结肠癌和直肠癌临床特点及癌变相关分子机制的异同分析
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摘要
研究背景：结直肠癌作为消化系统常见肿瘤之一,近来在我国的发病率呈逐年上升的趋势。随着我国流行病学调查的逐渐开展,目前认为结肠癌和直肠癌在发病模式和病因学方面存在着明显差异。在我国直肠癌较结肠癌多见,但90年代与80年代相比所占比例有所下降,这一变化表明生活习惯和饮食结构的西方化与结肠癌的发病有密切关系,但相对于直肠癌的关系较小。同时结肠癌和直肠癌由于癌变部位的不同,临床表现存在明显差异,其相应的实验室检查、治疗手段等方面也存在的异同,流行病学资料表明结肠癌和直肠癌在发生和发展中肯定存在着差异。目前结直肠癌的癌变机制较为明确,其中经典的为“正常粘膜—腺瘤—腺癌”的染色体不稳定途径,其中包括一系列按时间顺序的癌基因激活和抑癌基因失活,以及Wnt途径的激活；另一与结肠癌发生密切相关的是微卫星不稳定途径。现在的大部分研究将结肠癌和直肠癌混杂在一起,结肠癌和直肠癌的发生过程是否也遵循这两条途径,还是各有侧重,癌变的分子机制有无差异至今为止尚不清楚。近来有报道认为在结肠癌癌变过程中APC, K-ras, p53等基因突变较多见,并且微卫星不稳定途径占有一定比例,这些初步的研究说明结肠癌和直肠癌中基因的表达是有所不同的,两者之间可能存在差异,但均有待进一步系统研究予以阐明。临床特点并的异同,在此基础上通过对结肠癌和直肠癌中APC,β-catenin, p53、wnt-1、MSH-2和MLH-1等蛋白的变化和K-ras基因突变的检测,初步探讨两者癌变途径和重要癌变基因的异同；同时采用基因芯片技术初步检测了结肠癌和直肠癌基因表达的差异,较为系统地探讨了结肠癌和直肠癌的癌变机制的异同,研究结果为制定符合中国人群的预防和筛查方案,降低肿瘤发病率及针对性的个性化治疗奠定了理论基础。
研究目的：本研究首先通过总结近10年北京协和医院结肠癌和直肠癌住院病例1906例,回顾性分析其发病模式的变迁和临床表现、实验室检查、确诊方法、病理分期等临床特点的异同；同时分别选取结肠癌和直肠癌手术组织标本,通过高通量的基因表达谱芯片和免疫组化、基因测序等方法,探讨结肠癌和直肠癌癌变过程基因表达的差异,并针对结直肠癌癌变的染色体不稳定途径和微卫星不稳定途径中的重要蛋白表达和基因突变的异同进行检测,初步探讨我国结肠癌和直肠癌的发病模式、临床特点和癌变过程中分子机制的异同,为针对不同肿瘤类型进行早期诊断和预防、为大规模流行病学调查以及开展肿瘤筛查提供理论依据。
研究方法：回顾性分析总结北京协和医院1999-2008年期间1906例住院的结肠癌和直肠癌患者病历资料,探讨了近年来结肠癌和直肠癌发病模式的变迁,并初步分析其在临床表现、实验室检查、确诊方法、病变分期等的异同；同时选取了结肠癌和直肠癌手术石蜡组织标本各30例,通过免疫组化的方法,检测结直肠癌癌变过程中重要蛋白APC、Wnt1、β-catenin、p53、MLH1、PMS2、MSH2、MSH6的表达,切割和PCR测序的方法研究k-ras突变；在此基础上,采用基因表达谱芯片技术分别检测结肠癌和直肠癌各8例组织标本,探讨两者癌变相关基因表达的差异。
研究结果：临床资料分析表明,1999年～2008年期间结直肠癌收治比较80年代均明显增加(1.39% vs 0.97% p<0.05),但结肠癌和直肠癌分别增加幅度无明显差异；40以下年轻患者近10年呈下降趋势,而70岁以上的患者有所增加,其中以直肠癌的变化更有统计学差异(p<0.05)；直肠癌出现便血和大便习惯改变的几率高于结肠癌,分别为76.9% vs 31.7%和71.9% vs 33.9% (p<0.01)；结肠癌大便常规检查异常明显低于直肠癌(36.5% vs 76.6% p<0.01),血红蛋白下降在结肠癌中更为多见(40.9% vs 29.2% p＜0.01),CEA检查异常在结肠癌中更为常见(57.9% vs 31.1%p<0.01)；直肠指诊发现直肠癌的阳性率高达87.9%,结肠镜检查直肠癌合并息肉的人数少于结肠癌(35.7% vs 19.7% p<0.01),病理分期均以中晚期为主。免疫组织化学检测表明,结肠癌和直肠癌组APC蛋白表达缺失的比例分别为40.0%和46.7%,Wntl蛋白阳性表达的比例分别为50.0%和66.7%,虽直肠癌表达偏高,但无统计学差异,β-catenin阳性表达均在90%以上,p53阳性表达在直肠癌为86.7%,高于结肠癌的76.7%,但无统计学差异；MLH1、PMS2、MSH2、MSH6在结肠癌和直肠癌组织中的检测发现,结肠癌中有8例出现表达缺失,占26.7%,而直肠癌仅为4例,占13.3%(p<0.01)；4种蛋白缺失情况表明,无一例表现为单个蛋白的表达缺失,MLH1和PMS2蛋白同时缺失多见于结肠癌中(87.5%),MSH2和MSH6蛋白同时缺失多见于直肠癌(100%)。K-ras基因突变在结肠癌和直肠癌中为53.3%和36.6%(p<0.05)。表达谱基因芯片检测数据表明结肠癌和直肠癌癌变过程中存在10余种基因表达的差异。
结论：近来结肠癌和直肠癌的发病率呈明显升高趋势,发病年龄趋于老年化；结肠癌的临床表现比较隐匿,贫血和CEA异常主要见于结肠癌中,直肠癌较少合并结肠息肉,直肠指诊是诊断直肠癌简便易行的方法之一；癌变机制方面,Wnt信号途径的激活在结肠癌和直肠癌癌变过程均起着重要作用,在直肠癌中Wnt途径的激活与Wnt1信号蛋白高表达和APC基因突变关系更为密切；变异型p53蛋白表达在两种肿瘤发生过程中均有着重要作用,结肠癌中K-ras基因突变明显高于直肠癌；错配修复基因突变导致的蛋白表达缺失在结肠癌中更为多见,主要以MLH1和PMS2突变为主,直肠癌主要为MSH2和MSH6。基因表达谱芯片结肠癌和直肠癌癌变过程中存在明显的基因表达差异。总之,结肠癌和直肠癌癌变机制既有共性,又有各自的特点。
Background:Colorectal cancer is one of most common cancer in gastrointestinal tract, and the morbidity is gradually increased in China recently years. According to the epidemiological data, the distinguished difference between colon and rectal cancer in morbility model and etiology was existed. Rectal cancer is more common in China, Compared with 80's years, the percentage of rectal cancer is decreased within 10 years, this changing illustrated that onset of colon cancer is more associated with life style and west-habit of diets than rectal cancer. In the meantime, because of difference site of cancer, the clinical manisfastation, laboratory examination and treatment method were different, the difference mechanism must existed in cancer development. The carcinogenesis of colorectal cancer is clear right now, the typical is "normal—adenoma polyps—cancer, and also called chromosomal instability pathway, in which Wnt signal, many oncogenes and anti-oncogenes were involved. Another important pathway is microsatellite instability (MSI), in which several mis-match repared(MMR) gene were mutant. Right now many study confused colon cancer and rectal cancer and put them together. Whether the mechanism is similar or difference between these two tumors is not clear. Several paper reported that APC, p53 and K-ras mutation were higher in colon cancer than rectal cancer, and MSI also common in colon cancer. But further and systemic study should be done to confirm.
Objective:In-patient colon cancer and rectal cancer in recent 10 years were summarize for analysis the changing of morbidity and the difference of clinical features. Tissue samples of colon cancer and rectal were collected for immunohistochemistry and gene microarray detection, in order to investigate the difference the oncogenesis mechanism, which focus on the important factors in chromosomal instability pathway and MIS. This study will provide the information for early diagnosis, screening and prevention according different tumor site.
Methods and materials:1906 cases of in-patient colon cancer and rectal cancer in Peking Union Medical College Hospital from 1999-2008 were summarize and morbidity changing, clinical manifestation, laboratory examination, diagnosis methods, and pathological stage were analysis retrospective. Each 30 cases of colon and rectal cancer operated tissue sample were detected by immnohistochemistry for APC、Wnt1、β-catenin、p53、MLH1、PMS2、MSH2、MSH6 protein expression. Microdissection and PCR-sequecing were used to detect the mutation of K-ras in the specimens. Gene profile were analysis using microarray technique in 16 colorectal cancer sample for probe the difference of gene expression in colon and rectal cancer.
Results:The clinical data shown that the mobidity of colorectal was increased in recently 10 years(1.39% vs 0.97% p<0.05),More patients were rectal cancer aging between 40～60 and colon cancer aging over 70 years old (p<0.05).Hematochezia and changing of bowel habit were occurred in rectal cancer, which is 76.9% vs 31.7% and 71.9% vs 33.9%(p<0.01) respectively. Compared with rectal cancer, abnormal of stool routine was less and Hb decreased was more often significant in colon cancer (p<0.01). Less patients performed CEA test and abnormal was not common in rectal cancer (57.9% vs 31.1% p＜0.01).High positive rate(87.9%) of rectal touch was in rectal cancer, and colonoscopy was the mainly diagnosis method in colon cancer and polyps were found (35.7% vs 19.7% p<0.01). Operation was the mainly treatment in both patients. Immunohistochemistry detection shown that APC protein absent, wnt1 and p53 positive was higher in rectal cancer (46.7% vs 40.0%,66.7% vs 50.0% 86.7% vs 76.7%), but there was no significant difference.β-catenin positive above 90% in both tumor. MLH1、PMS2、MSH2、MSH6 absent were common in colon cancer (8 cases 26.7%) and rectal cancer only 4 cases (13.3% p＜0.01).In colon cancer, MLH1 and PMS2 disappeared at same time and account 87.5%,and MSH2 and MSH6 together absent in 100% of rectal cancer. K-ras mutant was detected in 53.3% colon cancer and 36.6% rectal cancer (p<0.05). The data of gene expression microarray analysis show that between colon and rectal cancer, the significant different was found in many genes expression.
Conclusion:Morbidity of colon cancer and rectal cancer were increased. The clinical manifestation was less specific in colon cancer. In clinic, if the symptom occurred in high risk patients, physical examination and endoscopy should be combined in order to early diagnosis. In carcinogenesis, the wnt signal was exist in both tumor, but the activated factor maybe difference. MSI was common in colon cancer and MLH1 and PMS2 were involved. In short, between colon cancer and rectal cancer, common factors and different features were existed in the meantime.
研究目的：本研究首先通过总结近10年北京协和医院结肠癌和直肠癌住院病例1906例,回顾性分析其发病模式的变迁和临床表现、实验室检查、确诊方法、病理分期等临床特点的异同；同时分别选取结肠癌和直肠癌手术组织标本,通过高通量的基因表达谱芯片和免疫组化、基因测序等方法,探讨结肠癌和直肠癌癌变过程基因表达的差异,并针对结直肠癌癌变的染色体不稳定途径和微卫星不稳定途径中的重要蛋白表达和基因突变的异同进行检测,初步探讨我国结肠癌和直肠癌的发病模式、临床特点和癌变过程中分子机制的异同,为针对不同肿瘤类型进行早期诊断和预防、为大规模流行病学调查以及开展肿瘤筛查提供理论依据。
研究方法：回顾性分析总结北京协和医院1999-2008年期间1906例住院的结肠癌和直肠癌患者病历资料,探讨了近年来结肠癌和直肠癌发病模式的变迁,并初步分析其在临床表现、实验室检查、确诊方法、病变分期等的异同；同时选取了结肠癌和直肠癌手术石蜡组织标本各30例,通过免疫组化的方法,检测结直肠癌癌变过程中重要蛋白APC、Wnt1、β-catenin、p53、MLH1、PMS2、MSH2、MSH6的表达,切割和PCR测序的方法研究k-ras突变；在此基础上,采用基因表达谱芯片技术分别检测结肠癌和直肠癌各8例组织标本,探讨两者癌变相关基因表达的差异。
研究结果：临床资料分析表明,1999年～2008年期间结直肠癌收治比较80年代均明显增加(1.39% vs 0.97% p<0.05),但结肠癌和直肠癌分别增加幅度无明显差异；40以下年轻患者近10年呈下降趋势,而70岁以上的患者有所增加,其中以直肠癌的变化更有统计学差异(p<0.05)；直肠癌出现便血和大便习惯改变的几率高于结肠癌,分别为76.9% vs 31.7%和71.9% vs 33.9% (p<0.01)；结肠癌大便常规检查异常明显低于直肠癌(36.5% vs 76.6% p<0.01),血红蛋白下降在结肠癌中更为多见(40.9% vs 29.2% p＜0.01),CEA检查异常在结肠癌中更为常见(57.9% vs 31.1%p<0.01)；直肠指诊发现直肠癌的阳性率高达87.9%,结肠镜检查直肠癌合并息肉的人数少于结肠癌(35.7% vs 19.7% p<0.01),病理分期均以中晚期为主。免疫组织化学检测表明,结肠癌和直肠癌组APC蛋白表达缺失的比例分别为40.0%和46.7%,Wntl蛋白阳性表达的比例分别为50.0%和66.7%,虽直肠癌表达偏高,但无统计学差异,β-catenin阳性表达均在90%以上,p53阳性表达在直肠癌为86.7%,高于结肠癌的76.7%,但无统计学差异；MLH1、PMS2、MSH2、MSH6在结肠癌和直肠癌组织中的检测发现,结肠癌中有8例出现表达缺失,占26.7%,而直肠癌仅为4例,占13.3%(p<0.01)；4种蛋白缺失情况表明,无一例表现为单个蛋白的表达缺失,MLH1和PMS2蛋白同时缺失多见于结肠癌中(87.5%),MSH2和MSH6蛋白同时缺失多见于直肠癌(100%)。K-ras基因突变在结肠癌和直肠癌中为53.3%和36.6%(p<0.05)。表达谱基因芯片检测数据表明结肠癌和直肠癌癌变过程中存在10余种基因表达的差异。
结论：近来结肠癌和直肠癌的发病率呈明显升高趋势,发病年龄趋于老年化；结肠癌的临床表现比较隐匿,贫血和CEA异常主要见于结肠癌中,直肠癌较少合并结肠息肉,直肠指诊是诊断直肠癌简便易行的方法之一；癌变机制方面,Wnt信号途径的激活在结肠癌和直肠癌癌变过程均起着重要作用,在直肠癌中Wnt途径的激活与Wnt1信号蛋白高表达和APC基因突变关系更为密切；变异型p53蛋白表达在两种肿瘤发生过程中均有着重要作用,结肠癌中K-ras基因突变明显高于直肠癌；错配修复基因突变导致的蛋白表达缺失在结肠癌中更为多见,主要以MLH1和PMS2突变为主,直肠癌主要为MSH2和MSH6。基因表达谱芯片结肠癌和直肠癌癌变过程中存在明显的基因表达差异。总之,结肠癌和直肠癌癌变机制既有共性,又有各自的特点。
Background:Colorectal cancer is one of most common cancer in gastrointestinal tract, and the morbidity is gradually increased in China recently years. According to the epidemiological data, the distinguished difference between colon and rectal cancer in morbility model and etiology was existed. Rectal cancer is more common in China, Compared with 80's years, the percentage of rectal cancer is decreased within 10 years, this changing illustrated that onset of colon cancer is more associated with life style and west-habit of diets than rectal cancer. In the meantime, because of difference site of cancer, the clinical manisfastation, laboratory examination and treatment method were different, the difference mechanism must existed in cancer development. The carcinogenesis of colorectal cancer is clear right now, the typical is "normal—adenoma polyps—cancer, and also called chromosomal instability pathway, in which Wnt signal, many oncogenes and anti-oncogenes were involved. Another important pathway is microsatellite instability (MSI), in which several mis-match repared(MMR) gene were mutant. Right now many study confused colon cancer and rectal cancer and put them together. Whether the mechanism is similar or difference between these two tumors is not clear. Several paper reported that APC, p53 and K-ras mutation were higher in colon cancer than rectal cancer, and MSI also common in colon cancer. But further and systemic study should be done to confirm.
Objective:In-patient colon cancer and rectal cancer in recent 10 years were summarize for analysis the changing of morbidity and the difference of clinical features. Tissue samples of colon cancer and rectal were collected for immunohistochemistry and gene microarray detection, in order to investigate the difference the oncogenesis mechanism, which focus on the important factors in chromosomal instability pathway and MIS. This study will provide the information for early diagnosis, screening and prevention according different tumor site.
Methods and materials:1906 cases of in-patient colon cancer and rectal cancer in Peking Union Medical College Hospital from 1999-2008 were summarize and morbidity changing, clinical manifestation, laboratory examination, diagnosis methods, and pathological stage were analysis retrospective. Each 30 cases of colon and rectal cancer operated tissue sample were detected by immnohistochemistry for APC、Wnt1、β-catenin、p53、MLH1、PMS2、MSH2、MSH6 protein expression. Microdissection and PCR-sequecing were used to detect the mutation of K-ras in the specimens. Gene profile were analysis using microarray technique in 16 colorectal cancer sample for probe the difference of gene expression in colon and rectal cancer.
Results:The clinical data shown that the mobidity of colorectal was increased in recently 10 years(1.39% vs 0.97% p<0.05),More patients were rectal cancer aging between 40～60 and colon cancer aging over 70 years old (p<0.05).Hematochezia and changing of bowel habit were occurred in rectal cancer, which is 76.9% vs 31.7% and 71.9% vs 33.9%(p<0.01) respectively. Compared with rectal cancer, abnormal of stool routine was less and Hb decreased was more often significant in colon cancer (p<0.01). Less patients performed CEA test and abnormal was not common in rectal cancer (57.9% vs 31.1% p＜0.01).High positive rate(87.9%) of rectal touch was in rectal cancer, and colonoscopy was the mainly diagnosis method in colon cancer and polyps were found (35.7% vs 19.7% p<0.01). Operation was the mainly treatment in both patients. Immunohistochemistry detection shown that APC protein absent, wnt1 and p53 positive was higher in rectal cancer (46.7% vs 40.0%,66.7% vs 50.0% 86.7% vs 76.7%), but there was no significant difference.β-catenin positive above 90% in both tumor. MLH1、PMS2、MSH2、MSH6 absent were common in colon cancer (8 cases 26.7%) and rectal cancer only 4 cases (13.3% p＜0.01).In colon cancer, MLH1 and PMS2 disappeared at same time and account 87.5%,and MSH2 and MSH6 together absent in 100% of rectal cancer. K-ras mutant was detected in 53.3% colon cancer and 36.6% rectal cancer (p<0.05). The data of gene expression microarray analysis show that between colon and rectal cancer, the significant different was found in many genes expression.
Conclusion:Morbidity of colon cancer and rectal cancer were increased. The clinical manifestation was less specific in colon cancer. In clinic, if the symptom occurred in high risk patients, physical examination and endoscopy should be combined in order to early diagnosis. In carcinogenesis, the wnt signal was exist in both tumor, but the activated factor maybe difference. MSI was common in colon cancer and MLH1 and PMS2 were involved. In short, between colon cancer and rectal cancer, common factors and different features were existed in the meantime.
引文
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14. Spratlin JL, Hui D, Hanson J, et al. Community compliance with carcinoembryonic antigen:follow-up of patients with colorectal cancer. Clin Colorectal Cancer 2008;7:118-1251
15. Yakabe T, Nakafusa Y, Sumi K, et al. Clinical significance of CEA and CA19-9 in postoperative follow-up of colorectal cancer. Ann Surg Oncol.2010;17:2349-56.
16. Li M, Li JY, Zhao AL, Gu J. Colorectal cancer or colon and rectal cancer? Clinicopathological comparison between colonic and rectal carcinomas. Oncology, 2007;73:52-7
17. Aleksandrova K, Jenab M, Boeing H, et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer:a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010;172:407-418
18. Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA.2004;291:585-590
19. Aleksandrova K, Jenab M, Boeing H, et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer:a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010;172:407-18
20. Sudoyo AW. Biomolecular markers as determinants of patients selection for adjuvant chemotherapy of sporadic colorectal cancers.Acta Med Indones.2010;42:45-50
21. Ahlquist DA. Molecular detection of colorectal neoplasia. Gastroenterology. 2010;138:2127-39
22. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps,2008:a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology.2008 May;134:1570-1595.
23. Meza R, Jeon J, Renehan AG, et al. Colorectal cancer incidence trends in the United States and United kingdom:evidence of right-to left-sided biological gradients with implications for screening. Cancer Res.2011;70:5419-5429
24. Netzer P, Buttike U, Pfister M, et al. Frequency of advanced neoplasia in the proximal colon without an index polyp in the rectosigmoid.Dis Colon Rectum. 1999;42:661-667
25. Ju JH, Chang SC, Wang HS, et al. Changes in disease pattern and treatment outcome of colorectal cancer:a review of 5,474 cases in 20 years. Int J Colorectal Dis 2007;22:855-862
26. Cercek A, Saltz L Evolving treatment of advanced colorectal cancer. Curr Oncol Rep. 2010;12:153-9
27. Wadlow RC, Ryan DP. The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer.2010;116:3537-3548
28. Minoo P, Zlobec I, Peterson M, et al. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37:707-718
1. Akehi S, Murao S, Ueda N, et al. Immunohistochemical detection of truncated APC protein in sporadic human colorectal adenomas and adenocarcinomas. Virchows Arch. 1996;429:21-26
2. Khor TO, Gul YA, Ithnin H, et al. A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma. Int J Colorectal Dis. 2006;21:291-300
3. South CD, Yearsley M, Martin E, et al. Immunohistochemistry staining for the mismatch repair proteins in the clinical care of patients with colorectal cancer. Genet Med.2009;11:812-817
4.李新燕丛全.手工显微切割技术在分子病理学研究中的应用.肿瘤研究与临床.2006；18：273-274
5. Brink M, de Goeij AF, Weijenberg MP, et al. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis.2003;24:703-710
6.李景南,赵莉,郑威扬,等.结肠癌近20年临床特点的变迁分析.中华内科杂志.2010；49：384-387
7.赵莉,李景南,钱家鸣,等.近10年北京协和医院直肠癌发病模式的变迁和临床特点分析.临床内科杂志,2010；27：252-254
8. Slattery ML, Herrick JS, Lundgreen A, Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk:mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Aktl. Carcinogenesis.2010;31:1604-11
9. Aamodt R, Jonsdottir K, Andersen SN, et al. Differences in protein expression and gene amplification of cyclins between colon and rectal adenocarcinomas. Gastroenterol Res Pract.2009;2009:285830
10. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl. J. Med.1998,319:525-532
11. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073-2087
12. Bufill JA. Colorectal cancer:evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med.1990;113:779-788
13. Rampazzo E, Bertorelle R, Serra L, et al. Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. Br J Cancer. 2010;102:1300-1305
14. Christophe Beroud, Thierry Soussil. APC gene:database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Research,1996,24(1):121-124
15. Maple JT, Boardman LA.Genetics of colonic polyposis. Clin Gastroenterol Hepatol. 2006;4:831-5
16. Luchtenborg M, Weijenberg MP, de Goeij AF, et al. Meat and fish consumption, APC gene mutations and hMLHl expression in colon and rectal cancer:a prospective cohort study (The Netherlands). Cancer Causes Control.2005;16:1041-1054
17. Behrens J. The role of the Wnt signalling pathway in colorectal tumorigenesis. Biochem Soc Trans.2005;33:672-675
18. Gavert N, Ben-Ze'ev A. beta-Catenin signaling in biological control and cancer. J Cell Biochem.2007 Nov; 102:820-822
19. Munemitsu S, Albert I, Souza B, et al. Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA.1995;92:3046-3050
20. Minoo P, Zlobec I, Peterson M, et al. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37:707-18
21. Wong NA, Pignatelli M.Beta-catenin--a linchpin in colorectal carcinogenesis? Am J Pathol.2002;160:389-401
22. Iacopetta B. TP53 mutation in colorectal cancer. Hum Mutat.2003;21:271-6
23. Okubo R, Masuda H, Nemoto N. p53 mutation found to be significnet prognostic indicator in distal colorectal cancer. Oncol Rep.2001,8:509-514
24. Herring JA, Hall CC, Johnson JA, et al. K-ras mutation in a tubular adenoma originating at an ileostomy in a familial adenomatous polyposis patient. Am J Gastroenterol.1996;91:587-591
25. Chiang JM, Wu Chou YH, Ma SC, Chen JR. Influence of age on adenomatous polyposis coli and p53 mutation frequency in sporadic colorectal cancer-rarity of co-occurrence of mutations in APC, K-ras, and p53 genes. Virchows Arch. 2004;445:465-471
26. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res.2004; 10:4015-4021
27. Slattery ML, Curtin K, Wolff RK et al. A comparison of colon and rectal somatic DNA alterations. Dis Colon Rectum.2009;52:1304-1311.
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2.万德森.结直肠癌流行趋势及其对策.癌症2009；28：897-902
3.李明,顾晋.中国结直肠癌20年来发病模式的变化趋势.中华胃肠外科杂志2004：7：214-217
4.杨工,郑树,金凡,等.结直肠癌发病率趋势变化的病因探索.实用肿瘤杂志,1998.13：136-137
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8. Meyer JE, Narang T, Schnoll-Sussman FH, et al. Increasing incidence of rectal cancer in patients aged younger than 40 years:an analysis of the surveillance, epidemiology, and end results database. Cancer.2010;116:4354-4359
9. Strul H, Kariv R, Leshno M, et al. The prevalence rete and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years. Am J Gastroenterol,2006;101:255-262
10.李景南,赵莉,郑威扬,等.结肠癌近20年临床特点的变迁分析.中华内科杂志.2010;49：384-387
11.7.赵莉,李景南,钱家鸣,等.近10年北京协和医院直肠癌发病模式的变迁和临床特点分析.临床内科杂志,2010；27：252-254
12. Mitchell E, Macdonald S, Campbell NC, et al. Influences on pre-hospital delay in the diagnosis of colorectal cancer:a systematic review. Br J Cancer,2008;98:60-70
13. Olde Bekkink M, McCowan C, Falk GA, et al. Diagnostic accuracy systematic review of rectal bleeding in combination with other symptoms, signs and tests in relation to colorectal cancer. Br J Cancer,2010;102:48-58
14. Spratlin JL, Hui D, Hanson J, et al. Community compliance with carcinoembryonic antigen:follow-up of patients with colorectal cancer. Clin Colorectal Cancer 2008;7:118-1251
15. Yakabe T, Nakafusa Y, Sumi K, et al. Clinical significance of CEA and CA19-9 in postoperative follow-up of colorectal cancer. Ann Surg Oncol.2010;17:2349-56.
16. Li M, Li JY, Zhao AL, Gu J. Colorectal cancer or colon and rectal cancer? Clinicopathological comparison between colonic and rectal carcinomas. Oncology, 2007;73:52-7
17. Aleksandrova K, Jenab M, Boeing H, et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer:a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010;172:407-418
18. Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA.2004;291:585-590
19. Aleksandrova K, Jenab M, Boeing H, et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer:a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010;172:407-18
20. Sudoyo AW. Biomolecular markers as determinants of patients selection for adjuvant chemotherapy of sporadic colorectal cancers.Acta Med Indones.2010;42:45-50
21. Ahlquist DA. Molecular detection of colorectal neoplasia. Gastroenterology. 2010;138:2127-39
22. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps,2008:a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology.2008 May;134:1570-1595.
23. Meza R, Jeon J, Renehan AG, et al. Colorectal cancer incidence trends in the United States and United kingdom:evidence of right-to left-sided biological gradients with implications for screening. Cancer Res.2011;70:5419-5429
24. Netzer P, Buttike U, Pfister M, et al. Frequency of advanced neoplasia in the proximal colon without an index polyp in the rectosigmoid.Dis Colon Rectum. 1999;42:661-667
25. Ju JH, Chang SC, Wang HS, et al. Changes in disease pattern and treatment outcome of colorectal cancer:a review of 5,474 cases in 20 years. Int J Colorectal Dis 2007;22:855-862
26. Cercek A, Saltz L Evolving treatment of advanced colorectal cancer. Curr Oncol Rep. 2010;12:153-9
27. Wadlow RC, Ryan DP. The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer.2010;116:3537-3548
28. Minoo P, Zlobec I, Peterson M, et al. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37:707-718
1. Akehi S, Murao S, Ueda N, et al. Immunohistochemical detection of truncated APC protein in sporadic human colorectal adenomas and adenocarcinomas. Virchows Arch. 1996;429:21-26
2. Khor TO, Gul YA, Ithnin H, et al. A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma. Int J Colorectal Dis. 2006;21:291-300
3. South CD, Yearsley M, Martin E, et al. Immunohistochemistry staining for the mismatch repair proteins in the clinical care of patients with colorectal cancer. Genet Med.2009;11:812-817
4.李新燕丛全.手工显微切割技术在分子病理学研究中的应用.肿瘤研究与临床.2006；18：273-274
5. Brink M, de Goeij AF, Weijenberg MP, et al. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis.2003;24:703-710
6.李景南,赵莉,郑威扬,等.结肠癌近20年临床特点的变迁分析.中华内科杂志.2010；49：384-387
7.赵莉,李景南,钱家鸣,等.近10年北京协和医院直肠癌发病模式的变迁和临床特点分析.临床内科杂志,2010；27：252-254
8. Slattery ML, Herrick JS, Lundgreen A, Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk:mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Aktl. Carcinogenesis.2010;31:1604-11
9. Aamodt R, Jonsdottir K, Andersen SN, et al. Differences in protein expression and gene amplification of cyclins between colon and rectal adenocarcinomas. Gastroenterol Res Pract.2009;2009:285830
10. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl. J. Med.1998,319:525-532
11. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073-2087
12. Bufill JA. Colorectal cancer:evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med.1990;113:779-788
13. Rampazzo E, Bertorelle R, Serra L, et al. Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. Br J Cancer. 2010;102:1300-1305
14. Christophe Beroud, Thierry Soussil. APC gene:database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Research,1996,24(1):121-124
15. Maple JT, Boardman LA.Genetics of colonic polyposis. Clin Gastroenterol Hepatol. 2006;4:831-5
16. Luchtenborg M, Weijenberg MP, de Goeij AF, et al. Meat and fish consumption, APC gene mutations and hMLHl expression in colon and rectal cancer:a prospective cohort study (The Netherlands). Cancer Causes Control.2005;16:1041-1054
17. Behrens J. The role of the Wnt signalling pathway in colorectal tumorigenesis. Biochem Soc Trans.2005;33:672-675
18. Gavert N, Ben-Ze'ev A. beta-Catenin signaling in biological control and cancer. J Cell Biochem.2007 Nov; 102:820-822
19. Munemitsu S, Albert I, Souza B, et al. Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA.1995;92:3046-3050
20. Minoo P, Zlobec I, Peterson M, et al. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37:707-18
21. Wong NA, Pignatelli M.Beta-catenin--a linchpin in colorectal carcinogenesis? Am J Pathol.2002;160:389-401
22. Iacopetta B. TP53 mutation in colorectal cancer. Hum Mutat.2003;21:271-6
23. Okubo R, Masuda H, Nemoto N. p53 mutation found to be significnet prognostic indicator in distal colorectal cancer. Oncol Rep.2001,8:509-514
24. Herring JA, Hall CC, Johnson JA, et al. K-ras mutation in a tubular adenoma originating at an ileostomy in a familial adenomatous polyposis patient. Am J Gastroenterol.1996;91:587-591
25. Chiang JM, Wu Chou YH, Ma SC, Chen JR. Influence of age on adenomatous polyposis coli and p53 mutation frequency in sporadic colorectal cancer-rarity of co-occurrence of mutations in APC, K-ras, and p53 genes. Virchows Arch. 2004;445:465-471
26. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res.2004; 10:4015-4021
27. Slattery ML, Curtin K, Wolff RK et al. A comparison of colon and rectal somatic DNA alterations. Dis Colon Rectum.2009;52:1304-1311.
28. O'Brien H, Matthew JA, Gee JM, et al. K-ras mutations, rectal crypt cells proliferation, and meat consumption in patients with left-sided colorectal carcinoma. Eur J Cancer Prev.2000;9:41-47
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