结直肠肿瘤预后相关分子标记物

近20年来，国内外许多学者对与结直肠癌发生发展有关的分子改变进行了深入研究。这些分子改变有些可作为结直肠癌预后判断的标记物，有些主要用来预测肿瘤对治疗的反应性，而有些则主要与结直肠癌的诊断有关。本文就近年来结直肠癌预后相关分子标记物研究进展作一综述。     

结直肠癌的遗传异质性与分子分型

结直肠癌中存在明显的遗传异质性,可分为染色体不稳定及微卫星不稳定及甲基化等,不同类型具有不同临床表型,可以依据遗传异质性对结直肠癌进行分子分型。     

结直肠癌筛查技术的研究进展

结直肠癌(CRC)是常见恶性肿瘤之一,近年来随着人们生活方式及饮食结构的改变,中国CRC的发病率逐年升高。CRC的转归和预后与肿瘤分期密切相关,大部分早期CRC患者可获得良好预后,而发生远处转移的晚期CRC患者的5年生存率仅为12%。因此开展CRC筛查,以期及早发现并治疗早期CRC和癌前病变,对提高患者的生存率及生活质量具有重要的临床价值。该文就CRC的早期筛查技术的研究进展作一综述,主要包括基于粪便的检查和内镜及影像学检查。     

结直肠肿瘤预后相关分子标记物

近20年来,国内外许多学者对与结直肠癌发生发展有关的分子改变进行了深入研究。这些分子改变有些可作为结直肠癌预后判断的标记物,有些主要用来预测肿瘤对治疗的反应性,而有些则主要与结直肠癌的诊断有关。本文就近年来结直肠癌预后相关分子标记物研究进展作一综述。     

分子标志物在结直肠癌筛查中的应用

结直肠癌在我国的发病率呈逐渐升高趋势,结直肠癌筛查是降低发病率的有效手段。分子标志物检测由于 其无创性和较高的特异性,在结直肠癌筛查中发挥着越来越重要的作用。文章总结了近年来分子标志物在结直肠 癌筛查中的应用情况。     

结直肠癌相关信号通路研究进展

结直肠癌不是一种疾病而是一系列高度异质的复杂疾病,每个患者都具有各自的遗传学和表观遗传学背景。有充分的证据提示,从正常细胞到肿瘤细胞的转化归根到底是细胞的信号调控机制发生紊乱造成的,肿瘤在形成的过程中不仅存在异常信号的转导,信号转导的异常对肿瘤的发生也似乎是必需的。目前发现与结直肠癌有关的细胞信号转导通路主要有Wnt-β-catenin信号通路、Hedgehog信号通路、Notch信号通路、TGFβ-Smads信号通路、Jak-STAT信号通路、Ras-Raf-MAPK信号通路、PI3K-Akt-mTOR信号通路。本文对结直肠癌相关信号通路的研究进展进行综述。     

结直肠癌的分子分型及精准医学时代展望

结直肠癌（CRC）的发生发展是一个多步骤、多阶段演进的复杂过程,近30年来,随着现代科学技术的飞跃发展,人们发现除了经典的"腺瘤——癌序贯"模型外,还有15%的病例通过"锯齿状"通路癌变。结直肠癌具有高度的异质性,微卫星不稳定、染色体不稳定、CpG岛甲基化等遗传学和表观遗传学特征可以以各种组合形式共存于肿瘤细胞中。因此随着个体化精准医学的发展,对结直肠癌精准分子分型的需求也日益迫切。本文将就结直肠癌的基因和蛋白分子分型体系及其临床意义展开探讨。     

结直肠癌发生机制研究进展

结直肠癌是最常见的恶性肿瘤之一,其发生由遗传和环境等诸多因素相互作用所致,是一个涉及多基因、多阶段的复杂过程。本文就结直肠癌发生机制包括染色体不稳定（CIN）、微卫星不稳定（MSI）、CpG岛甲基化表型（CIMP）等的研究进展作一综述。     

结直肠癌筛查发现的7 408例肠道病变临床特征及病理类型分析

目的 探讨结直肠病变患者临床与病理特征,为结直肠癌早期临床诊断与干预提供依据。方法 基于2007至2012年海宁市32万余40～74岁目标人群结直肠癌筛查结果,对筛查检出的肠道病变进行临床特征（包括性别、年龄、大小、部位、形态、数目）及病理类型等分析探讨。结果 共完成初筛286 470例,顺应率88.96％;完成结肠镜检查29 069例,检出肠道病变7 408例,检出率25.48％;男性检出率高于女性（32.62%比19.48%,P＜0.001）;40～49岁组检出率18.30％,70～74岁组检出率35.06％,显示年龄越大检出率越高（P＜0.001）。7 408例肠道病变中,左半结肠约占69.40%,多发性病变占37.23％,＞1.0 cm病变占19.60％。检出结直肠癌205例（早期癌161例、中晚期癌44例）,进展期腺瘤1 365例,早诊率为97.20％。手术切除的5 030例病变病理提示腺瘤型及以上病变所占比重最大（63.00％）。直径＞1.5 cm病变癌变率为34.08%。结论 在高危人群中男性肠道病变检出率明显高于女性,年龄越大检出率越高;病理类型以腺瘤所占比重最高。     

结直肠癌黏液腺癌临床病理及治疗进展

黏液腺癌作为结直肠腺癌的一个特殊病理亚型,具备特殊的组织病理学特征,在肿瘤的生长、复发转移模式与腺癌具有明显差异。黏液腺癌对目前基于腺癌的治疗方案相对不敏感,临床预后较差。治疗效果的差异及个体化治疗理念的快速发展引起临床医生对黏液亚型的关注。本综述通过对黏液腺癌组织病理学特征的回顾,结合结直肠癌治疗的新进展对结直肠黏液腺癌进行了系统阐述。     

Underutilization of microsatellite instability analysis in colorectal cancer patients at high risk for Lynch syndrome

Objective. The revised Bethesda Guidelines were published to improve the efficiency of recognizing Lynch syndrome (LS) by identifying LS-related malignancies that should be analyzed for microsatellite instability (MSI). The aim of this study was to evaluate whether MSI analysis was performed in colorectal cancer patients at risk for LS according to the revised Bethesda Guidelines. Material and methods. Patients diagnosed with colorectal cancer in 11 Dutch hospitals in 2005 and 2006 were selected from a regional database. The patients were included in the study if they met any of the following criteria; 1) diagnosed with colorectal cancer <50 years, 2) a second LS-associated tumor prior to the diagnosis of colorectal cancer in 2005/2006, and 3) colorectal cancer <60 years with a tumor displaying mucinous or signet-ring differentiation or medullary growth pattern. Results. Of 1905 colorectal cancer patients, 169 met at least one of the inclusion criteria. MSI analysis had been performed in 23 (14%) of the 169 tumors. MSI status had been determined in 18 of 80 included patients aged <50 years, in 4 of 70 patients with a second LS-related tumor, and in 3 of 41 patients aged <60 years with high-risk pathology features. Conclusions. There is marked underutilization of MSI analysis in patients at risk for LS. As a result LS might be underdiagnosed both in patients with colorectal cancer and in their relatives.     

Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II)

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features. Supported by the National Institutes of Health, Grants #5 RO1 CA41371-01 and 1 RO1 CA42705-01.     

林奇综合征诊疗进展

林奇综合征是一种由错配修复基因突变造成的遗传性结直肠癌综合征,属常染色体显性遗传病,过去又称遗传性非息肉病性大肠癌,约占全部大肠癌的5%~15%,错配修复基因的种系突变和微卫星不稳定是其分子遗传学基础。近年来随着分子生物学的进展,林奇综合征的诊断及治疗越来越受到人们的关注,本文就林奇综合征的诊断与治疗进展做一综述。     

Perspectives for tailored chemoprevention and treatment of colorectal cancer in Lynch syndrome

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research.     

Identification of patients at-risk for Lynch syndrome in a hospital-based colorectal surgery clinic

AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer.Clinical data and pathology features of the tumor were obtained from chart review.RESULTS:Of the 212 CRC patients recruited,61 (29%) reported a family history of CRC,45 (21.2%) were diagnosed under a...     

免疫组化筛查林奇综合征的缺陷和应对策略

林奇综合征（LS）是由于错配修复基因（MLH1、MSH2、MSH6、PMS2）的胚系突变引起的,是最常见的遗传性结直肠癌综合征,约占所有结直肠癌的3%。目前,多个权威国际组织建议对所有初诊的结直肠癌患者进行LS的普查。LS的普查方法包括免疫组化（IHC）检测错配修复蛋白缺陷（dMMR）和微卫星不稳定性（MSI）检测两种。IHC由于具有检测费用低、对检测设备的要求低、便于基层医院开展、可以提示突变基因等优点,成为LS筛查的首选。但是,由于组织固定、抗体质量、IHC染色技术问题以及不寻常的染色模式,IHC结果容易出现各种误读。干扰IHC结果解读的因素包括：肿瘤细胞的胞浆染色、内对照细胞染色弱、肿瘤细胞的异质性、特殊的病理形态表现（如：淋巴细胞浸润肿瘤上皮,印戒细胞癌）、新辅助放化疗等。注意避免IHC结果解读的各种陷阱,对于准确识别LS至关重要,有助于节省患者和亲属的监测费用,并避免不必要的焦虑。同时,由于采用IHC进行LS的普查本身还存在一些固有缺陷,所以不能将IHC作为LS的唯一筛查手段,应综合应用各种筛查标准、IHC、MSI、BRAF V600E突变、MLH1启动子甲基化和基因的胚系突变检测,以便对LS做出准确的诊断。     

Advances in the study of Lynch syndrome in China

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers due to inherited mutations in mismatch repair(MMR) genes. During the last decades, therehave been great advances in research on Chinese Lynch syndrome. This review mainly focuses on the genetic basis, clinicopathologic features, diagnosis, intervention,chemoprevention, and surveillance of Lynch syndrome in China. In addition to frequently altered MMR genes, such as MLH1, MSH2, MSH6, and MLH3,other MMR-associated genes, such as those encoding human exonuclease 1, transforming growth factor βreceptor 2, and alanine aminopeptidase, metastasisassociated protein 2, adenomatosis polyposis coli down-regulated 1, and hepatic and glial cell adhesion molecule have also been implicated in Chinese Lynch syndrome. Most Chinese researchers focused on the clinicopathologic features of Lynch syndrome, and it is noticeable that the most frequent extracolonic tumor in northeast China is lung cancer, which is different from other areas in China. The Chinese diagnostic criteria for Lynch syndrome have been established to identify gene mutation or methylation. With regard to chemoprevention, celecoxib may be effective to prevent polyps relapse in Lynch syndrome carriers. Additionally,a colonoscopy-based surveillance strategy for the prevention and early detection of neoplasms in Lynchsyndrome carriers has been proposed.     

Epithelial-mesenchymal transition in colorectal cancer tissue of patients with Lynch syndrome

AIM:To explore the epithelial-mesenchymal transition(EMT)in tissue from patients with Lynch syndrome,and to interpret biological behaviour of Lynch syndrome.METHODS:Sixty-eight formalin-fixed and paraffin embedded tissue blocks were analyzed in this study,including tissues from Lynch syndrome(n=30),sporadic colorectal carcinoma(CRC)(n=30),and tumoradjacent tissues(n=8).Tissue sections were stained for human mutS homolog 2(hMSH2),human mutL homolog 1(hMLH1),transforming growth factor-βtypeⅡreceptor(TGFβRⅡ),E-cadherin,β-catenin,matrix metalloproteinase-7(MMP-7)and tissue inhibitor of metalloproteinase-2(TIMP-2)by immunohistochemical staining.Furthermore,clinical data such as age,gender and tumor-node-metastasis stage were also collected retrospectively.RESULTS:The positive expression rates of hMSH2,hMLH1,TGFβRⅡ,E-cadherin,β-catenin,MMP-7 and TIMP-2 were significantly related to the depth of invasion and lymph node metastasis,but not to sex or tumour size or location.The differences in the positive expression rates of hMSH2,hMLH1,TGFβRⅡ,E-cadherin,cytomembraneβ-catenin,cytoplasmicβ-catenin,MMP-7 and TIMP-2 were significant between sporadic CRC and Lynch syndrome.The expression of hMSH2 had a positive correlation with that of hMLH1 in Lynch syndrome and sporadic CRC.The expression of TGFβRⅡhad a positive correlation with that of hMSH2,hMLH1 and MMP-7,and a negative correlation with that of TIMP-2.The expression of MMP-7 had a negative correlation with that of TIMP-2 in Lynch syndrome and sporadic CRC.The expression of E-cadherin was positively correlated with that of cytomembraneβ-catenin.However,the expression of cytomembraneβ-catenin was negatively correlated with that of cytoplasmicβ-catenin,and the expression of cytoplasmicβ-catenin was positively correlated with that of MMP-7.CONCLUSION:EMT may play an important role in the development and progression of Lynch syndrome.Lynch syndrome was caused by the mutations of mismatch repair genes,mainly hMSH2 and hMLH1,which also beget the mutational inactivation of TGFβRⅡ.Therefore,the colorectal cancer of Lynch syndrome can escape the inhibitory effect of TGFβ1.However,TGFβ1 can up-regulate the expression of MMP-7 and down-regulate the expression of TIMP-2 in tumors by disassembling the E-cadherin/β-catenin complex in the cytomembrane.