Cancer frequency among the patients with myotonic dystrophy in the South Korean population using the national health insurance database

Abstract

•Based on the 7294 patients identified during the 8-year period, we estimate a prevalence of around 14 DM1 patients per 100,000.•This study revealed that the distribution of cancer in DM1 is different to general population.•The most common cancer in DM1 was thyroid cancer and a large difference in cancer frequencies was observed between sexes. Myotonic dystrophies (DMs) are autosomal dominant, multisystemic disorders characterized by myotonia and progressive muscle weakness [[1]Harper P.S. Myotonic Dystrophy. Oxford University Press, London, UK2001Google Scholar]. DM type 1 (DM1) results from a trinucleotide repeat expansion (CTG) in the myotonic dystrophy protein kinase (DMPK) gene [[2]Fu Y.H. Pizzuti A. Fenwick Jr., R.G. et al.An unstable triplet repeat in a gene related to myotonic muscular dystrophy.Science. 1992; 255: 1256-1258Crossref PubMed Scopus (1249) Google Scholar,[3]Mahadevan M. Tsilfidis C. Sabourin L. et al.Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene.Science. 1992; 255: 1253-1255Crossref PubMed Scopus (1392) Google Scholar], and DM type 2 (DM2) is caused by an expansion of CCTG repeats in the CCHC-type zinc finger, nucleic acid binding protein (CNBP) gene [[4]Liquori C.L. Ricker K. Moseley M.L. et al.Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.Science. 2001; 293 (864–867)Crossref PubMed Scopus (966) Google Scholar]. DM1 is the most common adult muscular dystrophy with a prevalence ranging between 0.5 and 18.1 per 100,000 [[5]Theadom A. Rodrigues M. Roxburgh R. et al.Prevalence of muscular dystrophies: a systematic literature review.Neuroepidemiology. 2014; 43: 259-268Crossref PubMed Scopus (126) Google Scholar]. The exact prevalence of DM is not known in South Korea, DM1 is prevalent, whereas no case of DM2 has been reported to dates. In addition to main symptom of myotonia and weakness of DM1, other common manifestations include cardiac conduction defects, endocrine abnormalities, testicular atrophy, respiratory insufficiency, cognitive impairment, and premature cataract [[1]Harper P.S. Myotonic Dystrophy. Oxford University Press, London, UK2001Google Scholar]. Interestingly, recent epidemiological studies have reported a possible link between DM1 and cancer risk [6Win A.K. Perattur P.G. Pulido J.S. Pulido C.M. Lindor N.M. Increased cancer risks in myotonic dystrophy.Mayo Clin. Proc. 2012; 87: 130-135Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 7Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar, 8Abbott D. Johnson N.E. Cannon-Albright LA. A population-based survey of risk for cancer in individuals diagnosed with myotonic dystrophy.Muscle Nerve. 2016; 54: 783-785Crossref PubMed Scopus (17) Google Scholar, 9Wang Y. Pfeiffer R.M. Alsaggaf R. et al.Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink.Int J Cancer. 2018; 142: 1174-1181Crossref PubMed Scopus (18) Google Scholar]. In this study, we estimated cancer frequencies in Korean myotonic dystrophy patients using national health insurance service data and then compared these with frequencies in the general population. This study was performed using data from the NHIS database established by the Health Insurance Review and Assessment Service (HIRA) of Republic of Korea, and was approved by the Institutional Review Board of Dongguk University Gyeongju Hospital (110757-201,806-HR-05-02). Claims are accompanied by information regarding diagnosis, procedure, prescription record, demographic information, and direct medical cost. All Korean citizens are expected to register for Korean National Health Insurance, which covers about 98% of the Korean population [[10]Kim L. Kim J.A. Kim S. A guide for the utilization of Health Insurance Review and Assessment Service national patient samples.Epidemiol Health. 2014; 36e2014008Crossref PubMed Google Scholar]. We conducted a retrospective cohort analysis of patients with the G711 code, as defined by the Korean Classification of Diseases 6th edition (a version of the International Classification of Diseases 10th revision (ICD-10) adapted for use by the Korean health system), registered from January 1, 2010 to December 31, 2017. HIRA data did not differentiate specific DM subtypes. However, based on the evidence presented in the Discussion, we assumed that all cases included in this study were of DM1. Concomitant cancer morbidity was determined using the cancers codes C00 ~ C99, which includes all types of cancers and secondary cancers. In order to avoid presumptive diagnoses, we used disease codes received from hospitals, general hospitals, or superior general hospitals, and not from clinics. Frequencies of cancers in DM1 patients were compared with those in the general Korean population using Korea national statistical data [[11]Jung K.W. Won Y.J. Kong H.J. Lee E.S. Community of population-based regional cancer registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015.Cancer Res. Treat. 2018; 50: 303-316Crossref PubMed Scopus (267) Google Scholar]. A total of 7294 DM1 patients with a G711 diagnosis were identified in the NHIS database. There were 3801 (52.1%) male and 3493 (47.9%) female patients of overall average age of 42.0 ± 19.2 years at first diagnosis (male: 38.9 ± 18.9, female: 45.5 ± 19.0) and 396 (5.43%) neonatal and infant patients (aged ≤1 year). Of the 7294 DM1 patients, 103 (1.41%; males 56, females 47) had accompanying cancer (Table 1), and the mean age of these 103 patients was 53.4 ± 13.3 years (males: 53.8 ± 13.7, females: 52.9 ± 12.9). Thyroid cancer was most common among these 103 patients (15 patients, 14.6%). In descending order, numbers and frequencies of other cancers were; colorectal cancer (14, 13.6%), bronchial and lung cancer (12, 11.7%), hepatic/intrahepatic bile duct cancer (9, 8.7%), corpus uteri cancer (7, 6.8%), breast cancer (7, 6.8%), stomach cancer (6, 5.8%), thymic cancer (5, 4.9%), cancer of parotid/salivary gland/nasopharynx (5, 4.9%), ovarian cancer (4, 3.9%), and skin cancer (3, 2.9%). Brain, connective and soft tissue, pancreatic, and secondary cancers of unknown primary origin were confirmed in two cases each, whereas bone/cartilage, esophageal, renal, larynx, lymphoid, other endocrine gland, and penile cancers and non-Hodgkin lymphoma were observed in one patient each (Fig. 1).Table 1Cancer frequencies in Korean myotonic dystrophy patients.Overall (%)Age at diagnosisMale (%)Age at diagnosisFemale (%)Age at diagnosisBone/cartilage1(1.0)50.00(0.0)–1(2.1)50.0Brain2(1.9)32.5±3.540(0.0)–2(4.3)32.5±3.54Breast7(6.8)56.7±14.000(0.0)–7(14.9)56.7±14.00Bronchus and lung12(11.7)66.3±6.718(14.3)66.5±7.754(8.5)66.0±4.97Colon and rectum14(13.6)55.4±9.947(12.5)55.4±11.527(14.9)55.3±9.01Connective and soft tissue2(1.9)31.0±28.281(1.8)51.01(2.1)11.0Corpus uteri7(6.8)46.7±8.280(0.0)–7(14.9)46.7±8.28Esophageal1(1.0)44.01(1.8)44.00(0.0)–Renal1(1.0)77.01(1.8)77.00(0.0)–Larynx1(1.0)58.01(1.8)58.00(0.0)–Hepatic, intrahepatic bile ducts9(8.7)64.4±12.419(16.1)64.4±12.410(0.0)–Lymphoid, hematopoietic tissue1(1.0)60.00(0.0)–1(2.1)60.0Non-Hodgkin lymphoma1(1.0)39.01(1.8)39.00(0.0)–Other endocrine glands1(1.0)49.01(1.8)49.00(0.0)–Ovary4(3.9)51.8±9.910(0.0)–4(8.5)51.8±9.91Pancreatic2(1.9)54.0±8.491(1.8)48.01(2.1)60.0Parotid gland, salivary gland and nasopharynx5(4.9)40.4±18.233(5.4)29.7±12.662(4.3)56.5±12.02Penile1(1.0)52.01(1.8)52.00(0.0)–Secondary others2(1.9)38.0±1.412(3.6)38.0±1.410(0.0)–Skin3(2.9)51.3±11.932(3.6)54.0±15.561(2.1)46.0Stomach6(5.8)57.0±11.563(5.4)52.0±12.293(6.4)62.0±10.39Thymic5(4.9)50.2±6.025(8.9)50.2±6.020(0.0)–Thyroid15(14.6)48.4±10.599(16.1)45.8±9.356(12.8)52.3±11.96Total103(100.0)53.4±13.2856(100.0)53.8±13.7047(100.0)52.9±12.90 Open table in a new tab Data was also analyzed by sex. The most common cancers in males were thyroid (9, 16.1%) and hepatic/intrahepatic bile duct (9, 16.1%) cancers, while the most common cancers in females were breast (7, 14.9%), colorectal cancer (7, 14.9%), and corpus uteri (7, 14.9%) cancers. This study provides epidemiologic information on carcinomas in Korean myotonic dystrophy type 1 patients. A variety of cancers have been reported in DM1 and cancer type frequency patterns appear to differ from those in Korean population. In Korean national cancer statistics (2015) [[11]Jung K.W. Won Y.J. Kong H.J. Lee E.S. Community of population-based regional cancer registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015.Cancer Res. Treat. 2018; 50: 303-316Crossref PubMed Scopus (267) Google Scholar], the total number of cancer cases was 1,611,487, and cancer type frequencies in descending order were; thyroid (22.0%), stomach (15.9%), colon and rectum (15.9%), breast (13.7%), lung (4.3%), prostatic (4.3%), hepatic (3.8%), cervix uteri (3.1%), renal (2.2%), and bladder (1.9%) cancers. In the present study, the most common cancer in DM1 was thyroid cancer, which is in accord with that observed in the general population. However, a large difference in cancer frequencies was observed between sexes. In the general population, thyroid cancer was most common in females (32.6%) but only the fourth most common cancer in males (8.5%). On the other hand, among DM1 patients, thyroid cancer was only slightly more common in males (14.6% vs. 12.8%). Notably, although thymic cancer was not listed among the most common cancers in the Korean population, it was the fifth most common cancer in male DM1 patients (8.9%). Isaacs syndrome may also be under-recognized within diagnostic code G711, and thymic carcinoma that is known to be associated with Isaacs syndrome [[12]Seo J.Y. Shin B.S. Seo M.W. et al.Isaacs’ syndrome associated with acetylcholine receptor antibodies developed after removal of malignant thymoma.J. Korean Neurol. Assoc. 2010; 28: 203-205Google Scholar], and thus, this syndrome might be considered to provide a possible explanation for the high frequency of thymic carcinoma observed in G711 code cases. However, to the best of our knowledge only three cases of Isaacs syndrome have been reported in Korea and further studies are needed for clarification [[12]Seo J.Y. Shin B.S. Seo M.W. et al.Isaacs’ syndrome associated with acetylcholine receptor antibodies developed after removal of malignant thymoma.J. Korean Neurol. Assoc. 2010; 28: 203-205Google Scholar]. A previous study reported high frequencies of endometrial and ovarian cancers in female DM1 patients (10.6%, 7%) [[7]Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar]. Similarly, we also found female genital cancers had a prevalence of 23.4% among DM1 patients, which was significantly higher than the 9.9% observed in the general population. Epidemiologic studies are needed in other countries to confirm these results. Win et al. reported that DM patients had elevated risks of thyroid cancer, choroidal melanoma, testicular, and prostatic cancer [[6]Win A.K. Perattur P.G. Pulido J.S. Pulido C.M. Lindor N.M. Increased cancer risks in myotonic dystrophy.Mayo Clin. Proc. 2012; 87: 130-135Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar], and Swedish and Danish DM patients were reported to be at significantly higher risk of endometrial, brain, ovarian and colon cancer [[7]Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar]. In Utah, DM patients were found to be at significantly greater risk of testicular and endometrial cancer, and Non-Hodgkin lymphoma [[8]Abbott D. Johnson N.E. Cannon-Albright LA. A population-based survey of risk for cancer in individuals diagnosed with myotonic dystrophy.Muscle Nerve. 2016; 54: 783-785Crossref PubMed Scopus (17) Google Scholar], whereas in the UK, DM patients were reported to be at high risk of contracting skin cancer and basal cell carcinoma [[9]Wang Y. Pfeiffer R.M. Alsaggaf R. et al.Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink.Int J Cancer. 2018; 142: 1174-1181Crossref PubMed Scopus (18) Google Scholar]. Similarly to these studies, thyroid cancer was frequent in Korean DM1 patients. And the frequency of female genital cancer (except endometrial cancer) was also high as was the frequency of colon cancer, which agreed with that observed as in previous study [[7]Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar]. However, the prevalence of other cancers (e.g., brain, testicular, and skin cancers and non-Hodgkin lymphoma), which were reported to be high in DM patients in other studies, were not found to be so in the present study. Further studies are needed to determine the causes of this variability and the influence of ethnic differences. We recruited DM patients using disease code, as has been done in several other studies [7Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar, 8Abbott D. Johnson N.E. Cannon-Albright LA. A population-based survey of risk for cancer in individuals diagnosed with myotonic dystrophy.Muscle Nerve. 2016; 54: 783-785Crossref PubMed Scopus (17) Google Scholar, 9Wang Y. Pfeiffer R.M. Alsaggaf R. et al.Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink.Int J Cancer. 2018; 142: 1174-1181Crossref PubMed Scopus (18) Google Scholar]. Despite the fact that DM1 and DM2 differ clinically and genetically, this code does not differentiate DM1 and DM2. DM2 is known to be prevalent in Caucasians [13Suominen T. Bachinski L.L. Auvinen S. Hackman P. Baggerly K.A. Angelini C. Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland.Eur. J. Hum. Genet. 2011; 19: 776-782Crossref PubMed Scopus (87) Google Scholar, 14Bachinski L.L. Udd B. Meola G. et al.Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect.Am. J. Hum. Genet. 2003; 73: 835-848Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 15Liquori C.L. Ikeda Y. Weatherspoon M. et al.Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract.Am. J. Hum. Genet. 2003; 73: 849-862Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. However, it seems to show ethnic differences as a recent Japanese study failed to identify a single DM2 patient with expanded CCTG repeats in the CNBP gene among undiagnosed limb-girdle muscular dystrophy patients or undiagnosed patients with electrical or clinical myotonia [[16]Matsuura T. Minami N. Arahata H. et al.Myotonic dystrophy type 2 is rare in the Japanese population.J. Hum. Genet. 2012; 57: 219-220Crossref PubMed Scopus (9) Google Scholar]. Furthermore, no report on DM2 has ever been issued in South Korea. Although it is true that a G711 diagnosis may embrace other myotonic disorders, including non-dystrophic myotonias and Issacs syndrome, these disorders are rare in the Korean population. Despite the limitation imposed by the use of disease codes (G711 in ICD-10 and 359.21 in ICD-9), this disease codes represents mostly DM1 patients [[7]Gadalla S.M. Lund M. Pfeiffer R.M. et al.Cancer risk among patients with myotonic muscular dystrophy.JAMA. 2011; 306: 2480-2486Crossref PubMed Scopus (76) Google Scholar,[9]Wang Y. Pfeiffer R.M. Alsaggaf R. et al.Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink.Int J Cancer. 2018; 142: 1174-1181Crossref PubMed Scopus (18) Google Scholar]. Therefore, we believe that subjects with DM1 mostly were included in the present study, and that the results presented are representative of Korean DM1 patients. The prevalence of DM varies widely between countries from 0.5 to 18.1 per 100,000 [[5]Theadom A. Rodrigues M. Roxburgh R. et al.Prevalence of muscular dystrophies: a systematic literature review.Neuroepidemiology. 2014; 43: 259-268Crossref PubMed Scopus (126) Google Scholar]. Based on the 7294 patients identified during the 8-year period in our dataset, we estimate a prevalence of around 14 DM1 patients per 100,000 in the Korean population. Annual prevalence and incidence of DM1 were not analyzed. As mentioned above, some other diseases that share the same code may be involved, the actual prevalence of DM1 may be lower. This study was conducted using HIRA data, which is representative of the Korean population. However, the study has several additional limitations that warrant consideration. First, accessible data was limited to an 8-year period from 2010, and the exclusion of patients diagnosed with DM or with DM and cancer before 2010 would have affected average ages at diagnosis. Second, HIRA data does not contain clinical data such as disease onset, symptoms, disabilities, laboratory results, or genetic information, and this limited our investigating the natures of relationships between the number of CTG repetitions in DMPK gene and DM1 severity, and cancer prevalence. Third, a comparison of the frequencies of carcinomas in DM1 and in the general population by age should be conducted to clarify cancer risks. However, Korea national statistical data does not contain information on cancer prevalence by age [[11]Jung K.W. Won Y.J. Kong H.J. Lee E.S. Community of population-based regional cancer registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015.Cancer Res. Treat. 2018; 50: 303-316Crossref PubMed Scopus (267) Google Scholar]. We suggest this topic be addressed by further study. This is the first study undertaken to determine cancer frequency in Korean DM1 patients using national health data. In Korean DM1 patients, the frequency of cancer was 1.41%, and thyroid cancer was the most common cancer in males, while breast cancer was most common in females. The study indicates distribution of cancer in DM1 might differ from those observed in the general population. Further study is needed to determine cancer risks in DM1 patients in comparison to the cancer risks in the general population.