2例遗传性非息肉病性大肠癌家系分析

目的分析2例遗传性非息肉病性大肠癌（HNPCC）家系的临床病理特征。方法对2个HNPCC家系进行病例回顾及家系调查。结果HNPCC的主要特点是病灶好发于右半结肠，发病年龄较轻，预后好于散发性大肠癌。结论应对HNPCC患者及其家族严密监测、随访，以便早期诊断、及时治疗、改善预后。     

遗传性非息肉病性大肠癌家系及可疑家系的临床诊断分析

目的 提高对遗传性非息肉病性大肠癌（HNPCC）临床诊断的认识。方法：对有2例以上大肠癌，或1例大肠癌并1例以上HNPCC相关肿瘤以及发病年龄小于40岁患者的家系进行家系调查和诊断分析。结果：70个家系中有8个家系符合HNPCC诊断标准，8个家系共有24例大肠癌病人，平均年龄44岁。共有大肠癌灶35个，20个分布于脾曲近端的结肠。6例为多原发大肠癌。62个家系符合可疑；HNPCC诊断标准，其中2个家系符合可疑HNPCC诊断标准Ⅰ，60个家系符合可疑HNPCC诊断标准Ⅱ。62个家系共有65例大肠癌病人，平均年龄30．5岁。共有大肠癌灶68个，49个癌灶分布于脾曲近端的结肠或直肠。2例为多原发大肠癌。结论 熟悉HNPCC诊断标准和可疑HNPCC诊断标准对临床诊断至关重要。有必要对可疑HNPCC诊断标准Ⅱ进行修改。     

遗传性非息肉病性大肠癌家系两例报告并文献复习

目的探讨遗传性非息肉病性大肠癌（HNPCC）家系的临床特征。方法对2个HNPCC家系共12例患者进行病例回顾及家系调查。结果2个家系共有HNPCC12例患者，男3例，女9例，年龄31—70岁，中位发病年龄为41岁，其中多原发癌患者4例，占33％，肠外肿瘤以子宫内膜癌多见。结论HNPCC垂直传递突出，多原发癌多见，应对HNPCC患者及其家系成员进行严密监测随访，以便达到早期诊断、早期治疗、改善预后的目的。     

检测微卫星不稳在中国遗传性非息肉病性结直肠癌患者诊断中的应用

背景与目的：遗传性非息肉病性结直肠癌（hereditary nonpolyposis colorectal cancer，HNPCC）是常染色体显性遗传综合征，国外报道90％的HNPCC肿瘤表现为微卫星不稳（microsatellite instability，MSI），可作为筛查HNPCC的金标准。本研究旨在了解中国HNPCC肿瘤MSI发生率以及可疑HNPCC患者大肠癌肿瘤中的MSI发生率，由此探讨大肠癌患者家族中的胃癌等HNPCC相关肿瘤对发现HNPCC患者的意义。方法：选择符合Amsterdam标准的HNPCC组大肠癌标本18例，和不符合Amsterdam标准、但高度怀疑为HNPCC的可疑HNPCC组大肠癌标本16例，检测BAT26、D2S123、BAX、IGFIIR、hMSH3和hMSH66个做卫星位点的微卫星不稳在两组中的发生率，比较两组微卫星不稳频率的差异。结果：上述各傲卫星位点在HNPCC组和可疑HNPCC组标本中均显示较高的突变率。高度微p星不稳肿瘤在两组标本中的检出率分别为94．4％和93．7％．差异无显著性。BAT26对高度微卫星不稳肿瘤敏感度高。结论：MSI在中国HNPCC患者中的发生频率与国外类同。仅用BAT26可发现大部分高度微卫星不稳肿瘤。将胃癌等HNPCC相关肿瘤纳入临床诊断标准，可能有助于避免在中国大肠癌人群中漏诊HNPCC患者。     

中国北方人HNPCC微卫星不稳定性的研究

目的:通过对遗传性非息肉病性大肠癌(hereditary nonposis colorectal cancer,HNPCC)与普通遗传性大肠癌微卫星不稳定性(microsatellite instability,MSI)的检测,为临床筛检HNPCC家系提供依据。方法:选取符合中国人HNPCC诊断标准家系(A组)和普通遗传性大肠癌诊断标准家系(B组)的先证者各20例,另选散发性大肠癌(C组)20例为对照组,用PCR-SSCP的方法对上述肿瘤标本进行MSI检测。结果:A、B、C3组高度微卫星不稳定性(MSI-H)的发生率分别为55.0%(17/20)、40.0%(8/20)和10.0%(2/20),3组之间比较差异有统计学意义,P<0.05。MSI-H在A、B、C3组平均发病年龄分别为43.6、52.2和61.8岁,逐渐升高;右半结肠癌发生率分别为55.0%(11/20)、25.0%(5/20)和0,逐渐下降,差异有统计学意义,P<0.05。所选5个位点中BAT26和BAT25的表达率最高,均为94.1%(16/17)。在MSI-H中,A组低分化腺癌占70.6%(12/17),明显高于B、C两组的4/8和1/2,P<0.05。结论:MSI与HNPCC的临床病理特征高度相关,该方法经济、易行,可作为HNPCC的筛检手段。     

遗传性非息肉病性结直肠癌相关肿瘤累计危险度分析

目的 了解各遗传性非息肉病性结直肠癌（HNPCC）相关肿瘤在中国HNPCC家族中发病的危险度,探讨中国HNPCC患者的诊断和治疗策略.方法 收集符合Amsterdam标准的HNPCC家族41个,以寿命表法对213例发生各种肿瘤的HNPCC家族成员做相关肿瘤的累计危险度分析.结果 肠外肿瘤中胃癌发生率最高（25例）,其次为子宫内膜癌（11例）.各HNPCC常见肿瘤的累计危险度分别为大肠癌89.5%,胃癌24.5%,子宫内膜癌29.6%（女性）,肝癌8.2%.结论 肠外肿瘤中胃癌、子宫内膜癌及肝癌的累计危险度均较高,忽视胃癌在中国HNPCC诊断中的价值,可能会漏诊部分患者.     

遗传性非息肉病性结直肠癌7个家系的临床分析

目的：总结遗传性非息肉病性结直肠癌（HNPCC）家系的临床特点,提高临床诊断和治疗水平。方法：收集7个HNPCC家系的病例资料,分析其发病特点并记录随访结果。结果：7个HNPCC家系共有癌症患者23例,肿瘤灶27处：大肠外瘤灶3处;大肠瘤灶24处,其中有13处位于脾曲近侧结肠,占54.1%。平均发病年龄为41.2岁,17例（73.5%）发病在50岁以前。1家系累及连续三代人、4家系累及连续两代人。多原发癌患者4例,其中3例为肠外癌。结论：HNPCC具有发病年龄轻、垂直传递、肠外癌发病率高、常见多原发癌、好发于右半结肠、病理分化较差的特点,但预后相对较好。     

遗传性非息肉病性大肠癌和普通遗传性大肠癌临床表型分析

目的:探讨遗传性非息肉病性大肠癌(HNPCC)与普通遗传性大肠癌临床表型的异同,为临床辨认HNPCC家系提供依据。方法:选择符合阿姆斯特丹标准Ⅱ或日本标准的22个HNPCC家系(A组)和普通遗传性大肠癌20个家系(B组)为研究对象进行随访分析。结果:1)A、B两组男女发病的比例分别为1.4:1(41/30)和1.5:1(38/26),无显著性差异(P>0.05)。2)A、B两组确诊的中位年龄分别为48岁(32～70岁)和61岁(30～83岁),50岁以前发病比例分别为59.2%和26.6%,A组较B组发病年龄明显提前,差异显著(P<0.01)。3)A、B两组右半结肠癌发病比例分别为56.9%(29/51)和29.2%(7/24),差异显著(P<0.05)。4)A组多发癌7例,B组未见多发癌。5)A组第一、二、三代的平均发病年龄分别为64岁、56岁、48岁,逐渐年轻化,B组无此现象。结论:HNPCC与普通遗传性大肠癌临床表型不尽相同,提示两者各自有其独特的遗传学特征。     

HSP27和GST在大肠腺瘤和大肠癌中表达的临床病理研究

目的探讨热休克蛋白27（HSP27）和谷胱甘肽-S-转移酶（GST）在正常大肠黏膜、大肠腺瘤和大肠癌中的表达及其临床病理意义。方法应用免疫组织化学S-P法检测HSP27和GST在大肠组织中的表达。结果HSP27在正常肠黏膜、大肠腺瘤、无淋巴结转移的大肠癌、有淋巴结转移的大肠癌中表达阳性率分别为30％,33．3％,65％,70％,多组间比较具有显著性差异（x^2=12．723,P=0．013）。两组间比较发现,HSP27表达率在正常组与大肠癌组存在差异,在有淋巴结转移的大肠癌组中的表达具有差异最为显著（x^2=8．688,P=0．003）,而其它组间比较无显著性差异。GST在正常肠黏膜、大肠腺瘤、无淋巴结转移的大肠癌、有淋巴结转移的大肠癌中表达阳性率分别为60％,80．9％,90％,100％,多组间比较具有显著性差异（x^2=16．707,P=0．001）;进一步进行两组间比较发现,GST表达率在有淋巴结转移的大肠癌组中的表达具有差异最为显著（x^2=10．909,P=0．001）,而其它组间比较无显著性差异。GST和HSP27表达无显著相关。结论HSP27和GST在大肠癌中的表达可能在大肠癌发生发展中发挥作用,特别在大肠癌恶性演进中以及预后预测中具有重要意义,可能作为独立的生物标志物。     

遗传性非息肉病性大肠癌分子机理研究进展

大肠癌是我国常见的恶性肿瘤,以往研究表明其发生常涉及等位基因的杂合性缺失(loseofhetero-zygosity,LOH)这一途径,并与多个癌基因和抑癌基因的突变有关。近年来对遗传性非息肉病性结直肠癌(hereditarynon-polyposiscolorectalcancer,HNPCC)的发现和研究,使人们对大肠癌的发生机制有了新的认识。1913年Warthin首次描述了HNPCC的临床病理特征,并报道了一些胃癌、大肠癌聚集的家系。但直到半世纪后,Lynch等才更详细地描述了这些家系的遗传和临床病理学特征,并根据是否发生肠外肿瘤将其分为LynchI和Lynch型。因此,HNPCC又被称为Lync…     

Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features. EXPERIMENTAL DESIGN: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations. RESULTS: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers. CONCLUSIONS: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.     

Familial aggregation of colorectal cancer in Egypt

We have investigated the familial aggregation of colorectal cancer and hereditary nonpolyposis colorectal cancer (HNPCC) in Egypt because of the high incidence of colorectal cancer in Egyptian children and young adults and the prevalence of consanguinity there. In a pilot study, we conducted detailed interviews with 111 Egyptian colorectal cancer patients and 111 healthy Egyptian controls about their family histories of colorectal cancer, and other cancers, consanguinity, age at diagnosis, symptoms and recurrence. Eight patients (7.2%) had one or more first- or second-degree relatives under age 40 with colorectal cancer, suggestive of HNPCC by the Amsterdam criteria. One of these families had a typical history of HNPCC, with 4 relatives having colorectal cancer in 3 generations; 3 of these relatives were younger than age 45 at colon cancer diagnosis, and other relatives had extracolonic tumors. Another 14 patients (12.6%) had a first- or second-degree relative with a family history of other neoplasms such as endometrial, urinary and hepatobiliary cancers that could also be related to HNPCC. Four patients with early-onset colon cancer and a family history of other HNPCC-related cancers reported that their parents were first-degree cousins. Int. J. Cancer 77:811–816, 1998.© 1998 Wiley-Liss, Inc.     

Second primary cancers after sporadic and familial colorectal cancer.

Second cancers were studied among 68,104 cases of colorectal cancer (CRC) from the Swedish Family-Cancer Database. A total of 1,113 patients received a diagnosis of second CRC; 25 of them had a family history of CRC. Cases of second CRC with a family history were diagnosed up to 10 years before sporadic cases. The relative risk (RR) of all second CRCs was 2.21 compared with the first CRC. Familial second CRCs had a 2-fold risk compared with the sporadic forms. Age of onset was the most important covariate of second CRCs; the relative risk at ages 15-39 years was 27 compared with the first CRC. Familial CRC was associated with a high risk of small-intestinal, endometrial, and gastric cancers apart from CRC, all typical of hereditary nonpolyposis CRC (HNPCC). Among familial cases, 36% of second CRCs and 100% of endometrial cancers came from families that fulfilled the Bethesda criteria for HNPCC. Only 12 families conformed to the Amsterdam criteria; in family members, the risk of second CRC was 127-fold and that of endometrial cancer 257-fold. Other sites that were in excess among all second cancers were many cancers linked to HNPCC and, additionally, breast, prostate, thyroid and other endocrine, skin, and genital cancers. The high risk of second cancer after early-onset CRC calls for evaluation of family history and clinical surveillance.     

遗传性非息肉病性结直肠癌7个家系的临床分析

目的:总结遗传性非息肉病性结直肠癌(HNPCC)家系的临床特点,提高临床诊断和治疗水平。方法:收集7个HNPCC家系的病例资料,分析其发病特点并记录随访结果。结果:7个HNPCC家系共有癌症患者23例,肿瘤灶27处:大肠外瘤灶3处;大肠瘤灶24处,其中有13处位于脾曲近侧结肠,占54.1%。平均发病年龄为41.2岁,17例(73.5%)发病在50岁以前。1家系累及连续三代人、4家系累及连续两代人。多原发癌患者4例,其中3例为肠外癌。结论:HNPCC具有发病年龄轻、垂直传递、肠外癌发病率高、常见多原发癌、好发于右半结肠、病理分化较差的特点,但预后相对较好。     

Familial risk of endometrial cancer after exclusion of families that fulfilled Amsterdam, Japanese or Bethesda criteria for HNPCC.

BACKGROUND: Endometrial cancer is the second most common lesion within hereditary non-polyposis colorectal cancer (HNPCC) syndrome. The importance of the non-HNPCC genetic predisposition to endometrial cancer is unclear, and the familial aggregation of endometrial cancer after exclusion of HNPCC families may offer valuable clues about the involvement of non-HNPCC-related genes. PATIENTS AND METHODS: The families of the nationwide Swedish Family-Cancer Database were classified as HNPCC families according to the Amsterdam I or II, the modified Amsterdam, the Japanese and the Bethesda criteria. Standardized incidence ratios (SIRs) for endometrial cancer when parents or siblings were diagnosed with cancer at the most common sites were calculated before and after exclusion of HNPCC families. RESULTS: The proportion of individuals in the families with endometrial cancer was highest when the criteria required three cancers within a family or multiple HNPCC-related cancers in the same individual. Consideration of the Amsterdam or the Japanese criteria hardly reduced the familial aggregation of endometrial cancer. After exclusion of families that fulfilled the Bethesda criteria, SIRs were significant when the parents were diagnosed with endometrial or thyroid gland cancers; 75.7% (95% confidence interval 60% to 99.1%) of the familial cases of endometrial cancer were not related to HNPCC according to the Bethesda criteria. The reduction of SIRs for cancers at the colon, pancreas, prostate and ovary was limited when the Bethesda criteria were applied. However, the Bethesda criteria identified most of the familial aggregation when endometrial cancers were diagnosed before the age of 55 years. CONCLUSIONS: The data suggest that additional effects, not related to HNPCC, contribute to the familial aggregation of endometrial cancer.     

Amsterdam criteria II and endometrial cancer index cases for an accurate selection of HNPCC families

Endometrial carcinoma (EC) is the second most common tumor in hereditary nonpolyposis colorectal cancer (HNPCC), with an incidence rate of 60% by the age of 70 in mutation carriers. The International Collaborative Group on HNPCC revised the Amsterdam criteria and proposed a new, wider definition including extracolonic cancers. The aim of our study was to evaluate the accuracy of a new definition called Amsterdam criteria II. We updated, reclassified and compared the pedigrees of 29 women, already reported as being affected by EC and having a colorectal cancer familial background, according to the two clinical diagnostic criteria for HNPCC (Amsterdam criteria I, ACI, and Amsterdam criteria II, ACII) after two periods of observation (1990-1995 and 1995-2000). According to ACII the frequency of HNPCC in the population under study increased from 0.9% to 3.7% in the period 1990-1995 and from 3.2% to 3.7% in the period 1995-2000. ACII allowed early detection of HNPCC families and thus made it possible to provide them with a suitable surveillance program and genetic testing.     

hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer

The pattern of hMLHI and hMSH2 mutations was assessed to identify the genetic correlation between hereditary gastric and colorectal cancers. Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33). In the CG group, three were included in AMS + and six in AMS- criteria. Peripheral blood was obtained from them to detect hMLHI and hMLH2 mutations using PCR-SSCP analysis and direct sequencing. The incidence of mutations was 9.4% in the FG group, 54.5% in the CG group, 31.6% in the HS group, and none in the SG group. The incidence, type, and number of the mutation were not different between the CG and HS groups. Thirty-four different mutations included 19 in hMLH1 and 15 in hMSH2. Gastric cancer was the most common extracolonic malignancy in HNPCC and suspected HNPCC families (9/28, 32.1%). The hMLH1 or hMSH2 mutation occurred in seven of 10 families with AMS+, whereas it occurred in four of 18 with AMS- (70% vs. 22.2%, P = .013). Five mutations in the hMLH1 and six mutations in the hMSH2 were exclusively found in families with gastric cancer. All three mutations in the FG group were in hMLHI and there was no mutation in their healthy family members. This study demonstrates that some familial clustering type of gastric cancer appears to be associated with hMLHI mutations thereby indicating a difference from the hereditary gastric cancer studies previously reported. In addition, hMLHI and hMSH2 mutations may impact the gastric cancer carcinogenesis in HNPCC or suspected HNPCC.     

BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes

Recently, it was shown that the oncogenic activation of BRAF, a member of the RAS/RAF family of kinases, by the V600E mutation is characteristic for sporadic colon tumors with microsatellite instability. Further, it was shown to associate with the silencing of the mismatch repair (MMR) gene MLH1 by hypermethylation. Moreover, BRAF mutations proved to be absent in tumors from hereditary nonpolyposis colorectal cancer syndrome (HNPCC) families with germline mutations in the MMR genes MLH1 and MSH2. These data suggest that the oncogenic activation of BRAF is involved only in sporadic colorectal tumorigenesis. In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2. BRAF-V600E mutations were analysed by automatic sequencing in 38 tumors from HNPCC families with germline mutations in the MSH6 gene and also in HNPCC (suspected) families that do not have mutations in the MMR genes MLH1, MSH2 and MSH6. All patients belong to different families. No mutations were detected in 14 tumors from HNPCC patients with germline mutations in MSH6. Further, no mutations of BRAF were found in tumors from 23 MMR-negative families, from which 13 fulfilled the Amsterdam criteria (HNPCC) and 10 were suspected for HNPCC as they were positive for the Bethesda criteria. Overall, our data reinforce the concept that BRAF is not involved in the colorectal tumorigenesis of HNPCC. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer.