Hereditary nonpolyposis colorectal cancer (HNPCC)

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1 GASTROENTEROLOGY 2000;118: Controlled 15-Year Trial on Screening for Colorectal Cancer in Families With Hereditary Nonpolyposis Colorectal Cancer HEIKKI J. JÄRVINEN,* MARKKU AARNIO,* HARRI MUSTONEN,* KATJA AKTAN COLLAN, LAURI A. AALTONEN, PÄIVI PELTOMÄKI, ALBERT DE LA CHAPELLE, and JUKKA PEKKA MECKLIN *Second Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; and Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland See editorial on page 969. Background & Aims: Identification of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of colonoscopy and polypectomies. We evaluated the efficacy of screening in a controlled trial over 15 years. Methods: Incidence of CRC and survival were compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic screening at 3-year intervals was arranged for 133 subjects; 119 control subjects had no screening. Genetic testing was offered to subjects in whose families the causative mutation was known. Results: CRC developed in 8 screened subjects (6%) compared with 19 control subjects (16 %; P 0.014). The CRC rate was reduced by 62%. In mutationpositive subjects alone, the CRC rates were 18% in screened subjects and 41% in controls (P 0.02). The decrease resulted from the removal of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with unknown mutation status (40%). All CRCs in the study group were local, causing no deaths, compared with 9 deaths caused by CRC in the controls. The overall death rates were 10 vs. 26 subjects in the study and control groups (P 0.003), 4 vs. 12 in mutationpositive subjects (P 0.05). Conclusions: Colonoscopic screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families. Hereditary nonpolyposis colorectal cancer (HNPCC) is a mendelian-dominant cancer syndrome characterized by a high risk of colorectal cancer (CRC) and endometrial cancer at a young age, 1 and an increased risk of many less frequent tumor types, such as gastric, ovarian, renal cell, uroepithelial, and biliary tract adenocarcinomas. 2 Mutations in 1 of 5 DNA mismatch repair genes cause the cancer susceptibility. 3 6 Identification of a specific germline mutation in a member of a clinically suspected family enables predictive genetic testing to be offered to at-risk family members. Public and professional awareness of the existence and nature of HNPCC and the high risk of CRC (greater than 80% 2,7 ) associated with its germline mutations have led to the detection of increasing numbers of cancer-free individuals who are mutation positive. It is therefore very important to devise strategies to prevent cancer or cancer death in such individuals through clinical screening. Colonoscopy is one potential tool for the detection and treatment of premalignant adenomas or early CRC probably resulting in improved survival. 8,9 We previously reported on a cohort of at-risk members of HNPCC families that were offered colonoscopic screening beginning in After 10 years of study, a statistically significant reduction in CRC rate was noted as a result of polypectomies in individuals who opted for screening compared with those who did not. 10 We now describe the results after completion of 15 years of this study. Importantly, we have now conducted predictive mutation analyses in the majority of the entire cohort and are able to correlate clinical data in screened subjects and controls with their mutation status. Materials and Methods Subjects and Examinations The subjects consisted of 252 asymptomatic individuals, aged years, belonging to 22 HNPCC families and being at 50% a priori risk to be mutation carriers. The inclusion criteria, selection of subjects to the study and control groups by free choice, and screening procedures have been described in detail previously. 10 The final study group of 133 subjects had their first colonic examination between 1982 and 1986, whereas the 119 control subjects declined screening (78 Abbreviations used in this paper: CI, confidence interval; CRC, colorectal cancer; HNPCC, hereditary nonpolyposis colorectal cancer by the American Gastroenterological Association /00/$10.00 doi: /gg

2 830 JÄRVINEN ET AL. GASTROENTEROLOGY Vol. 118, No. 5 subjects) or could not be traced (41 subjects), and were not contacted before genetic testing became feasible in The 78 subjects declining screening were personally contacted and informed about the increased cancer risk in their family at least once, often several times. One previously unknown at-risk family member was added to the control group. The original study plan was approved by the ethical committee of the Medical Faculty of Helsinki University and Helsinki University Hospital. The study and control groups were comparable in terms of mean ( SD) age ( vs years at the beginning of study) and sex (73 men and 60 women vs. 59 men and 60 women). At the end of 1998, the median follow-up time was 14.5 years (range, 2 years 8 months to 16 years) in the study group and 15 years (range, 1 year 4 months to 15 years) in the control group. The number of person-years at the follow-up was 1854 in the study group and 1618 in controls. The point of reference for the start of the study was the date of the first examination in the study group and January 1, 1984, in the control group. A mutated MLH1 gene has been shown to segregate in 19 of the families. Finnish founder mutation 1 (deletion of exon 16) occurs in 13 families; founder mutation 2 (a splice site mutation leading to the loss of exon 6) occurs in 2 families. Three different mutations in exons 3 5, 12, and 17 account for 1 family each One family has a mutation in the MSH2 gene (exon 12), and a suspected DNA mismatch repair gene mutation that has not yet been fully characterized occurs in another family. In 2 families, no germline mutations have yet been identified; one of these fulfills the clinical diagnostic criteria for HNPCC (Amsterdam criteria), 14 the other does not. Predictive genetic testing for the mutation segregating in each particular family was offered for 205 individuals and performed in 193 study subjects between 1996 and 1998: 116 in the study group and 77 in the controls. Before testing, the subjects were counseled individually and gave written, informed consent. Three subjects (who died of cancer) were classified as obligate mutation-positive carriers because at least 1 child had the expected mutation. Six further subjects were regarded as mutation positive because they had a cancer belonging to the HNPCC tumor spectrum: CRC (2), renal cell adenocarcinoma (2), endometrial cancer (1), and lymphoma (1). In total, there were 44 mutation-positive and 74 mutationnegative individuals in the study group compared with 46 positive and 38 negative in the controls. Mutation status was unknown in 50 subjects (15 study subjects and 35 controls): 17 had died before testing was available, 12 declined testing (2 were study subjects and 10 controls), and the remaining 21 subjects belonged to families with no test available. After initial colonoscopy (43 subjects) or double-contrast barium enema and sigmoidoscopy (90 subjects), the examination was repeated at 3-year intervals, and the use of colonoscopy has reached nearly 100%. Actually, the original screening interval was 5 years. An approximately 5-year interval between the first and second examination did occur in 40% of the subjects. The 3-year interval was followed since Polyps detected were removed by snare polypectomy when appropriate. Four subjects underwent total abdominal colectomy (3 in the study group, 1 in the control group) and 1 subject (study group) a segmental resection of the sigmoid colon either for large adenomas, severe dysplasia (2 subjects), or simply to facilitate further surveillance. CRC was treated by means of total abdominal colectomy in all study group subjects and in 9 control group cases; 10 control patients underwent hemicolectomy or segmental resection. Of the latter, 7 had palliative surgery for disseminated CRC, whereas in 2 cases the HNPCC background was not recognized at the time of surgery and 1 patient had anterior resection for rectal cancer. The planned screening program was considered complete or nearly complete with some delays in 123 study subjects (93%). Of the 10 noncompliant subjects, 5 have died of causes other than CRC (1 mutation positive) and 4 have had negative gene test results. The control subjects were not actively contacted after 1986, but screening was arranged when requested. This happened in 24 control subjects (20%) between 1988 and After genetic testing, all mutation-positive subjects were recommended screening, whereas endoscopies were discontinued in mutation-negative subjects in whom no adenomas had been found. At present, excluding mutation-negative subjects (38) and those who have died (27), most of the control subjects are participating in screening (34/54). Data Collection and Statistical Analysis The cancer morbidity data, survival, and causes of death in each group were checked at the Finnish Cancer Registry and the Population Registry of Finland considering December 31, 1998, as the closing date. For persons living abroad, foreign consulates and national registries in Sweden and Norway were contacted in addition to questioning of relatives. Clinical data including tumor site and stage, classified according to the modified Dukes system, 15 were obtained from the hospital records. All analyses between the study and control groups were performed with an intent-to-treat principle disregarding any dropouts from screening in the study group or examinations outside the original study plan in the controls. Differences between 2 proportions were tested using the Fisher exact test (2-tailed) or the Mann Whitney U test. Cumulative incidences of CRC and survival rates were calculated using the Kaplan Meier product limit method, and the significance of differences was tested by the log rank test. The significance of a trend in proportions falling into a natural order was tested with exact Cochran Armitage trend test. Results The number of subjects developing CRC was 8 (6%) of 133 in the study group compared with 19 (16%) of 119 in the control group (P 0.014). The relative risk

3 May 2000 SCREENING FOR COLORECTAL CANCER IN HNPCC 831 of CRC was (95% confidence interval [CI], ) in the study group vs. controls, corresponding to a reduction of 62% (95% CI, 17% 83%). Considering only known mutation-positive subjects, the frequencies of CRC were 18% (8 of 44) in the study group and 41% (19 of 46) in the controls (P 0.02). The corresponding relative CRC risk of the screened mutationpositive individuals was (95% CI, ) and the reduction due to screening 56% (95% CI, 10% 79%). The cumulative proportions of CRC-free subjects were significantly higher in the study group than control group both when all subjects (P 0.019) and when mutation-positive subjects alone (P 0.034) were included (Figure 1). Also, the stage distribution of the CRCs in the study subjects was significantly more favorable than that in the control group (Table 1). Two CRCs in the screening group were detected at the first examination (stages A and B). The remaining 6 CRC patients, 2 with stage A and 4 with stage B tumors, had undergone previous colonoscopies with no findings 26, 34, 36, 37, 59, and 60 months before the diagnostic screening examination. Two of the 19 CRC cases in the control group were detected in a screening colonoscopy, 1 outside the study plan (stage A) and the other after a positive genetic test result (2 tumors, both stage B). Adenomas were detected exclusively in screening examinations, in 31 study subjects (23%) and in 4 controls (3%; P 0.001). Two of the latter were detected after the genetic testing had shown a mutation. Adenomas were detected in 15 mutation-positive individuals and in 8 subjects whose mutation status was unknown, but also in 12 mutation-negative subjects. The adenomas were larger in mutation-positive subjects (mean, 6.7 mm; range, 1 20 mm) than in mutation-negative subjects (mean, 3.1 Table 1. Stage Distribution of CRC Cases Stage a Study group (n 133) Control group (n 119) A 3 3 B 5 7 C 1 D 8 Total 8 19 a The stages in the study group were significantly more favorable than in the control group (P 0.03). mm; range, 1 10 mm; P 0.02), and the age was younger at the time of adenoma detection (mutationpositive: mean, 42.2 [range, 24 65] years vs. mutationnegative: 48.5 [range, 36 78] years; P 0.16). Severe dysplasia was found in 2 of 25 adenomas in mutationpositive subjects compared with none of 19 adenomas in mutation-negative subjects. Among all the subjects who had at least 1 complete colonoscopy, the 85 mutationpositive subjects had a 3.4-fold frequency of colorectal neoplasms compared with 83 negatives, 44 (52%) vs. 12 (14%; P 0.001). The sites of the neoplastic lesions were characteristically more proximal in mutation-positive than mutation-negative subjects (Figure 2). No significant complications were observed after more than 600 screening colonoscopies/sigmoidoscopies. None of the 133 subjects in the study group has died of CRC compared with 9 of 119 (8%) among the control subjects (P 0.001). The overall 5-year survival rate of the present CRC patients was 67%: 100% in the study group and 54% in the control group. Altogether, there were 10 deaths (8%) in the study group compared with 26 deaths (22%) in controls within the 15-year period (P 0.001; Table 2). Four (9%) and 12 (26%) of the deaths occurred in known mutation-positive subjects (P 0.05). The relative risks of death for the screened subjects vs. controls within the study period were (95% CI, ) and (95% CI, Figure 1. Cumulative proportion of subjects free of CRC. a P between the screening and control groups including all subjects. b P between mutation-positive subjects of the screening and control groups. Figure 2. Locations of all neoplastic tumors detected within 15 years: (A) mutation-positive subjects (n 85); (B) mutation-negative subjects (n 83)., CRC; a, metachronous CRC;, adenoma.

4 832 JÄRVINEN ET AL. GASTROENTEROLOGY Vol. 118, No. 5 Table 2. Causes of Death Within the 15-Year Study Period Cause Study group (n 133) Control group (n 119) CRC a 9 Gastric cancer a 1 Bile duct carcinoma a 1 Lymphoma a 1 1 Glioblastoma multiforme a 1 Renal cell carcinoma a 1 Pulmonary embolism (postoperative) a 1 Heart attack 4 3 Cerebral hemorrhage 1 2 Duodenal ulcer hemorrhage 1 Pulmonary disease 3 Suicide 1 1 AIDS 1 Accident/violence 3 Total AIDS, acquired immunodeficiency syndrome. a Cause related to the HNPCC syndrome ) for all subjects and for mutation-positive subjects, respectively. Thus, the corresponding reductions in death rate were 66% (95% CI, 32% 83%) or 65% (95% CI, 0.1% 88%). Other HNPCC-related cancers occurred in 23 study subjects (Table 3), and were responsible for all 4 deaths of mutation-positive subjects in the study group and 2 deaths in the control group. One control subject died of pulmonary embolism after a successful colectomy for a severely dysplastic adenoma detected in screening colonoscopy after a positive gene test result. The cumulative overall survival was significantly better in the original study group than control group (P 0.003) and also significant (P 0.05) if mutation-positive subjects only were compared (Figure 3). Of note, an additional Table 3. Extracolonic Cancers and Tumors Within the 15-Year Study Period Tumor type/site Study group (n 133) Control group a (n 119) Endometrial cancer 5 5 Ovarian cancer 3 c Gastric cancer 2D b 1 Urinary bladder/ureteric cancer 2 Lymphoma 1D 1D Renal cell adenocarcinoma 2D Cholangiocarcinoma 1D Epidermoid carcinoma (skin) 1 Melanoma 1 Brain (glioblastoma multiforme) 1D Acoustic neurinoma 1 b Breast 1 b Total 14 (12 patients) 14 (11 patients) D, each D denotes a case of death. a An additional subject had a meningioma within the study period; he tested negative for mutation. b One metachronous tumor. c Two metachronous tumors. Figure 3. Cumulative overall survival. a P between the screening and control groups including all subjects. b P 0.05 between mutation-positive subjects of the screening and control groups. subject in the control group died of CRC less than 2 months after the closing date of the study. Discussion The most important new finding of our extended screening trial was that colonoscopic screening and polypectomies not only reduce the incidence of CRC but also decrease the overall death rate by approximately 65%. This reduction was largely a result of the complete prevention of CRC deaths in the screened subjects compared with 9 deaths among 19 CRC cases in control subjects. The survival advantage was statistically significant both between the original study groups and in the subgroups composed exclusively of mutation-positive subjects. The difference in survival rate was marginal (P 0.05) in mutation-positive individuals. Because all subjects of the 2 groups could not be tested but the mutation status was deduced as positive in 6 cases (2 study subjects, 4 controls) by typical tumor status (e.g., lymphoma), the significance of the survival difference may be questioned if one or more of these tumors (in controls) were in fact unrelated to HNPCC. However, several arguments can be adduced to support the view that a real difference in favor of screening indeed exists. First, an increasing number of control subjects underwent screening examinations during the latter period of the trial, resulting in the detection and treatment of asymptomatic adenomas, and even 2 early-stage CRC cases, thus weakening the power of the study. Second, an additional case of death due to CRC was observed in the control group immediately after the closing date of the study, illustrating the fact that CRC deaths continue to

5 May 2000 SCREENING FOR COLORECTAL CANCER IN HNPCC 833 occur in these individuals not surveilled. On the other hand, ascertainment bias cannot be totally excluded because the selection between the 2 groups was not random. For example, socioeconomic status may have influenced the acceptance of screening, and nonacceptance may be associated with excess of morbidity due to poor health awareness. However, formal randomization of members of the same family to screening or no screening was considered impossible at the beginning of the study. With the possibility for genetic tests, such a randomization is even more problematic now. In survival, the screening group benefited from complete prevention of CRC deaths, yet suffered from the common occurrence of extracolonic cancers. These caused (probably by chance) more deaths in the study group than control group, 4 vs. 2 cases, respectively. In total, 28 tumors of 12 different types were diagnosed in 23 subjects. The frequencies of subjects with extracolonic tumors were 12 (27%) and 11 (24%) in the mutationpositive subjects of the study and control groups, respectively. Because the CRC rates were 18% and 41% in the same groups, it is clear that detecting extracolonic cancer becomes increasingly critical when the CRC risk is largely controlled under colonoscopic surveillance. Interestingly, in female mutation-positive subjects, the risk of endometrial cancer exceeds that of CRC even before any screening arrangements. 2,16 The appropriate screening methods and intervals remain to be solved in future studies, but this is not easy in view of the multiple predisposed organ sites and the relative rarity of most of the cancer types involved. 2 We have started offering screening for endometrial cancer using vacuum abrasion in mutation-positive women. In this particular series the outcome for most subjects with extracolonic cancer was favorable, and it is difficult to see how cases with a fatal outcome could have been managed better. The most cost-effective interval of screening colonoscopies also remains open for future trials. Many authorities suggest that the interval should be shorter than the 3 years used in the present trial, perhaps only 1 or 2 years. 17,18 The efficacy in the prevention of deaths could not have been improved in our trial, but some CRC cases might have been prevented at an adenoma stage and treated without surgery if shorter intervals had been used. Actually, the figures for the reduction in the CRC rate by 62% overall, or 56% in mutation-positive subjects, are underestimates because 2 CRC cases detected during the first screening visit were included and in 2 other cases the screening intervals were 59 and 60 months instead of the planned 36 months. 9 The problem of overlooked adenomas remains despite more frequent endoscopies, and this hazard cumulates with time. Therefore, the option of prophylactic colectomy must be borne in mind as one alternative to repeated colonoscopies. 19 However, prophylactic surgery carries an additional risk of complications, or even death, as observed in 1 control patient who died of pulmonary embolism. The number of subjects who had adenomas removed during the 15-year screening was quite low among the mutation-positive individuals (30%). In fact, mutationnegative subjects had almost as many adenomas, although the total number of neoplasms in the colon was much higher in mutation-positive subjects. Additionally, the age at detection of adenomas was slightly younger in mutation-positive than -negative subjects. It can be seen that an equal number of CRCs would have developed in the 2 groups if the adenomas of 11 mutation-positive subjects had not been removed during screening but progressed to cancer. Our observations support the view that the adenoma-carcinoma sequence is accelerated and almost guaranteed in HNPCC. 20,21 In conclusion, this long-term screening trial proved that repeated colonoscopies can reduce the CRC rate in at-risk or mutation-positive members of HNPCC families by at least 56% 62%, prevent CRC deaths, and reduce overall mortality by about 65%. Given that CRC will largely be controlled by colonoscopic surveillance, the increasing problem of the occurrence of extracolonic cancers at several organ sites merits further attention in screening programs. References 1. Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 1996;78: Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomäki P, Mecklin J-P, Järvinen HJ. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81: Rhyu MS. Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. J Natl Cancer Inst 1996;88: Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yanuso M, Igari T, Koikechiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997;17: Kinzler KW, Vogelstein B. Lessons from the hereditary colorectal cancer. Cell 1996;87: Peltomäki P, Vasen HFA. The ICG on HNPCC. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 1997;113: Vasen HFA, Wijnen J Th, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard M-L, Mohr J, Fodde R, Meera Khan P. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110: Vasen HFA, Taal BG, Nagengast FM, Griffioen G, Menko FH, Kleibeuker JH, Offenhaus GJA, Meera Khan P. Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families. Eur J Cancer 1995;31A:

6 834 JÄRVINEN ET AL. GASTROENTEROLOGY Vol. 118, No Vasen HFA, van Ballegooijen M, Buskens E, Kleibeuker JK, Taal BG, Griffioen G, Nagengast FM, Menko FH, Meera Khan P. A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers. Cancer 1998; 82: Järvinen HJ, Sistonen P, Mecklin J-P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995;108: Nyström-Lahti M, Kristo P, Nicolaides NC, Chang S-Y, Aaltonen LA, Moisio A-L, Järvinen HJ, Mecklin J-P, Kinzler KW, Vogelstein B, de la Chapelle A, Peltomäki P. Founding mutations and Alu-mediated recombination in hereditary cancer. Nat Med 1995;1: Nyström-Lahti M, Wu Y, Moisio A-L, Hofstra RMW, Osinga J, Mecklin J-P, Järvinen HJ, Leisti J, Charles HC, Buys M, de la Chapelle A, Peltomäki P. DNA mismatch gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996;5: Holmberg M, Kristo P, Chadwicks RB, Mecklin J-P, Järvinen HJ, de la Chapelle A, Nyström-Lahti M, Peltomäki P. Mutation sharing, predominant involvement of the MLH1 gene and description of four novel mutations in hereditary non-polyposis colorectal cancer. Hum Mutat 1998;11:482 [Mutation Note 144; online 1997]. 14. Vasen HFA, Mecklin J-P, Meera Khan P, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991;34: Davis NC, Evans EB, Cohen JR, Theile DE. Staging of colorectal cancer. The Australian clinico-pathological staging (ACPS) system compared with Dukes system. Dis Colon Rectum 1984;26: Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B. Cancer risk associated with germline DNA-mismatch-repair gene mutation. Hum Mol Genet 1997;6: Vasen HFA, Nagengast FM, Meera Khan P. Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome). Lancet 1995;345: Thorson AG, Knezetic JA, Lynch HT. A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). Dis Colon Rectum 1999;42: Church JM. Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med 1996;28: Ahlquist DA. Aggressive polyps in hereditary nonpolyposis colorectal cancer: targets for screening. Gastroenterology 1995;108: Jass JR, Stewart SM, Lane MR. Hereditary non-polyposis colorectal cancer morphologies, genes and mutations. Mutat Res 1994;310: Received July 27, Accepted January 13, Address requests for reprints to: Heikki J. Järvinen, M.D., Second Department of Surgery, Helsinki University Central Hospital, P.O. Box 260, FIN HUCH, Helsinki, Finland. Fax: (358) Supported by grants from the National Institutes of Health (CA and CA 16058), European Union (BMH4-CT ), Foundation for Gastroenterological Research in Finland, the Sigrid Juselius Foundation, and the Finnish Cancer Foundation. The authors thank Dr. Annika Lindblom for the genetic testing of several subjects living in Sweden and Tuula Lehtinen, Kirsi Pylvänäinen, and Marjo Molin for organizing the screening, genetic testing, and data collection.

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