遗传性非息肉病性结直肠癌家系分析

目的　探讨遗传性非息肉病性结直肠癌在我国的发病遗传规律以及流行病学特点。方法　自 1999年 1月至 2 0 0 2年 12月 ,对天津市人民医院 (原名天津市滨江医院 )收治的 2 92例结直肠癌患者进行家系调查 ,从中筛选出符合以下标准的遗传性非息肉病性结直肠癌家系 3 8个 ,对家系的肿瘤发生率、肿瘤谱和临床特点等进行了分析和总结。诊断标准使用Amsterdam标准Ⅰ、Amsterdam标准Ⅱ (ICG HNPCC)和日本HNPCC诊断标准。结果　 3 8个遗传性非息肉病性结直肠癌家系中共有 14 5例癌症患者 ,其中男性 76例 ,女性 69例 ,男女比例为 1.1∶1。原发性结直肠癌平均诊断年龄为 ( 5 5 .73± 15 .88)岁 ,在所有 99例结直肠癌中 ,左半结肠癌及直肠癌 2 9例 ,占 2 9.3 % ;右半结肠癌 70例 ,占 70 .7% ,右半结肠癌占有绝对的优势 ;异时性多发性原发结直肠癌患者占大肠癌患者的 13 .1% ( 13 /99) ;HNPCC相关肿瘤共 46例其发生率由高到低前三位是 :子宫内膜癌 9例 ( 19.6% )、乳腺癌 7例 ( 15 .2 % )、肺癌、胃癌各 6例 ( 13 .0 % ) ;在男女性共患癌中 ,除胰腺癌、纵隔癌外 ,男性发生率均高于女性 ;第一代、第二代以及第三代患者的平均诊断年龄有逐渐年轻化的趋势 ,并具有统计学意义。结论　我国遗传性非息肉病性结直肠癌很可能     

遗传性非息肉病性结直肠癌的研究进展

遗传性非息肉病性结直肠癌（ｈｅｒｅｄｉｔａｒｙｎｏｎ－ｐｏｌｙｐｏｓｉｓｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ，ＨＮＰＣＣ）是一种常染色体显性遗传性肿瘤，外显率高达８０％～８５％，约占所有大肠癌的５％～１５％。与一般散发性大肠癌相比，它在临床表现、病理学检查和遗传背景上都有着独特的特征，其诊断主要根据临床与家系表征而定。近年来关于ＨＮＰＣＣ的国内外研究范围有新的积累，获得了一些新的认识和看法。１国际诊断标准的确立与修改为了规范和统一ＨＮＰＣＣ的诊断，便于世界范围内的协作研究，１９９０年国际ＩＣＧ－ＨＮ…     

遗传性非息肉病性结直肠癌研究进展

结直肠癌的发生率呈逐年上升趋势,已成为某些发达国家和地区导致死亡的主要疾病之一.遗传性非息肉性结直肠癌(hereditary non-polyposis colorectal cancer,HNPCC)作为结直肠癌的一种,为常染色体显性遗传,约占结直肠癌的5％-15％,HNPCC又称Lynch综合征,其原因主要是错配修复基因(mismatch repair genes,MMR)缺陷,导致MSI,从而引起结直肠癌,近年来其相关研究已受到普遍关注.     

遗传性非息肉病性结直肠癌

遗传性非息肉病性结直肠癌(HNPCC)是一种由错配修复(MMR)基因突变造成的常染色体显性遗传病.作为大肠癌的一个重要临床亚型,HNPCC约占全部大肠癌的5%～15%.MMR基因的种系突变和微卫星不稳定(MSI)是其分子遗传学基础.由于HNPCC的遗传病因特殊、临床病理特点突出,是目前大肠癌和遗传性肿瘤的研究热点.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

Use of microsatellite analysis in young patients with colorectal cancer to identify those with hereditary nonpolyposis colorectal cancer

BACKGROUND AND OBJECTIVES: The frequency of microsatellite instability (MSI) in young patients with colorectal cancer was evaluated, including reexamination of the medical and family history of each patient, and interviews with the patients to determine any possible new occurrence of hereditary nonpolyposis colorectal cancer (HNPCC) in the patients themselves or their family members. METHODS: Fifty-three young patients (younger than 40 years of age) with colorectal cancer were selected and investigated. DNA was extracted from paraffin sections and microsatellite analysis was performed. RESULTS: The frequency of MSI among the young patients with colorectal cancer was 50.9%, which was significantly higher than the rate of 12-21% noted in older patients with colorectal cancer (P < 0.001). For the 24 young patients with colorectal cancer who did not have MSI, only one case of HNPCC kindred and two cases with a family history of cancer were identified. In contrast, among the 20 young patients with colorectal cancer who had MSI, five cases of HNPCC kindred, two cases with metachronous patients with colorectal cancer, and three cases with a family history of cancer were identified. CONCLUSION: Our results suggest that a defect in the DNA mismatch repair system may play some role in carcinogenesis in young patients with colorectal cancer. Microsatellite analysis and subsequent interviews regarding medical and family history are useful tools for efficiently identifying possible cases of HNPCC among young patients with colorectal cancer.     

Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome

The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32-60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment.     

遗传性非腺瘤病性结直肠癌的诊治进展

遗传性非腺瘤病性结直肠癌（HNPCC）是一种常染色体显性遗传的综合症,占总的结直肠癌的56%--10%。该病由错配修复基因缺陷造成,肿瘤表现出高度的微卫星不稳。临床上辨别HNPCC患者对诊断和治疗以及监测HNPCC家庭成员发病有指导意义。     

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。     

Hereditary nonpolyposis colorectal cancer in endometrial cancer patients

Endometrial cancer is the second most common cancer in hereditary nonpolyposis colorectal cancer (HNPCC). It has often been overlooked to explore the possibility of HNPCC in endometrial cancer patients. Our study was to investigate how many HNPCC patients existed among endometrial cancer patients. Among patients who underwent hysterectomy for endometrial cancer at Seoul National University Hospital from 1996 to 2004, 113 patients were included, whose family history and clinical data could be obtained and tumor specimens were available for microsatellite instability (MSI) testing and immunohistochemical (IHC) staining of MLH1, MSH2 and MSH6 proteins. There were 4 (3.5%) clinical HNPCC patients fulfilling the Amsterdam criteria II, and 2 (2/4, 50%) of them carried MSH2 germline mutations. There were also 8 (7.1%) suspected HNPCC (s-HNPCC) patients fulfilling the revised criteria for s-HNPCC, and one (1/8, 12.5%) of them revealed MLH1 germline mutation. In 101 patients, who were not clinical HNPCC or s-HNPCC, 11 patients showed both MSI-high and loss of expression of MLH1, MSH2 or MSH6 proteins, and 2 (2/11, 18.2%) of them showed MSH6 germline mutations. In 113 patients with endometrial cancer, we could find 5 (4.4%) HNPCC patients with MMR germline mutation and 2 (1.8%) clinical HNPCC patients without identified MMR gene mutation. Family history was critical in detecting 3 HNPCC patients with MMR germline mutation, and MSI testing with IHC staining for MLH1, MSH2 and MSH6 proteins was needed in the diagnosis of 2 HNPCC patients who were not clinical HNPCC or s-HNPCC, especially for MSH6 germline mutation.     

Colon cancer screening practices and disclosure after receipt of positive or inconclusive genetic test results for hereditary nonpolyposis colorectal cancer

BACKGROUND:

Patients who receive conclusive genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) tend to adopt appropriate colorectal cancer screening behaviors and disclose their test results. However, little is known about the disclosure processes or screening behaviors of individuals who receive inconclusive genetic test results. This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received.

METHODS:

Individuals with a personal history of cancer and suspected of having HNPCC participated in genetics education and counseling, underwent HNPCC testing, and received genetic test results (GCT) within a prospective cohort study. Demographic, psychosocial, and behavioral data were obtained from questionnaires and interviews completed before and after GCT.

RESULTS:

Index cases with inconclusive genetic test results were less likely to screen within 12 months. Index cases who disclosed test results to children within 6 months were more likely to screen within 12 months, controlling for mutation status. Index cases with inconclusive genetic test results were less likely to share results with a healthcare provider within 6 months. Index cases who disclosed genetic test results to healthcare providers within 6 months were more likely to have endoscopy within 12 months.

CONCLUSIONS:

Genetic test results and disclosure significantly affected colon cancer screening at 12‐month follow‐up. Interventions to improve adherence to colorectal cancer screening should consider increased education of those receiving inconclusive results and encourage disclosure to healthcare providers and family members. Cancer 2009. Published 2009 by the American Cancer Society.     

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation‐negative familial ovarian cancers

BACKGROUND:

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC‐related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

METHODS:

Seventy‐seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC‐associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.

RESULTS:

None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious.

CONCLUSIONS:

HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing. Cancer 2009. © 2009 American Cancer Society.     

Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain

HNPCC is an autosomal dominantly inherited cancer-susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancers. The underlying pathogenic mutation lies in 1 of the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened a total of 140 individuals from 56 Spanish families with suspected HNPCC for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE and direct DNA sequencing. Families were selected on the basis of a history of HNPCC-related tumors or the occurrence of other associated tumors in members besides the index case affected with colorectal cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1 and 5 in MSH2 in 13 unrelated families selected by the Amsterdam criteria and Bethesda guidelines (1 family carries 2 mutations) and 3 missense mutations in 3 unrelated families selected by the Amsterdam criteria. Among the 17 germline mutations noted in the Spanish cohort, 10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different mutational spectra in the Spanish population, where no founder mutation has been identified. Based on our results, we suggest that in the Spanish population not only HNPCC families fulfilling the Amsterdam criteria but also those following Bethesda guidelines should undergo genetic testing for MSH2 and MLH1 mutations.