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In Hong Kong, colorectal cancer has increased rapidly in recent decades to become the second commonest cancer with more than 3500 new patients diagnosed in the year 2001-2 (notes 1-2). The following chart (adopted from the Hong Kong Cancer Registry (note 2) of the Hospital Authority) shows the increasing trend in the past 12 years period.
We have previously shown that Hong Kong has an exceptionally high incidence of colorectal cancer in the young population1. According to international literature, it is estimated that about 5 - 10% of these patients are predisposed to colorectal cancer due to defects in their genesnotes 3-4. The two main types of hereditary colorectal cancers are Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndromes. These are caused by germline mutation of the Adenomatous Polyposis Coli (APC) and Mismatch Repair (MMR) genes, respectively. Members of these families will have 50% chance of inheriting the disease gene and predispose to colorectal cancer and other cancers such as brain, stomach, duodenal, gynaecological and urinary tract cancers. Moreover, they tend to develop these cancers early in their life. This is reflected in our local data which shows that many of our young colorectal cancer patients are suffering from one of these hereditary colorectal cancer syndromes notes 5-6. The psychological and economic burdens on these families are profound.
Two Main Types of Hereditary Colon Cancer
The two main types of hereditary colorectal cancers are Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndromes. They are caused by germline mutation of the Adenomatous Polyposis Coli (APC) and Mismatch Repair (MMR) genes respectively. Members of these families have 50% chance of inheriting the diseased gene and will be predisposed to colorectal cancer and other cancers from organs such as brain, stomach, duodenum, gynaecological organs and urinary tract. Moreover, they tend to develop these cancers earlier in their life. This fact is reflected in our local data, which shows that many of our young colorectal cancer patients are suffering from one of these hereditary colorectal cancer syndromes (note 5-6). The psychological and economic burdens on these families are profound.
For these high-risk individuals, pre-symptomatic detection and treatment of precancerous adenomas or early cancers by screening is the most effective way to prevent colorectal cancer and its associated morbidity and mortality (notes 7-11). Recent advances in molecular technology have allowed detection of these abnormal genes that caused the two syndromes (notes 12-13). Moreover, our recent findings of two commonly occurring founder mutations in Southern Chinese have facilitated our genetic diagnosis (notes 14-15). Genetic diagnosis and screening make it possible to distinguish accurately the disease-gene carriers from those who have not inherited the defective gene within affected families, thus allowing an accurate risk assessment of all the at-risk family members. The non-disease-gene carriers will be relieved from the psychological burden as well as the chore of continuous screening. Resources can then be concentrated on counselling and vigilant surveillance of those carrying the defective gene to prevent cancer development.
Management of these hereditary colorectal cancer families requires a multidisciplinary approach and is best organised by a dedicated registry. Since its establishment in 1995, the Hereditary Gastrointestinal Cancer Registry has developed a unique service for these hereditary colorectal cancer families in Hong Kong (notes 7-8).
References
1. Yuen ST, Chung LP, Leung SY, Chan ASY, Ho J, Ho JWC and Wyllie AH. Colorectal carcinomas in Hong Kong: epidemiology and genetic mutations. Br J Cancer 1997; 76(12):1610-1616.
2. Hong Kong Cancer Registry, Hospital Authority, Hong Kong, 2005. (http://www.ha.org.hk/cancereg).
3. Cannon-Albright LA et al. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancer. N Eng J Med 1988; 319:533-537.
4. Winawer SJ et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112:594-642.
5. Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan KYM, Chan ASY, Ho JCY, Leung SY and Wyllie AH. Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. J Natl Cancer Inst 1999; 91(14):1221-6.
6. Yuen ST, Chan TL, Ho JW, Chan AS, Chung LP, Lam PW, Tse CW, Wyllie AH, Leung SY. Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 2002;21(49):7585-92.
7. Ho JWC and Yuen ST. Screening of hereditary colorectal cancer syndromes (review). Asian J Surg. 2000;23(4):332-343.
8. Ho JW, Chu KM, Tse CW, Yuen ST. Phenotype and management of patients with familial adenomatous polyposis in Hong Kong: perspective of the Hereditary Gastrointestinal Cancer Registry. Hong Kong Med J 2002; 8(5):342-7.
9. Jarvinen HJ. Epidemiology of familial adenomatous polyposis in Finland : impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357-360.
10. Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108:1405-1411.
11. Vasen HFA, van Ballegooijen M, Buskens E et al. A cost effective analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers. Cancer 1998; 82:1632-1637.
12. Yuen ST, Chung LP, Ho J, Chan TL, So KC, and Leung SY. Genetic diagnosis for hereditary colorectal cancer syndromes. In: Proceedings of First Hong Kong Medical Genetics Conference. Edited by Stephen Lam, Mary Tang, Ivan Lo and WK Chan. The Hong Kong Society of Medical Genetics, Hong Kong. 1998; pp71-75.
13. Yuen ST. Colorectal cancer - Hereditary cancer syndromes and significance of genetic diagnosis. Hong Kong Society of Gastroenterology Newsletter 2001, pp.6.
14. Chan TL, Yuen ST, Ho JWC, Chan ASY, Kwan KYM, Chung LP, Lam PWY, Tse CW and Leung SY. A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: A founder mutation in Chinese population. Oncogene 2001;20(23):2976-81.
15. Chan TL, Chan YW, Ho JW, Chan C, Chan AS, Chan E, Lam PW, Tse CW, Lee KC, Lau CW, Gwi E, Leung SY, Yuen ST. MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population. Am J Hum Gene 2004; 74(5):1035-42.
我們曾報告香港年輕的華人有特別高的大腸癌發病率(註1) 。而根據國際文獻顯示,估計10% 至15% 的病患者是由於本身的基因出現問題,而容易患上結直腸癌 (註3,4) 。
兩種主要的遺傳性結直腸癌
兩種主要的常染色體顯性遺傳性結直腸癌是 家族性結直腸瘜肉綜合症(簡稱FAP) 和 遺傳性(非瘜肉)結直腸癌綜合症(簡稱HNPCC)。這兩種病症分別是由APC基因及錯配修補(MMR)基因突變所引起的。這兩類家庭的成員有一半的機會帶有引發癌症的基因,所以他們較普通人容易患上結直腸癌及其他相連的癌症,例如胃、十二指腸、腦、婦科類及泌尿道癌。同時, 這些癌瘤傾向在這些家庭成員年輕時就發生, 所以這些癌症對這些家庭造成沉重的心理和經濟負擔。
早期監察及普查的重要性
大部份的結直腸癌是由無徵狀的癌前病害即瘜肉,經過十年或以上的演變而成為癌症。可是受基因影響的人士,如FAP患者,在年紀輕輕時大腸已生了很多瘜肉或如HNPCC患病,瘜肉演變成為癌症的過程祗需三至四年。由於早期的癌症又或是迅速演變成癌症的瘜肉均缺乏病徵,這便對及早診斷十分困難。
當結直腸癌病徵出現時(即患者因病徵而求醫),超過一半的患者所患的癌症已是後期的癌病,即使經過最恰當及最佳的治療,生存機會也低於三成。相反,進行病徵前的普查,若發現癌前期的瘜肉,可以用內窺鏡將它切除,阻止癌病的發展。即就算發現癌症, 一般來說都是較早期性的, 其治癒率及生還率達九成以上。顯而易見,對高危人士而言,利用普查的手段來診治無病徵的癌前病害或早期癌症,是預防結直腸癌病發和引致死亡的最有效方法。(註4, 5, 6, 7)
遺傳學及風險評估
近年分子科技的發達令醫療人員可測試出導致這兩種遺傳性綜合症的變異基因 (註12,13)。遺傳學診斷及普查更可準確地在高危家庭裡,分辨出那一位成員帶有致癌基因及那一位沒有帶有致癌基因。這樣,帶有正常基因的家庭成員便可放下心理負擔和不用再接受持續普查所帶來的不便。再者, 資源可集中用在帶有致癌基因的家庭成員身上,以提供完整的諮詢服務及定期的癌瘤普查以預防癌症的發生。
遺傳性腸胃癌資料庫於1995年投入服務
服務受遺傳性結直腸癌影響的家庭涉及跨部門的醫療人員,因此有必要成立一專門的資料庫來統籌這項服務。自1995年成立以來,遺傳性腸胃癌資料庫為香港的遺傳性結直腸癌家庭提供獨有的服務。
References
1. Yuen ST, Chung LP, Leung SY, Chan ASY, Ho J, Ho JWC and Wyllie AH. Colorectal carcinomas in Hong Kong: epidemiology and genetic mutations. Br J Cancer. 1997; 76(12):1610-1616.
2. Hong Kong Cancer Registry, Hospital Authority, Hong Kong. 2001. (http://www.ha.org.hk/cancereg)
3. Cannon-Albright LA et al. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancer. N Eng J Med 1988; 319:533-537.
4. Winawer SJ et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112:594-642.
5. Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan KYM, Chan ASY, Ho JCY, Leung SY and Wyllie AH. Frequent Microsatellite Instability and Mismatch Repair Gene Mutations in Young Chinese Patients with Colorectal Cancer. J Natl Cancer Inst. 1999; 91(14):1221-6.
6. Yuen ST, Chan TL, Ho JW, Chan AS, Chung LP, Lam PW, Tse CW, Wyllie AH, Leung SY. Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 2002;21(49):7585-92
7. Ho JWC and Yuen ST. Screening of hereditary colorectal cancer syndromes (review). Asian J Surg. 2000 Oct;23(4):332-343.
8. Ho JW, Chu KM, Tse CW, Yuen ST. Phenotype and management of patients with familial adenomatous polyposis in Hong Kong: perspective of the Hereditary Gastrointestinal Cancer Registry. Hong Kong Med J 2002; 8(5):342-7
9. Jarvinen HJ. Epidemiology of familial adenomatous polyposis in Finland : impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357-360.
10. Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108:1405-1411.
11. Vasen HFA, van Ballegooijen M, Buskens E et al. A cost effective analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers. Cancer 1998; 82:1632-1637.
12. Yuen ST, Chung LP, Ho J, Chan TL, So KC, and Leung SY. Genetic diagnosis for hereditary colorectal cancer syndromes. In: Proceedings of First Hong Kong Medical Genetics Conference. Edited by Stephen Lam, Mary Tang, Ivan Lo and WK Chan. The Hong Kong Society of Medical Genetics, Hong Kong. 1998; pp71-75.
13. Yuen ST. Colorectal cancer - Hereditary cancer syndromes and significance of genetic diagnosis. Hong Kong Society of Gastroenterology Newsletter 2001 Jan, pp.6.
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