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1.
目的探讨描述遗传性非息肉病性结直肠癌(HNPCC)家系内在特性的量化方法学。方法将不同来源的符合Amsterdam标准(AC)Ⅰ或Ⅱ的HNPCC家系按照年龄和结直肠癌构成比分组,采用自定义的量化参数与家系内恶性肿瘤累及世代数、患者例数、家系类型等描述HNPCC临床表型。结果家系首发恶性肿瘤中位诊断年龄(FMA-DFMT)和家系首发结直肠癌(CRC)中位诊断年龄(FMA-DFCRC)均为非正态分布;在符合ACⅠ的HNPCC家系中,大部分家系的FMA-DFMT、FMA-DFCRC为35~50岁,分别占73.6%(39/53)、69.8%(37/53),中位数分别为44.0岁和43.5岁;家系首发恶性肿瘤中CRC构成比(FPCRC-FMT)、家系结直肠癌患者构成比(FP.CRCP)小于0.6的家系分别占13.2%(7/53)、7.5%(4/53);FMA-DFMT、FMA—DFCRC与患者例数、累及世代数、家系类型、FPCRC-FMT、FP-CRCP等参数之间均无相关性(均P〉0.05)。结论与传统方法相比较,应用量化参数能更准确地描述HNPCC家系的临床表型特点。 相似文献
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Background At least five mismatch repair (MMR) genes, including hMSH2, hMLH1, hPMS, hPMS2, and hMSH6/GTBP, are associated with hereditary nonpolyposis colorectal cancer (HNPCC). More than 90% of families with HNPCC harbor the hMSH2and hMLH1 gene mutations. We have analyzed the clinical features of HNPCC among Chinese patients and report the results of screening for mutations in the hMSH2 and hMLH1 genes.
Methods The data concerning gender, site of colorectal cancer (CRC), age at diagnosis, history of synchronous and/or metachronous colorectal cancer, instance of extracolonic cancers, and histopathology of tumors for 126 patients from 28 independent families with HNPCC were collected. Fifteen of the families met the Amsterdam I criteria, and 13 met the Japanese clinical criteria for diagnosis. Genomic DNA was extracted from the peripheral lymphocytes. Polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) were used to screen the coding region of the hMSH2 and hMLH1 genes. Samples showing abnormal DHPLC profiles were sequenced.
Results One hundred and seventy malignant neoplasms were found in the 126 patients, of whom 23 had multiple cancers. Ninety-eight of the patients (77.8%) had colorectal cancers, with an average age at onset of 45.9 years and a right-sided predominance. Eight hMSH2 or hMLH1 gene sequence variations were found in 12 families, and a germ-line G204X nonsense mutation in the third exon of hMSH2 was found, representing the first mutation in an MMR gene ever found in people of Chinese Mongolian ethnicity.
Conclusions HNPCC is a typical autosomally dominant hereditary disease, characterized by early onset, a predominance of proximal colorectal cancer, and multiple synchronous and metachronous colorectal cancers. DHPLC is a powerful tool for detecting mutations in the hMSH2 and hMLH1 genes, Mutations in the first nine exons of the hMLH1 gene were more common in Chinese patients. 相似文献
Methods The data concerning gender, site of colorectal cancer (CRC), age at diagnosis, history of synchronous and/or metachronous colorectal cancer, instance of extracolonic cancers, and histopathology of tumors for 126 patients from 28 independent families with HNPCC were collected. Fifteen of the families met the Amsterdam I criteria, and 13 met the Japanese clinical criteria for diagnosis. Genomic DNA was extracted from the peripheral lymphocytes. Polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) were used to screen the coding region of the hMSH2 and hMLH1 genes. Samples showing abnormal DHPLC profiles were sequenced.
Results One hundred and seventy malignant neoplasms were found in the 126 patients, of whom 23 had multiple cancers. Ninety-eight of the patients (77.8%) had colorectal cancers, with an average age at onset of 45.9 years and a right-sided predominance. Eight hMSH2 or hMLH1 gene sequence variations were found in 12 families, and a germ-line G204X nonsense mutation in the third exon of hMSH2 was found, representing the first mutation in an MMR gene ever found in people of Chinese Mongolian ethnicity.
Conclusions HNPCC is a typical autosomally dominant hereditary disease, characterized by early onset, a predominance of proximal colorectal cancer, and multiple synchronous and metachronous colorectal cancers. DHPLC is a powerful tool for detecting mutations in the hMSH2 and hMLH1 genes, Mutations in the first nine exons of the hMLH1 gene were more common in Chinese patients. 相似文献
3.
中国人遗传性非息肉病性结直肠癌相关肿瘤谱及累计发病风险 总被引:3,自引:1,他引:3
目的:探讨中国人遗传性非息肉病性结直肠癌(HNPCC)相关肿瘤谱和累计发病风险,为制定HNPCC诊治方案提供依据.方法:随访31个HNPCC家系中167例肿瘤患者,以Kaplan-Meier生存曲线法估计各种肿瘤发生比例和累计发病风险.结果:167例HNPCC相关肿瘤患者的首发肿瘤中,结直肠癌135例(80.8%),胃癌10例(6.0%),子宫内膜癌8例(4.8%),卵巢癌3例(1.8%),膀胱癌、乳腺癌、肺癌和脑胶质瘤各2例(分别占1.2%),肝癌、胰腺癌和胆囊癌各1例(分别占0.6%).70岁时,大肠癌发生累计发病风险为93.3%,肠外肿瘤发生累计发病风险为56.1%.结论:中国人HNPCC肿瘤谱中,胃癌发生率较高;40~60岁大肠癌发生风险最大,50岁后肠外肿瘤发生风险明显增加. 相似文献
4.
目的研究遗传性非息肉病性结直肠癌的分子病理特征,评估该病在北京地区住院人群中的发病情况。方法 94例结直肠癌组织标本均采集自2012年3~9月于北京市中西医结合医院及解放军总医院住院接受手术治疗并经病理确诊为结直肠癌的患者。使用免疫组化方法对肿瘤组织内错配修复基因MLH1、MSH2、MSH6及PMS2的蛋白表达情况进行检测。结果 94例结直肠癌患者中,至少有一种错配修复基因表达为阴性的共有13例,其中MLH1表达为阴性的有3例,MSH2表达为阴性的有11例,MSH6表达为阴性的有2例,PMS2表达为阴性的仅有1例,遗传性非息肉病性结直肠癌的发病率为13.83%,MSH2基因突变所占比例达84.62%,与遗传性非息肉病性结直肠癌国际合作组织提供的数据(40%)相比,差异有统计学意义(P〈0.05)。结论北京地区住院的结直肠癌患者中,遗传性非息肉病性结直肠癌发病率高于世界每年新发病例的水平,且MSH2基因突变致病尤为突出。 相似文献
5.
目的分析遗传性非息肉病性结直肠癌(HNPCC)家系临床及病理特点。方法收集符合Amsterdam标准Ⅱ的8例HNPCC家系资料,绘制家系图谱。结果HNPCC发病率为1.59%,8个HNPCC家系总发病人数为31例,其中结直肠癌患者为25例,肠外相关肿瘤6例,8例先证者中6例为女性,2例为男性,4例发病年龄小于40岁,发病部位位于右半结肠为2例,左半结肠3例,直肠3例,组织学分型以中至低分化腺癌为主;均未出现淋巴结及远处转移;8例先证者错配修复(MMR)蛋白表达异常的为5例。结论HNPCC先证者发病年龄轻,组织学分型较好,家系成员发病率高,对其家族成员进行定期检查和及时治疗将能有效地预防其发生并降低死亡率;MMR基因突变检测对提高HNPCC的诊断起重要作用。 相似文献
6.
多重连接依赖的探针扩增技术检测中国人遗传性非息肉病性结直肠癌错配修复基因大片段缺失 总被引:3,自引:0,他引:3
目的了解中国人遗传性非息肉病性结直肠癌(HNPCC)家系hMSH2和hMLH1基因大片段缺失特点。方法采用多重连接依赖的探针扩增(MLPA)技术和GeneMapper分析技术检测17个HNPCC家系先证者hMSH2和hM-LH1基因种系大片段缺失。结果在3个家系中分别发现hMSH2基因第8外显子、1~6外显子和1~7外显子3种大片段缺失类型,未发现hMLH1基因大片段缺失。大片段缺失占hMSH2和hMLH1基因总种系病理性突变的19%。结论中国人HNPCC错配修复(MMR)基因大片段缺失发生率较高,hMSH2基因缺失可能更为常见。在分子遗传学检测中有必要开展MMR基因大片段缺失的检测。 相似文献
7.
目的 探讨中国人遗传性非息肉病性结直肠癌(HNPCC)患者hMLH1与hMSH2基因的突变特点.方法 对76个HNPCC家系先证者的DNA样本用PCR法扩增其hMLH1与hMSH2基因的35个外显子,再进行测序以确定突变类型.结果 (1)25个样本发现hMLH1或hMSH2基因突变,总突变率为33%(25/76);(2)检测到的22种突变中:hMLH1基因突变16个,hMSH2基因突变6个;(3)突变类型包括移码突变、无义突变、剪接区突变、错义突变,其中错义突变较多见(hMLH1基因错义突变11个、hMSH2基因5个).结论 中国人HNPCC家系hMLH1和hMSH2突变谱广泛,突变类型多样,hMLH1突变较hMSH2突变多见. 相似文献
8.
目的研究修订Bethseda标准筛选遗传性非息肉病性结直肠癌(HNPCC)的价值及在结直肠癌中的构成比。方法对2004年8月至2005年12月进行手术治疗的连续110例患者建立队列、多重荧光聚合酶链反应方法检测肿瘤的微卫星不稳定(MSI)状态,对于MSI结直肠癌患者检测hMSH2、hMLH1和hMSH6基因种系突变。结果110例患者中共检出MSI结直肠癌患者23例(20.9%)。在23例MSI结直肠癌患者中,共发现病理性突变7个(30.4%),占所有结直肠癌6.4%;其中hMSH6基因种系突变3个,hMSH2基因突变3个,hMLH1基因突变1个。结论以修订Bethesda标准,MSI结直肠癌检出率为20.9%,HNPCC检出率6.4%;在中国人错配修复基因种系突变中hMSH2和hMSH6错义突变比较多见。 相似文献
9.
遗传性非息肉病性大肠癌临床表型分析 总被引:19,自引:2,他引:17
目的 探讨我国遗传性非息肉病性大肠癌(HNPCC)患者的临床表型,为临床辨认HNPCC家系提供依据。方法 选择符合阿姆期特丹Ⅱ和日本的HNPCC标准的34个HNPCC家系为研究对象。研究发病的一般规律:(1)确诊时的年龄和性别;(2)绘出家系图;(3)肿瘤发生的部位(包括肠外癌);(4)同时多原发结肠癌;(5)异时多原发结肠癌;(6)临床表现。结果 (1)34个家系中,18岁以上的家族成员共612人,确诊HNPCC的患者140例,女性47例,男性93例。(2)34个家系均为常染色体显性遗传。(3)确诊时的中位年龄为45.3岁,50岁以前发病者占62.1%,60岁以前发病者占87.1%;(4)154个原发癌灶中,肠外癌灶31个(20.1%),其中胃癌占肠外癌的41.9%(13/31),大肠癌灶123个(79.9%)。116例大肠癌患者中,右半结肠癌占66.4%(77/116),左半结肠癌占33.6%(39/116)。(5)同时多原发癌5例,其中2例为3次多原发癌,3例为2次多原发癌;异时多原发癌6例(含肠外癌)。结论 本组HNPCC的临床特点为(1)发病年龄比西方患者更年轻;(2)右半结肠癌的比例高;(3)大肠癌的垂直传递特征突出;(4)肠外癌以胃癌比例较大;(5)同时原发癌和异时原发癌较多。 相似文献
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中国部分地区结直肠癌遗传易感性与遗传性非息肉病性结直肠癌流行状况分析 总被引:7,自引:1,他引:6
目的了解结直肠癌患者的遗传易感性与结直肠癌人群中遗传性非息肉病性结直肠癌(HNPCC)的流行状况。方法结直肠癌患者分为两部分:第一部分为作者连续调查的结直肠癌患者,第二部分来源于近年来公开发表的有关中国人HNPCC发病率的文献。采用阿姆斯特丹标准Ⅰ、Ⅱ和日本标准等诊断HNPCC。结果17.2%的患者具有恶性肿瘤遗传易感性,5.2%的患者具有结直肠癌遗传易感性;多原发恶性肿瘤、多原发结直肠癌等分别占13.1%、10.1%;多原发恶性肿瘤(P=0.001)、多原发结直肠癌(P=0.000)等的发生均与恶性肿瘤家族史相关;低龄结直肠癌(≤50岁)患者占21.4%,其发生与恶性肿瘤家族史(P=0.000)、结直肠癌家族史(P=0.000)等均呈密切相关;符合阿姆斯特丹标准Ⅰ、Ⅱ和日本标准等HNPCC的检出率分别为1.24%、2.15%和2.93%,南、北地区间的差异没有统计学意义(P〉0.05)。结论恶性肿瘤家族史、多原发恶性肿瘤和低龄结直肠癌(≤50岁)是3种恶性肿瘤及结直肠癌遗传易感性的临床标志。多原发恶性肿瘤、低龄结直肠癌等与恶性肿瘤家族史相关。我国HNPCC的流行率与西方国家相当。 相似文献
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青年大肠癌微卫星不稳定和hMLH1/hMSH2表达缺失在遗传性非息肉病性大肠癌初筛中的应用 总被引:2,自引:0,他引:2
目的 探讨青年大肠癌中微卫星不稳定发生率和hMLH1/hMSH2表达缺失率及其在遗传性非息肉病性大肠癌初步筛查中的作用.方法 对73例中国南方青年大肠癌患者(年龄≤40岁)进行微卫星不稳定和hMLH1/hMSH2蛋白免疫组化检测.结果 微卫星不稳定性发生率为56.16%,hMLH1和/或hMSH2表达缺失率为49.32%,二者皆随患者发病年龄的降低而迅速增加;二者对阳性病例的检出率相似.结论 中国人青年大肠癌DNA错配修复基因缺陷为频发事件,运用微卫星不稳定分析和hMLH1/hMSH2蛋白免疫组化检测可在青年大肠癌有效地进行HNPCC患者及家系的初步筛查. 相似文献
12.
目的研究遗传性非息肉病性结直肠癌(HNPCC)中环氧合酶2(COX-2)的表达及与错配修复基因(MMR)的关系。方法选择2008年5月~2011年10月19个家系的家族遗传性非息肉病性大肠癌20例;选择同期本院收治的散发性大肠癌23例为对照组,采用免疫组化及PCR技术检测两组患者COX-2表达及MMR基因表达情况。结果 HNPCC大肠癌中COX-2高表达率为40.0%,散发性大肠癌中COX-2的高表达率为91.3%,两组比较差异有统计学意义(χ2=10.172,P〈0.05)。HNPCC大肠癌中MMR表达缺失率为70%,散发性大肠癌中MMR表达缺失率为13%,两组比较差异有统计学意义(χ2=9.872,P〈0.05)。MMR表达缺失的遗传性大肠癌及散发性大肠癌COX-2高表达率(21.4%、66.7%)均明显低于MMR阳性表达者(83.3%、95.0%),差异有统计学意义(χ2=7.357、5.039,P〈0.05)。相关性分析显示,HNPCC大肠癌MMR表达缺失率与COX-2低表达率呈正相关(r=1.176,P〈0.05),散发性大肠癌患者中,MMR表达率与COX-2高表达率呈正相关(r=1.869,P〈0.05)。结论遗传性非息肉病性结直肠癌中COX-2的表达较散发性大肠癌减低,MMR基因表达缺失率增高,COX-2、MMR基因表达情况在遗传性非息肉型结直肠癌的筛查及发病机制的研究中有重要意义。 相似文献
13.
可疑遗传性非息肉病性结直肠癌的hMLH1和hMSH2基因突变研究 总被引:15,自引:1,他引:14
目的比较分析符合国际诊断标准的遗传性非息肉病性结直肠癌(ICGHNPCC)家系和提出的可疑HNPCC家系的分子特征的异同,建立可疑HNPCC诊断标准并评价其应用价值。方法根据AmsterdamHNPCC诊断标准和作者提出的可疑HNPCC诊断标准,分别收集得到29个ICG家系和34个可疑家系。提取先证者的外周血基因组DNA,应用PCRSSCP和DNA测序的方法进行hMLH1和hMSH2基因的突变筛选。结果29个ICG家系中有9个家系被检出含有hMLH1基因的种系突变,突变率为310%;34个可疑家系中有10个家系被检出含有hMLH1或hMSH2基因的突变,两个基因的突变率分别为235%和59%。ICG组和可疑组中两个基因总突变率之间差异无显著意义(P>005)。hMLH1基因同是两组家系中的主要相关基因。两组家系中,突变均较一致地分布于基因的后半部分,突变类型也极为相似,均以导致短缩蛋白的突变最为常见。结论ICG组和可疑组在遗传背景上有着相似之处,对HNPCC诊断标准有一定的临床应用价值,有助于HNPCC家系的临床诊断。 相似文献
14.
遗传性非息肉病性结直肠癌家庭肠外肿瘤病变特点分析 总被引:2,自引:0,他引:2
目的 通过分析遗传性非息肉病性结直肠癌 (HNPCC)肠外肿瘤的病变特点来探讨其发病规律。方法 采用Amsterdam标准Ⅱ收集HNPCC家系 ,对收集的 9个家系进行病例查阅、随访和回顾。结果 在 9个家系中 ,有 2 1例肠外肿瘤发生 ,4例为同步肿瘤 ,1 7例为异步性肿瘤。常见的为胃癌和子宫内膜癌。结论 大肠外肿瘤是HNPCC家系的重要组成部分 ,我国常见的为胃癌和子宫内膜癌。对其家系成员应定期随访监测 相似文献
15.
目的:考察遗传性非息肉病性结直肠癌(HNPCC)家系hMLH1/hMSH2生殖系突变的情况.方法:选择13个符合Amsterdam标准的HNPCC家系中的先证者,利用DNA 测序检测hMLH1/hMSH2基因突变情况.对其中不携带hMLH1/hMSH2生殖系突变的HNPCC 家系,利用免疫组化检测hMLH1/hMSH2基因表达、PCR-SSCP检测先证者肿瘤组织的微卫星不稳定性(MSI).结果:13个HNPCC家系的先证者中有3例检测不到hMLH1/hMSH2的生殖系突变.3例无hMLH1/hMSH2突变的先证者中,肿瘤组织的微卫星不稳定检测均为MSI-H,免疫组化检测hMLH1/hMSH2基因表达正常.结论:3个严格符合Amsterdam标准的HNPCC家系中未发现hMLH1/hMSH2基因系突变,提示可能存在其他基因突变导致该3个家系HNPCC肿瘤发生. 相似文献
16.
hMSH2蛋白表达缺失在筛选遗传性非息肉病性大肠癌中的意义 总被引:1,自引:0,他引:1
目的 探讨hMSH2蛋白表达缺失在筛选遗传性非息肉病性大肠癌中的作用及其意义。方法 对收集的166例石蜡包埋的疑似遗传性非息肉病性大肠癌组织进行hMSH2蛋白免疫组化染色。结果 hMSH2蛋白表达阴性 ( 0分 ) 3 5例 ,占 2 1 1% ,阳性 ( 1~ 4分 ) 12 6例 ,占 75 9%。在右半、左半结肠和直肠表达缺失率分别为 3 3 3 % ( 15 / 45 ) ,15 4% ( 6/ 3 9)和 18 2 % ( 14 / 77)。右半结肠癌的表达缺失明显高于左半结肠癌 (P <0 0 5 )和直肠癌 (P <0 0 5 )。结论 hMSH2蛋白免疫组化染色做为一个简单易行的方法在今后检测和确定遗传性非息肉病性大肠癌中将发挥重要作用。 相似文献
17.
中国人HNPCC家系的临床特征及M3胆碱能受体基因(A)8区突变检测 总被引:1,自引:1,他引:0
目的:分析中国人遗传性非息肉病性大肠癌(HNPCC)家系的临床特征并检测这些家系中M3胆碱能受体基因(A)8区的突变情况.方法:根据2003年4月杭州会议制定的中国人HNPCC家系标准收集HNPCC家系共15个,分析其临床特征;提取先证者的外周血基因组DNA,PCR扩增M3胆碱能受体基因第8外显子中一段长153 bp,包含有微卫星位点(A)8的基因片段,直接进行DNA测序.结果:15个家系共有恶性肿瘤患者55例,其中大肠癌患者41例,平均每个家系发生大肠癌2.73例,73%的大肠癌患者发病年龄<50岁,51%的病灶位于近端结肠,40%发生在直肠肛门,同时和异时多原发大肠癌总发生率为12%,2/3的家系属于Lynch Ⅱ型,共发生肠外恶性肿瘤14例(18个),其中胃癌最常见.15例先证者外周血中无1例检测到M3胆碱能受体基因(A)8区的突变.结论:M3胆碱能受体基因与中国人群中HPNCC的发病可能无密切关系.中国人HNPCC家系标准应在临床工作中推广应用,并进一步验证其合理性和科学性. 相似文献
18.
Background Checkpoint kinase 2 (CHK2) is a DNA damage-activated protein kinase which is involved in cell cycle checkpoint control, CHK2 gene could be a candidate gene for colorectal cancer susceptibility, But there are few systematic reports on mutation of CHK2 in colorectal cancer. Methods The mutations of all 14 exons of CHK2 in 56 colorectal cancer cell lines were screened systematically, using denaturing high-performance liquid chromatography (DHPLC) to screen the mismatches of the CHK2 exons amplified products, and then the suspected mutant cell lines were scanned by nucleotide sequence analysis. Results VACO400 in CHK2 exon la was suspected to have mutation by DHPLC and confirmed by sequence, but this was nonsense mutation. C106, CX-1, HT-29, SK01, SW480, SW620 and VACO400 in CHK2 exon lb were confirmed to have the same nonsense mutation in 11609 A〉G. DLD-1 and HCT-15 in CHK2 exon 2 were confirmed to have missense mutation R145W, which was heterozygous C〉T missense mutation at nucleotide 433, leading to an Arg〉Trp substitution within the FHA domain. Conclusions The CHK2 mutation in colorectal cancer is a low frequency event, There are just 10 cell lines to have sequence variations in all the 14 exons in 56 colorectal cancer cell lines and only DLD-1/HCT-15 had heterozygous missense mutation. These findings may give useful information of susceptibility of colorectal cancer as single nucleotide polvmorphvsim. 相似文献
19.
遗传性非息肉病性大肠癌30例临床病理特点与诊治分析 总被引:1,自引:0,他引:1
目的:探讨遗传性非息肉病性大肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)的临床病理及分子病理特征,提高对该病的认识和诊疗水平。方法:回顾性分析中南大学湘雅医院普通外科诊治的30例HNPCC病人,以同期在该院治疗的散发性结直肠癌25例为对照组。比较其发病年龄、肿瘤部位、病理类型、治疗方法及预后。采用免疫组织化学检测两组病人错配修复基因(mismatch repair genes,MMR)MLH1和 MSH2 表达缺失率。结果:与对照组相比,HNPCC组的发病年龄早,近段大肠癌比例高,易于合并多发癌,肿瘤高分化类型所占比例高(P<0.05)。MLH1和 MSH2 表达缺失率高于对照组(P<0.05)。HNPCC组中1/3的病人接受了大肠次全切除术,预后与散发大肠癌相当(P>0.05)。结论:HNPCC具有发病早,易合并多发癌的特点,结合MMR的检测可提高诊断的准确率。彻底手术和密切随访可取得好的效果。 相似文献
20.
Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. 总被引:3,自引:0,他引:3
CONTEXT: Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management. OBJECTIVE: To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management. DESIGN: Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity. SETTING AND PARTICIPANTS: Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC. MAIN OUTCOME MEASURE: Alterations of hMSH2 and hMLH1 genes. RESULTS: Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families. CONCLUSIONS: The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted. 相似文献