遗传性非息肉病性结直肠癌的微卫星不稳定研究

目的　探讨国人北方人群HNPCC的微卫星不稳定 (microsatelliteinstability ,MSI)发生情况及其意义。方法　 44例患者来源于 3 0个HNPCC (hereditarynonpolyposiscolorectalcancer)家系 ,这些家系主要分布于北方 5省市。所有患者均符合BGl 3 (Bethes dal 3 )HNPCC诊断标准。以荧光标记法检测 44例患者的石蜡包埋组织微卫星稳定性。结果　 44例患者中高度微卫星不稳定 (highfrequencymicrosatelliteinstability ,MSI H)为 81.81( 3 6/ 44 ) ,低度微卫星不稳定 (lowfrequencymicrosatelliteinstability ,MSI L)为 6.82 ( 3 / 44 ) ,微卫星稳定 (microsatellitestable ,MSS)为 11.3 ( 5 / 44 ) ;所选择的 5个微卫星位点中Bat2 5和Bat2 62个位点MSI H的表达率较高 ,分别为 10 0 %和 97.2 2 %。符合AmsterdamⅡ和符合BGl 3标准的HNPCC患者的MSI H表达率分别为 85 .2 9%和 81,81% ,仅符合BGl 3标准 ,而不符合AmsterdamII的 10个患者中 ,7个发现MSI H。结论　HNPCC肿瘤的MSI H发生率高 ,MSI检测方法简便、易行 ,可作为错配修复基因种系突变初筛方法 ,Bethesdal 3标准可更多地收集到可疑的HNPCC患者     

遗传性非息肉病性结直肠癌

遗传性非息肉病性结直肠癌高随宽徐文怀Ｓｕｂｊｅｃｔｈｅａｄｉｎｇｓｃｏｌｏｒｅｃｔａｌｎｅｏｐｌａｓｍｓ，ｈｅｒｅｄｉｔａｒｙｎｏｎｐｏｌｙｐｏｓｉｓ主题词结肠直肠肿瘤，遗传性非息肉性中国图书资料分类号Ｒ７３５３４１概述对遗传性非息肉病性结直肠...     

遗传性非息肉性结直肠癌中微卫星不稳定性的研究进展

遗传性非息肉性结直肠癌(HNPCC)是一种常染色体显性遗传病,肿瘤多发于近段结肠,并常发生肠外肿瘤。HNPCC的发生缘于错配修复缺陷所致的微卫星不稳定性(MSI),MSI的状态与HNPCC的临床特征密切相关。MSI在HNPCC的基因诊断、筛查及治疗等方面具有重要的运用价值。     

遗传性非息肉病性结直肠癌临床分子诊断的研究进展

遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)是一种由于错配修复基因(mismatch repair gene,MMR)突变导致的常染色体显性遗传性疾病,占结直肠癌的5%-15%.研究显示,与HNPCC发生相关的错配修复基因有hMSH2、hMLH1、hMSH6、hPSM1和hPSM2.HNPCC肿瘤具有发病早、近段结肠多见、原发癌多见、肠外肿瘤多见、病理以黏液腺癌为主的特点.到目前为止,HNPCC的诊断主要依赖病史及相关遗传检测结果.对于符合Amsterdam Ⅱ或Bethesda标准的结直肠癌患者应进行微卫星不稳定(microsatellite instability,MSI)和免疫组织化学错配修复蛋白的检测,继而进行错配修复基因等种系突变检测.     

遗传性非息肉病性结直肠癌家系临床特征及诊断标准分析

目的 探讨中国人遗传性非息肉病性结直肠癌(HNPCC)家系临床特点和诊断。方法 收集69个HNPCC家系(符合Amsterdam标准Ⅱ33个、Japan标准24个、Bethesda指导原则1～3项12个)，对其进行分组和比较分析。结果 69个家系共有癌症277人，肠癌213人，肠外癌64人。HNPCC癌患者中位年龄为46岁。发病高峰年龄为40～49岁。共有两代以上垂直传递家系65个，占所有家系的94．2％。肠癌患者中(右)半结直肠癌占62％。共有多原发癌33例，占癌患者的11．9％。共有肠外癌64人，占癌患者的23．1％，其中胃癌、子宫内膜癌分别占癌患者的6．5％和4％，列前两位。结论 HNPCC家系与SCRC相比具有发病年龄轻、垂直传递、肠外癌发病率高、肿瘤谱广、常见多原发癌、好发于右半结直肠的特点。某些特点与两方国家不完全相同。     

遗传性非息肉病性结直肠癌家系临床病理特征分析

目的 探讨中国人遗传性非息肉病性结直肠癌(HNPCC)家系发病特点及预后.方法 收集24个符合Amsterdam标准的HNPCC家系,绘制其家系图谱、收集临床病理及随访资料,分析中国人HNPCC的发病特点及预后.结果 24个HNPCC家系中,共有肿瘤患者116例(其中先证者多原发癌16例,家系成员多原发癌9例),发病年龄19～74岁,其中结直肠癌灶120个,肠外相关肿瘤32个.在24个HNPCC家系的先证者中,患第一结直肠癌的平均年龄为42.5岁,男性多于女性,右半结肠肿瘤多于左半结肠;肿瘤分化均较好,以中分化多见,病理类型以管状腺癌多见,占45.8%(11/24);截至随访结束时,术后生存≥5年者共14例,占58.3%(14/24),其中9例超过10年,最长1例存活时间已达27年.结论 中国人HNPCC以中分化管状腺癌多见,发病年龄较轻,右半结肠癌多见.     

遗传性非息肉病性结直肠癌的临床特征与诊断原则

目的：探讨遗传性非息肉病性结直肠癌（HNPCC）的临床特点和诊断。方法：收集22个符合Amsterdam标准的HNPCC家族，分析其临床特点。结果：本组符合Amsterdam标准的HNPCC发病率为2．6％＜22个家族有恶性肿瘤患者101例，结直肠癌患者84例，发生第一个结直肠癌的平均年龄为45．7岁，位于脾曲近侧结肠和直肠的分别占58．3％和23．8％。23．8％患者发生同时或异时多原发结直肠癌。20例患者发生肠外肿瘤，以胃癌居多。结论：HNPCC具有发病年龄早，近侧结肠多见，同时和异时多原发结直肠癌发生率高的特点，诊断治疗及随访应有别于散发性结直肠癌。本组肠外肿瘤以胃癌发生率高，与国外报道不同。建立中国人的HNPCC诊断标准是必要的。     

遗传性非息肉结直肠癌中微卫星不稳定性的研究进展

遗传性非息肉性结直肠癌（HNPCC）是一种常染色体显性遗传病，肿瘤多发于近段结肠，并常发生肠外肿瘤。HNPCC的发生缘于错修复缺陷所致的微卫星不稳定性（MSI），MSI的状态与HNPCC的临床特征密切相关。MSI在HNPCC的基因诊断、筛查及治疗等方面具有重要的运用价值。     

错配修复基因突变检测对遗传性非息肉病性结直肠癌患病风险的预测

目的 探讨错配修复(MMR)基因种系突变检测在遗传性非息肉病性结直肠癌(HNPCC)家系成员患癌风险预测中的作用.方法 对43个携带致病性突变的HNPCC家系的316名家庭成员的发病情况进行详细调查,并对结果进行统计学分析.结果 ①突变状态明确的HNPCC家系年龄大于20岁的成员共263例,其中突变携带者144例,非携带者119例;HNPCC相关恶性肿瘤的发生率分别为59.03%(85/144)和2.52%(3/119),二者差异有统计学意义(X2=93.44,P＜0.01).②在144例年龄大于20岁的突变携带者中,男、女HNPCC相关恶性肿瘤发生率分别为72.00%(54/75)和44.93%(31/69),二者差异有统计学意义(χ~2=10.89,P＜0.01).③随着年龄的增加,突变携带者发生HNPCC相关肿瘤的累计风险度逐渐增加.结论 在HNPCC家系中,MMR基因种系突变携带者为发生HNPCC相关肿瘤的高危人群,MMR基因种系突变的检测能很好地预测HNPCC相关肿瘤的发生危险.     

遗传性非息肉病性大肠癌的研究进展

遗传性非息肉病性大肠癌(HNPCC)是一种由错配修复基因(MMR)突变造成的常染色体显性遗传病,又称Lynch综合征,是遗传性大肠癌的代表.HNPCC约占全部大肠癌的5%-15%.错配修复基因(MMR)的种系突变和微卫星不稳定(MSI)是其分子遗传学基础.HNPCC的临床病理特点突出,具有右半结肠多见、发病早、病理分化差、多原发癌多见的特点.目前其治疗方法以手术为主,COX-2阻滞剂可能成为HNPCC治疗的一个新的途径.近年来分子生物学的进展也为人们对HNPCC生物学行为和治疗的认识提供了有益的参考.     

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites ( 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.     

微卫星不稳定性与结直肠癌的研究进展

结直肠癌(CRC)在全球范围内的发病率和死亡率均较高。目前研究认为CRC是一种由各种原因造成的遗传不稳定性长期积累、共同作用所致的异质性疾病,微卫星不稳定性(MSI)是其中的主要途径之一。本文就MSI与CRC的研究进展作一综述。     

结直肠无蒂型锯齿状腺瘤的临床病理特征

无蒂型锯齿状腺瘤（SSA）属结直肠锯齿状病变之一,具有独特的形态学特点、生物学行为和分子基因学改变,其内镜形态和组织学特征有别于其他结直肠锯齿状病变,且与新近提出的结直肠癌变的锯齿状通路密切相关.近年研究发现SSA是微卫星不稳定性癌的前期病变,可直接发生癌变.但目前国内尚缺乏对这一病变的认识.本文就SSA的定义、形态学特征和病理组织学诊断标准作一综述,旨在提高临床医师对这一病变的认识.     

Accumulation Profile of Frameshift Mutations During Development and Progression of Colorectal Cancer From Patients With Hereditary Nonpolyposis Colorectal Cancer

Purpose Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined. This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer. Methods Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes. Results The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency (94–100 percent) in all pathologic stages, and mutation of the MARCKS gene also was high (94 percent) in Dukes B and C cancers. These frequencies were higher than the frequency of TGFβRII gene inactivation (64–88 percent). Mutations of the hMSH3, TCF4, CASP5, RIZ, RAD50, and MBD4 genes were comparatively frequent (>35 percent) in all stages. Frequencies of inactivation of the MARCKS, BAX, IGFIIR, and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer (P < 0.05). The number of accumulated frameshift mutations was larger in Dukes B and C cancers (9.4) than in Dukes A cancer (6.8) (P = 0.003). Conclusions The present data suggest that the disruption of the transforming growth factor-β super-family signaling pathway by the alteration of the ACVR2 and/or TGFβRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer. Moreover, the further accumulation of alterations in the MARCKS, BAX, IGFIIR, and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.     

线粒体异常与结直肠癌

最近研究已证实许多肿瘤中存在线粒体突变,如点突变、大片段缺失以及编码区和非编码区微卫星不稳定性,而正常组织中却未发现。目前尚不能证明线粒体突变是肿瘤形成的惟一原因,但其在细胞凋亡和活性氧簇引起的DNA损伤过程中起重要作用,因此线粒体突变可能与肿瘤的发生有关。本文就线粒体异常与结直肠癌的关系作一综述。     

溃疡性结肠炎相关结直肠癌的基因组和表观遗传不稳定性

溃疡性结肠炎相关结直肠癌（UcCRC）是溃疡性结肠炎（UC）最严重的并发症。近年来,由遗传易感性与环境因素共同作用引起的、结直肠黏膜慢性炎症背景下的遗传学改变在UcCRC发生、发展中的作用备受关注。本文就UcCRC中的常见基因组和表观遗传不稳定性,包括染色体不稳定性（CIN）、微卫星不稳定性（MSI）、CpG岛甲基化表型（CIMP）作一综述。