM 605377)—is a protein text, because nucleotide repeat expan- disorder. kinase, ie, a member of a large gene fam- sions are longer in MMD patients Several biological mechanisms for the ily that contains numerous examples of compared with Huntington disease or apparent increased cancer risk have cancer susceptibility genes, such as RET fragile X patients,32 and case reports been proposed, including possible (multiple endocrine neoplasia type 2), have demonstrated longer nucleotide RNA-mediated alterations in tumor STK11 (Peutz-Jeghers syndrome), repeat expansion in tumor tissue from suppressor genes or oncogene expres- PRKAR1A (Carney complex), RAF1 MMD patients compared with their nor- sion, modification of the coding fea- (Noonan syndrome), ALK (neuroblas- mal tissue.33,34 If proven true, we would tures of proteins,27 up-regulation of the toma), and PDGFRA (gastrointestinal expect that patients with type 2 MMD, Wnt/β-catenin signaling pathway, or all stromal tumor).29 who are known to have the longest re- of these.13 Of note, alterations in RNA The absence of an excess cancer risk peat sizes, would have higher risk of binding proteins, suggested as a key in other repeat disorders, such as frag- cancer, a hypothesis that needs fur- player in MMD pathogenesis, have been ile X syndrome30 and Huntington dis- ther investigation. The observed can- observed in human carcinogenesis.28 ease,31 is noteworthy. It is possible that cer risk differences between various re- On the other hand, it is worth noting repeat expansion size may be a key de- peat disorders might also be related to

Table 3. Standardized Incidence Ratios of Cancers in Swedish and Danish Patients With Myotonic Muscular Dystrophy by Sex and Selected Anatomic Sitesa Men (n = 861) Women (n = 797) (7345 Person-Years) (6825 Person-Years) P Value for Anatomic Site No. Diagnosed Expected No. SIR (95% CI) No. Diagnosed Expected No. SIR (95% CI) Heterogeneity All sites except nonmelanoma skin 39 24.72 1.6 (1.1-2.1) 65 27.55 2.4 (1.8-3.0) .05 All sites except genital organs 35 19.69 1.8 (1.3-2.5) 44 23.3 1.9 (1.4-2.5) .81 Colon 5 1.75 2.9 (1.0-6.3) 5 1.72 2.9 (1.1-6.4) .98 Rectum 1 1.40 0.7 (0.0-3.5) 4 0.90 4.4 (1.4-1.7) .09 Pancreas 3 0.68 4.4 (1.1-12.0) 1 0.59 1.7 (0.1-8.4) .45 Lung 9 3.61 2.5 (1.2-4.6) 1 2.42 0.4 (0.0-2.0) .05 Central nervous system 4 0.85 4.7 (1.5-11.4) 3 0.75 4.0 (1.0-1.9) .85 Brain 4 0.71 5.6 (1.8-13.5) 3 0.62 4.9 (1.2-13.2) .87 Eye 1 0.09 11.0 (0.6-54.4) 1 0.08 13.1 (0.7-64.8) .91 Thyroid gland 0 0.12 0 3 0.30 9.8 (2.5-26.8) .37 Endometrium 11 1.45 7.6 (4.0-13.2) Other female genital organs 2 0.21 9.6 (1.6-31.8) Ovary, tube, and broad ligament 7 1.36 5.2 (2.3-10.2) Abbreviation: SIR, standardized incidence ratio. aAnatomic sites presented in this table are those with a statistically significant excess risk overall or sites with sex-specific risk.

Table 4. Standardized Incidence Ratios of Cancers in Swedish and Danish Patients With Myotonic Muscular Dystrophy by Age Group and Selected Anatomic Sitesa Ͻ50 y (9339 Person-Years) Ն50 y (4830 Person-Years) P Value for Anatomic Site No. Diagnosed Expected No. SIR (95% CI) No. Diagnosed Expected No. SIR (95% CI) Heterogeneity All sites except nonmelanoma skin 24 10.93 2.2 (1.4-3.2) 80 41.25 1.9 (1.6-2.4) .58 Esophagus 2 0.06 31.3 (5.2-103.3) 0 0.52 0 .01 Colon 1 0.40 2.5 (0.1-12.5) 9 3.08 2.9 (1.4-5.4) .98 Pancreas 1 0.14 7.4 (0.4-36.3) 3 1.13 2.6 (0.7-7.2) .42 Lung 3 0.60 5.0 (1.3-13.5) 7 5.38 1.3 (0.6-2.6) .08 Central nervous system 2 0.61 3.3 (0.5-10.8) 5 0.98 5.1 (1.9-11.3) .64 Brain 2 0.49 4.1 (0.7-13.5) 5 0.84 6.0 (2.2-13.2) .69 Eye 0 0.05 0 2 0.12 17.1 (2.9-56.5) .49 Thyroid gland 1 0.22 4.5 (0.2-22.1) 2 0.20 10.0 (1.7-33.1) .56 Endometrium 5 0.14 35.6 (13.0-78.9) 6 1.31 4.6 (1.9-9.5) .003 Ovary, tube, and broad ligament 0 0.34 0 7 1.02 6.9 (3.0-13.6) .14 Abbreviation: SIR, standardized incidence ratio. aAnatomic sites presented in this table are those with a statistically significant excess risk overall or sites with an age-specific risk.

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the precise repeat expansion location The study included MMD patients iden- ing which specific MMD subtype each within the affected gene. Myotonic mus- tified from both inpatient and outpa- participant had, so we could not deter- cular dystrophy differs from Hunting- tient registries, broadening the gener- mine whether the increased cancer risk ton disease by having expansion in a alizability of our results. However, the observed in MMD was common to all noncoding region, which is more likely severely affected MMD subset is still patients or confined to a specific sub- to produce a toxic RNA-mediated gain- likely to be overrepresented because the type. We expect that most of the cases of-function that can affect down- majority of patients in the study were in this study were type 1 MMD, be- stream effector genes,5,35 some of which identified from inpatient hospitaliza- cause it is more prevalent, and it was may be tumor suppressor genes, eg, tion records. identified and molecularly character- mismatch repair genes. Additional The remarkable similarity of find- ized before type 2 MMD. Further- analyses of paired normal tissue and tu- ings obtained from the Swedish and more, we did not have data on gene re- mor samples from well-characterized Danish components of the study pro- peat length. Thus, it remains to be MMD patients could shed further light vides substantial reassurance that our evaluated in future studies to what ex- on the relationship between expan- observations are genuine. The ab- tent gene repeat length modifies the sion repeat length and cancer risk in sence of excess screening-related can- cancer risk. Finally, we acknowledge MMD. cers such as breast, cervical, and pros- that the point estimates for some of the Surprisingly, the cancer spectrum we tate in our analysis argues against a cancer sites had wide confidence inter- observed in MMD patients included possible influence of surveillance bias vals, which prevent drawing firm con- many of the same excess cancers ob- on our results. Most of the excess can- clusions about these sites. served in patients with hereditary non- cers observed in the present study were polyposis colorectal cancer (HNPCC),36 lethal cancers that would be diag- CONCLUSION eg, cancers of the colon, brain, ovary, nosed regardless of whether a person Our study provides quantitative epide- and endometrium. In that context, had prior contact with the health care miologic evidence of an increased risk MMD-related pilomatricoma may be system. Thus, surveillance bias did not of cancer in MMD patients. The spe- analogous to the increased risk of se- appear to influence our results. Fur- cific cancer patterns observed in our baceous adenoma in the Muir-Torre thermore, we found MMD patients with study raise the possibility of a role for variant of HNPCC. Inherited DNA mis- a similarly increased risk of cancer when aberrant mismatch repair in the etiol- match repair abnormalities are the ge- restricting the analyses to more than 5 ogy of MMD-related cancer. Further re- netic basis for HNPCC, a prototypic years after the first MMD discharge di- search is needed to explore whether the cancer susceptibility disorder.36 Defec- agnosis, to those with MMD as main observed associations are similar in both tive mismatch repair may have a role diagnosis, and to those with no other type 1 and type 2 MMD; to determine in the formation of unstable nucleo- diagnoses besides MMD at the first whether cancer risk correlates with dis- tide repeats, perhaps through a disease- MMD admittance, arguing against the ease severity, repeat length, or both; and specific mechanism.37,38 The nexus be- possibility that our results may be con- to understand the biological mecha- tween the nucleotide repeat expansion founded by cause of hospitalization or nisms that might explain the associa- pathway and mismatch repair war- increased surveillance. tions we have reported. Our findings rants further investigation in this con- Because of the underreporting of have implications for the clinical man- text, because in vitro studies38 and nonmelanoma skin cancer in the Swed- agement of MMD patients, including at mouse models39-41 suggest that abnor- ish Cancer Registry, we were not able a minimum the implementation of ap- mal mismatch repair has a major role to fully evaluate its risk in MMD. How- propriate validated routine population- in mediating the biological effects of ever, data available from the Danish based cancer screening strategies, par- MMD-related nucleotide repeat insta- registry only suggested a possible ex- ticularly for colon cancer, and careful bility. eTable 2 summarizes the ob- cess risk of nonmelanoma skin cancer assessment of therapy-related risks and served cancer profile in MMD patients (SIR, 2.08; 95% CI, 1.2-3.4), an asso- benefits. The incidence rates for a num- vs HNPCC patients. The occurrence of ciation that needs further confirma- ber of the excess cancers are relatively a similar spectrum of malignancies in tion. Of note, our combined data sug- low, despite their large relative risks. both raises the possibility of shared gested an excess risk of cutaneous Screening for these uncommon can- causal pathways. melanoma, although it was not statis- cers should not be implemented in the Our study has several strengths. We tically significant. absence of demonstrated clinical util- used population-based registries, mini- The lack of information regarding ity. The evaluation of persistent central mizing selection bias and maximizing known cancer risk factors, eg, smok- nervous system and abdominopelvic complete cancer ascertainment. Both ing, which prevented evaluating them symptoms or dysfunctional uterine MMD and cancer diagnoses were de- as possible confounders, represents 1 bleeding warrants clinical consider- rived from registry-based records rather important study limitation. In addi- ation with a higher prior probability of than self-report, minimizing recall bias. tion, our data did not permit identify- neoplasm, in light of our new findings.

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Author Contributions: Dr Greene had full access to cular dystrophy. Science. 1992;255(5049):1256- J. The Danish Cancer Registry: history, content, qual- all of the data in the study and takes responsibility for 1258. ity and use. Dan Med Bull. 1997;44(5):535-539. the integrity of the data and the accuracy of the data 4. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myo- 24. Survey of Nordic Cancer Registries [2000]. Dan- analysis. Drs Gadalla and Lund contributed equally to tonic dystrophy mutation: an unstable CTG repeat in ish Cancer Society. http://www.ncu.nu/ancr/pdf this study. the 3Ј untranslated region of the gene. Science. 1992; /survey.pdf. Accessed November 15, 2011. Study concept and design: Gadalla, Lund, Pfeiffer, 255(5049):1253-1255. 25. Engholm G, Ferlay J, Christensen N, et al. Mueller, Moxley, Kristinsson, Hilbert, Landgren, 5. Ranum LP, Day JW. Myotonic dystrophy: clinical NORDCAN: a Nordic tool for cancer information, plan- Melbye, Greene. and molecular parallels between myotonic dystrophy ning, quality control and research. Acta Oncol. 2010; Acquisition of data: Gadalla, Lund, Kristinsson, Greene. type 1 and type 2. Curr Neurol Neurosci Rep. 2002; 49(5):725-736. Analysis and interpretation of data: Gadalla, Lund, 2(5):465-470. 26. Greenland S, Rothman KJ. Fundamentals of epi- Pfeiffer, Gørtz, Mueller, Moxley, Kristinsson, Bjorkholm, 6. Liquori CL, Ricker K, Moseley ML, et al. Myotonic demiology data analysis. In: Rothman KJ, Greenland Shebl, Hilbert, Landgren, Wohlfahrt, Melbye, Greene. dystrophy type 2 caused by a CCTG expansion in in- S, Lash TL, eds. Modern Epidemiology. 3rd ed. Phila- Drafting of the manuscript: Gadalla, Lund, Pfeiffer, tron 1 of ZNF9. Science. 2001;293(5531):864- delphia, PD: Lippincott Williams & Wilkins; 2008: Mueller, Landgren, Greene. 867. 213-237. Critical revision of the manuscript for important in- 7. Suominen T, Bachinski LL, Auvinen S, et al. Popu- 27. Panzer S, Kuhl DP, Caskey CT. Unstable triplet tellectual content: Gadalla, Lund, Gørtz, Mueller, lation frequency of myotonic dystrophy: higher than repeat sequences: a source of cancer mutations? Stem Moxley, Kristinsson, Bjorkholm, Shebl, Hilbert, expected frequency of myotonic dystrophy type 2 Cells. 1995;13(2):146-157. Landgren, Wohlfahrt, Melbye, Greene. (DM2) mutation in Finland. Eur J Hum Genet. 2011; 28. Lukong KE, Chang KW, Khandjian EW, Richard Statistical analysis: Gadalla, Pfeiffer, Gørtz, Shebl, 19(7):776-782. S. RNA-binding proteins in human genetic disease. Landgren. 8. de Die-Smulders CE, Ho¨ weler CJ, Thijs C, et al. Age Trends Genet. 2008;24(8):416-425. Obtained funding: Greene. and causes of death in adult-onset myotonic dystrophy. 29. Lahiry P, Torkamani A, Schork NJ, Hegele RA. Ki- Administrative, technical, or material support: Gadalla, Brain. 1998;121(pt 8):1557-1563. nase mutations in human disease: interpreting Lund, Mueller, Kristinsson, Bjorkholm, Hilbert, Melbye, 9. Mathieu J, Allard P, Potvin L, Pre´ vost C, Be´ginP. genotype-phenotype relationships. Nat Rev Genet. Greene. A 10-year study of mortality in a cohort of patients 2010;11(1):60-74. Study supervision: Moxley, Bjorkholm, Wohlfahrt, with myotonic dystrophy. Neurology. 1999;52 30. Sund R, Pukkala E, Patja K. Cancer incidence among Melbye, Greene. (8):1658-1662. persons with fragile X syndrome in Finland: a Conflict of Interest Disclosures: All authors have com- 10. Mankodi A, Urbinati CR, Yuan QP, et al. Muscle- population-based study. J Intellect Disabil Res. 2009; pleted and submitted the ICMJE Form for Disclosure blind localizes to nuclear foci of aberrant RNA in myo- 53(1):85-90. of Potential Conflicts of Interest and none were re- tonic dystrophy types 1 and 2. Hum Mol Genet. 2001; 31. 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