Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
S.C. Wei, M.H. Wang, M.C. Shieh, et al CLINICAL CHARACTERISTICS OF TAIWANESE HEREDITARY NON-POLYPOSIS COLORECTAL CANCER KINDREDS Shu-Chen Wei, Ming-Hsi Wang, Min-Chung Shieh, Cheng-Yi Wang, and Jau-Min Wong Background and purpose: The prevalence of colorectal cancer in Taiwan has increased gradually in recent years. Around 5% to 15% of colorectal cancer is hereditary, and hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. This study aimed to determine the clinical characteristics of Taiwanese HNPCC kindreds. Patients and methods: We reviewed the chart records of all HNPCC kindreds followedup in our hospital during the period from 1996 to 1999. Their clinical characteristics were recorded and analyzed. Results: There were 10 families, including a total of 202 persons, who met the Amsterdam criteria for HNPCC. Fifty-two persons in these families had a diagnosis of cancer, including 26 women and 26 men. There were 40 colorectal cancers, five endometrial cancers, five gastric cancers, two ovarian cancers, two hepatocellular carcinomas, and one each of lung cancer, breast cancer, thyroid cancer, and pancreatic cancer (six patients had two cancers). The mean age at cancer diagnosis was 42.1 years. Among the 12 occurrences in 11 colorectal cancer patients with complete clinical and pathological findings, most cancers (67%) were located proximal to the splenic flexure (right-side colon). One patient had metachronous colorectal cancer. Conclusions: This is the first report of the general clinical characteristics of Taiwanese HNPCC. The clinical characteristics of HNPCC in Taiwan were similar to those in Western countries. The genetic bases of Taiwanese HNPCC patients remain to be determined. Colorectal cancer is one of the most common forms of neoplasm in Western countries and its incidence is increasing [1]. The incidence of colorectal cancer increased during the period from 1987 to 1997 in Taiwan, replacing gastric cancer as the third leading cause of death from cancer during this period. The annual number of deaths from colorectal cancer also increased from 1,400 persons/year to 2,855 persons/ year during this 10-year period [2]. It is reasonable to expect that colorectal cancer incidence will continue to increase in the future in Taiwan. Hereditary nonpolyposis colorectal cancer (HNPCC) was first described nearly 100 years ago [3, 4]. However, its pathogenesis remained elusive until recently, when the disease was shown to be inher- (J Formos Med Assoc 2002;101:206–9) Key words: HNPCC Taiwanese ited in mandelian fashion and linked to mismatch repair (MMR) genes on chromosomes 2, 3, or 7 [5–13]. Five genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6) that apparently participate in mismatch repair in humans have been identified [7–15], and defects in these genes lead to a genetic instability in which short repeated sequences (microsatellites) are characteristically altered [16–18]. Caretaker genes serve to maintain genetic stability, and if one of these genes undergoes mutation, the rate of mutation increases significantly. This instability is believed to result in a rapid accumulation of somatic mutation once tumorigenesis is initiated [11]. Individuals in families with HNPCC have an increased incidence of colorectal cancer (70%) and endometrial cancer as well as an Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Received: 13 July 2001. Revised: 20 September 2001. Accepted: 6 November 2001. Reprint requests and correspondence to: Dr. Jau-Min Wong, Associate Professor, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. 206 J Formos Med Assoc 2002 • Vol 101 • No 3 Hereditary Non-Polyposis Colorectal Cancer in Taiwan Results Ten families with 202 persons met the Amsterdam criteria and were included in this study. The Figure shows an example family pedigree. Fifty-two persons in these 10 families had a diagnosis of cancer, including 26 men and 26 women, and six of these had two types J Formos Med Assoc 2002 • Vol 101 • No 3 Endometrial ca ▼ Ovarian ca, rectal ca ▼ Colon ca Rectal ca Gastric ca ▼ To standardize the classification of HNPCC kindreds and facilitate genetic linkage analysis, the International Collaborative Group on HNPCC, meeting in Amsterdam in 1991, issued a set of phenotypic requirements for HNPCC families. The “Amsterdam Criteria” stipulate that HNPCC families should include three members with a histologically verified diagnosis of colorectal cancer in two successive generations. One of the three individuals must be a first-degree relative of the other two, and one of the three affected individuals must be diagnosed prior to 50 years of age [20]. We searched for families with members who met the Amsterdam criteria and had been treated either at the outpatient clinic or hospitalized during the period from 1996 to 1999. The medical charts of these patients were reviewed and data were collected on family history and clinical characteristics. ▼ Patients and Methods Rectal ca ▼ increased risk for other tumors such as ovarian, gastric, ureter, and small bowel cancer. Tumor progression is also accelerated, and HNPCC patients therefore develop colorectal cancer at an average age of 42 years, more than two decades earlier than the general population [3]. Identifying mutations in families allows identification of mutation carriers who would benefit from screening and surveillance. Determination of the microsatellite instability (MSI) and MMR gene status is important in these kindreds to enable genetic consultation and facilitate clinical follow-up. All HNPCC families should undergo a thorough genetic analysis to determine their genetic background. A database of Taiwanese HNPCC kindreds from all hospitals in Taiwan is needed to determine the clinical and genetic basis for Taiwanese HNPCC kindreds. Although the incidence of colorectal cancer is increasing in Taiwan, there has only been one case report about HNPCC in Taiwan, which focused on the gynecologic field [19]. This is the first report about the general clinical characteristics of Taiwanese HNPCC kindreds, and their comparison to those from Western countries. Colon ca, gastric ca ▼ Figure. Hereditary nonpolyposis colorectal cancer (HNPCC) family pedigrees show cancers in three generations. Seven persons in the family already had cancer and at least three persons were in a firstdegree relationship. of cancer. Most had colorectal cancer (40), and other kinds of cancers included endometrial (5), ovarian (2), gastric (5), pancreatic (1), lung (1), breast (1), thyroid (1), and liver cancer (2). Among the 52 persons with cancers, the age of cancer onset could be traced in 27 persons. The age at cancer diagnosis ranged from 19 to 64 years (mean, 42.1 yr). The demographic data of these 10 HNPCC families is shown in the Table. One patient had metachronous colorectal cancer during the follow-up period. There were 170 persons who were still under regular follow-up at the end of the study period. There were complete data on clinical characteristics and pathologic results for 15 patients (10 women and five men). Eleven patients had colorectal cancer, four had endometrial cancer, two had gastric cancer, one had ovarian cancer, and one had hepatocellular carcinoma (four had two types of cancer). The most common initial presentations of colorectal cancer included bowel habit change (30.8%), body weight loss (30.8%), abdominal pain (23.0%), and anemia (15.4%). Most occurrences of colorectal cancer (eight of 12, 67%) were on the right side of the colon. Eleven patients had Duke’s stage B to C colorectal cancer. Only one patient had Duke’s stage A, and her colorectal cancer was found and resected by colonfibroscopy during a health check-up prompted by the recent occurrence of cancer in her family. Discussion There are several hereditary diseases with an excess risk of colorectal cancer, including familial adenomatous polyposis (FAP) and HNPCC. HNPCC, which was first described by Warthin in 1913 and named cancer family 207 S.C. Wei, M.H. Wang, M.C. Shieh, et al Table. Demographic characteristics of the 10 hereditary non-polyposis colorectal cancer (HNPCC) kindreds Kindred Total no. Cancer diagnosed Site of cancer No. under persons (alive/dead)/ follow-up (M/F) Colon Stomach Ovary Endometrium Liver Pancreas Lung Breast Thyroid during study 1 2 3 4 5 6 7 8 9 10 39 23 20 11 23 36 22 8 10 10 8 3 3 4 5 8 8 3 4 6 (3/5)/(4/4) (0/3)/(2/1) (2/1)/(1/2) (2/2)/(2/2) (2/3)/(3/2) (5/3)/(2/6) (3/5)/(4/4) (2/1)/(1/2) (1/3)/(3/1) (3/3)/(4/2) 5 3 2 3 4 7 5 3 3 5 3 1 1 1 1 1 1 1 1 1 1 1 syndrome in the 1960s [21], is a disease with a definite hereditary component [22]. Forty to sixty percent of classical HNPCC families are found to harbor a germline mutation in one of the MMR genes [21, 22]. Prior to the availability of molecular genetic diagnosis, the diagnosis of HNPCC was based exclusively on the family history of colon cancer and the following cardinal clinical features: an autosomal dominant mode of inheritance of colorectal cancer; a paucity of adenomatous colonic polyps, with number and site distribution conforming to general population expectations; gene penetrance of approximately 85% to 90%; development of colorectal cancer in gene carriers at an early age (around 45 yr); most (around 70%) colorectal cancers arising proximal to the splenic flexure; multiple colorectal cancers, both synchronous and metachronous are common; improved survival relative to sporadic colorectal cancer [23, 24]; distinguishing pathologic features of colorectal cancer are manifested, including an increased frequency of MSI; and increased risk for malignancy at certain extracolonic sites, especially the endometrium, and including the ovary, stomach, small bowel, hepatobiliary tract, pancreas, ureter, renal pelvis [25], brain, and breast [26]. In comparing the clinical characteristics of our Taiwanese HNPCC kindreds and the clinical features described in the literature (reports from Western countries), the characteristics were mostly similar but with some differences in the following areas. First, the mean age of cancer onset in our patients was 42.1 years, earlier than the reported mean age of 45 years [24, 26]. Both were younger than the usual age of cancer onset (around 60–65 yr for colorectal cancer, for example). Second, although the tumor spectrum involved in our 208 1 1 1 1 33 19 19 9 20 33 16 7 7 7 patients (colorectal, stomach, endometrium, ovarian, liver, pancreas, lung, breast, thyroid) was similar to those of previous reports [25–27], there were no small bowel or urinary tract cancers in our patients. Colorectal cancer remained the most common cancer, followed by gastric and endometrial cancers. Most colorectal cancers, both in our study and those from Western countries, developed in the right colon. There were synchronous and metachronous cancers in both our study and those from Western countries. Our HNPCC patients had a better prognosis than non-HNPCC colorectal cancer cases. Only two patients (one gastric cancer, one colorectal cancer) died during the followup period. We had only a few tissue blocks, so there was no adequate evidence of whether our patients also had the specific pathologic findings reported previously. The genetic bases (including the MMR genes and MSI status) of our HNPCC patients remain to be determined. These questions will be answered when there is a database of molecular diagnosis of HNPCC in Taiwan. Collecting more Taiwanese HNPCC kindreds will help to set up both clinical and genetic databases. Alertness to the possibility of this disease (detailed family history taking) is the only way to obtain an early diagnosis when molecular database methods are not available. Similar findings were reported by Chen et al in a study of two families [19]. Our series had 10 families, which is more representative. These results are the first report of the general clinical characteristics of Taiwanese HNPCC. ACKNOWLEDGMENTS: This study was supported by a grant from the National Science Council of the Republic of China (NSC-89-2315-B-002-028). J Formos Med Assoc 2002 • Vol 101 • No 3 Hereditary Non-Polyposis Colorectal Cancer in Taiwan References 1. Dunlop MG: Screening for large bowel neoplasm in individuals with a family history of colorectal cancer. Br J Surg 1992:79;488–94. 2. Health and vital statistics, Taiwan area, R.O.C. 1997;1: 10–11. 3. Warthin AS: Heredity with reference to carcinoma: as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895– 1913. Arch Intern Med 1913;12:546–55. 4. Lynch HT, Smyrk TC, Watson P, et al: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104:1535–49. 5. Peltimaki P, Aaltonen LA, Sistonen P, et al: Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993;260:810–2. 6. Lindblom A, Tannergard P, Werelius B, et al: Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet 1993;5:279–82. 7. Parson R, Li GM, Longley MJ, et al: Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 1993;75:1227–36. 8. Fishel R, Lescoe MK, Rao MRS, et al: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993;75:1027–38. 9. Leach FS, Nicolaides NC, Papadopoulos N, et al: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75:1215–25. 10. Bronner CE, Baker SM, Morrison PT, et al: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994;368:258–61. 11. Papadopoulos N, Nicolaides NC, Wei YF, et al: Mutation of a mutL homolog in hereditary colon cancer. Science 1994;263:1625–9. 12. Nicolaides NC, Papadopoulos N, Liu B, et al: Mutations of two PMS homologues in hereditary non-polyposis colon cancer. Nature 1994;371:75–80. 13. Palombo F, Hughes M, Jiricny J, et al: Mismatch repair and cancer. Nature 1994;367:417. 14. Palombo F, Gallinari P, Iaccarino I, et al: GTBP, a 160- J Formos Med Assoc 2002 • Vol 101 • No 3 kilodalton protein essential for mismatch-binding activity in human cells. Science 1995;268:1912–4. 15. Drummond JT, Li GM, Longley MJ, et al: Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 1995;268:1909–12. 16. Papadopoulos N, Nicolaides NC, Liu B, et al: Mutation in genetically unstable cells. Science 1995;268:1915–7. 17. Ionov YM, Peinado A, Malkhosyan S, et al: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993; 363:558–61. 18. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 1993;260:816–9. 19. Chen CH, Huang RL, Yu MS, et al: Hereditary nonpolyposis colorectal cancer with gynecologic malignancies: report of two families in Taiwan. J Formos Med Assoc 2001; 100:269–73. 20. Vasen HFA, Mecklin JP, Khan PM, et al: The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34:424–5. 21. Lynch HT, Shaw MW, Magnuson CW, et al: Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1996;117:206–12. 22. Voskuil DW, Vasen HFA, Kampman E, et al, and the National Collaborative Group on HNPCC: Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. Int J Cancer 1997; 72:205–9. 23. Sankila R, Aaltonen LA, Jarvinen HJ, et al: Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996;110:682–7. 24. Watson P, Lin KM, Rodriguez-Bigas MA, et al: Colorectal carcinoma survival among hereditary nonpolyposis colorectal cancer family members. Cancer 1998;83: 259–66. 25. Watson P, Lynch HT: The tumor spectrum in HNPCC. Anticancer Res 1994;14:1635–9. 26. Lynch HT, Lynch JF: Hereditary nonpolyposis colorectal cancer. Semin Surg Oncol 2000;18:305–13. 27. Benatti P, Sassatelli R, Roncucci L, et al: Tumour spectrum in hereditary non-polyposis colorectal cancer (HNPCC) and in families with “suspected HNPCC”. A population-based study in northern Italy. Colorectal Cancer Study Group. Int J Cancer 1993;54:371–7. 209