中国人家族性腺瘤性患肉病患者结肠腺瘤性患肉病基因的胚系突变

目的 探讨中国人家族性腺瘤性息肉病(familial adenomatous polyposis,FAr)患者的结肠腺瘤性息肉病(adenomatous polyposis coli,APC)基因的胚系突变类型.方法 对9个FAP家系18名成员进行多重连接依赖性探针扩增(multiplex ligation-dependent probe amplification,MLPA)检测APC基因有无大片段缺失.再应用PCR扩增APC基因的15个外显子区域,经变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)对每个扩增片段进行筛查,流出峰异常的片段,经DNA测序验证小片段的改变.结果 9个家系中有3个家系发现有APC基因的胚系突变:家系2为c.3184-3187 del CAhA,家系4为c.5432C＞T,家系9为c.3925-3929 del AAAAG.3种突变中c.5432C＞T在数据库中未见报道.结论 中国人不同的APC基因的胚系突变可引起FAP;无APC胚系突变的FAP患者的发病可能存在其他的机制.     

Non-allelic heterogeneity of familial adenomatous polyposis

Linkage studies on familial adenomatous polyposis (FAP) reported so far suggest that FAP is a genetically homogeneous disease. Recently, we found that the putative gene for Turcot syndrome, an apparently autosomal recessive clinical variant of FAP, is not allelic to FAP. Here we describe another family, segregating for an autosomal dominant disease clinically indistinguishable from FAP but genetically not linked to the APC locus, adding further evidence for the occurrence of non-allelic heterogeneity of FA. These observations have implications to the linkage-based genetic counselling of persons at risk for FAP especially when they are drawn from small families giving insufficient information. © 1993 Wiley-Liss, Inc.     

Pulmonary sclerosing hemangioma associated with familial adenomatous polyposis

A 45-year-old woman presented with asymptomatic solid tumor in the lower right lobe of the lung. Histologically, the tumor comprised a monolayer of surface cells and round stromal cells displaying sclerotic areas. Immunohistochemical studies suggested a diagnosis of sclerosing hemangioma. Interestingly, morular lesions were also observed. Analyses of the gastrointestinal (GI) tract showed mild familial adenomatous polyposis (FAP) and numerous fundal gland polyps, indicating attenuated FAP (AFAP). All components of the sclerosing hemangioma displayed aberrant nuclear and cytoplasmic expression of beta-catenin. However, such findings were much weaker in adenomas of the GI tract and were barely observed in fundal gland polyps. These results strongly suggest an association between sclerosing hemangioma and the AFAP. To the best of our knowledge, this is only the second report of lung tumor associated with FAP and is the first describing an association with sclerosing hemangioma. A new category of FAP-associated lung tumors may be indicated.     

Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm

Thyroid carcinoma has been described as occurring more frequently than expected in association with familial adenomatous polyposis. The histology of these cases has not been described in detail, although the reported cases were usually diagnosed as papillary carcinoma. We now report the pathological features of four cases of thyroid carcinoma associated with familial adenomatous polyposis, and review the findings in the literature. The tumours in these four cases were all of follicular cell origin as shown by thyroglobulin immunohistochemistry. In three they were multifocal. The tumours showed some features of papillary carcinoma—grooved nuclei and papillary architecture, but these were not consistent. They also showed features that were unusual for papillary carcinoma—a cribriform pattern and solid areas with spindle cell component. Commonly the tumours combined both patterns. A review of the reported cases of thyroid cancer associated with familial adenomatous polyposis showed that they also were commonly multifocal and occurred predominantly in young women. When the histology was adequately reported or illustrated it was, in most instances, consistent with the findings in our own cases. We therefore suggest that these thyroid tumours form a distinct type with some unusual features. Clearly it is likely that the APC gene is associated with their pathogenesis, and that other factors contribute to the predominantly female incidence in this as in sporadic tumours. Six of 63 reported cases showed metastasis or died from thyroid carcinoma. In a number of cases the tumours presented before the familial adenomatous polyposis was recognized. The findings of these unusual histological features in a thyroid tumour, and particularly of multicentricity, should alert the pathologist to the possibility of familial adenomatous polyposis with its implications for family screening. The tumours are often well demarcated but, because of the multicentricity, total thyroidectomy should be advocated.     

Risk of hepatoblastoma in familial adenomatous polyposis

Infantile and childhood hepatoblastoma occurs more frequently in persons heterozygous for the familial adenomatous polyposis (FAP) gene than in the general population. This observation is based on numerous case reports plus the results of an international survey of FAP registries. However, the frequency of this rare tumor in FAP patients is unknown. In a retrospective review of our family history data, 2/470 (0.42%) children born to 241 patients with FAP had hepatoblastoma. This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population. However, for genetic counseling purposes, an empiric risk of <1% for hepatoblastoma can be cited to persons with FAP for their children. © 1992 Wiley-Liss, Inc.     

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis

Germ‐line mutations in the 5′ half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ‐line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ‐line mutations and clinical manifestations of the disease. © 2001 Wiley‐Liss, Inc.     

Familial adenomatous polyposis associated with multiple adrenal adenomas in a patient with a rare 3' APC mutation

Familial adenomatous polyposis (FAP) is characterised by hundreds of colorectal adenomas. Endocrine neoplasms have occasionally been reported, as have gastric polyps, which are usually hamartomatous in the fundus of the stomach and adenomatous in the antrum. A 57 year old man with colorectal, gastric, and periampullary adenomatous polyposis, in association with three bilateral adrenocortical adenomas, is presented. Mutation screening showed a 5960delA germline mutation in the adenomatous polyposis coli (APC) gene predicted to lead to a premature stop codon. This mutation was found in three of the four children of the patient. Western blot analysis of a lymphoblastoid cell line derived from the patient failed to detect any truncated APC polypeptide. This rare 3' mutation is responsible for an unusually complex and late onset phenotype of FAP.


Keywords: familial adenomatous polyposis; APC mutation; adrenal adenoma     

Strategies and outcomes of PGD of familial adenomatous polyposis

Owing to adult onset of hereditary cancer, prenatal diagnosis (PND) raises numerous ethical issues on the acceptability to terminate an affected pregnancy (TOP). PND for these disorders is often considered as unacceptable by couples as well as geneticists and legal or ethical authorities, but preimplantation genetic diagnosis (PGD), even if subject to controversy, seems to be a more acceptable option. Therefore, many couples, who do not want to transmit their cancer to their children, consider PGD as their only reproductive option. This article describes our experience of PGD for familial adenomatous polyposis (FAP). Twelve couples were referred between 2000 and 2005. We developed PGD tests to detect the mutation alone, but we rapidly set up multiplex PCR combining mutation detection and indirect diagnosis. Finally, we set up duplex and triplex indirect diagnoses to be able to offer a PGD, whatever mutation was involved in familial cases. PGD strategies were based on (i) a new double allele-specific PCR approach (D-ARMS) allowing the detection of the wild-type and mutated allele; (ii) PCR fragments sizing and (iii) restriction length polymorphisms. For the 12 referrals, we developed eight tests, and 11 cycles have been performed for four couples, resulting in eight embryo transfers and five pregnancies, with the birth of one healthy boy and two ongoing pregnancies. We are now able to propose PGD to most couples at risk of transmitting FAP to their offspring, whether the mutation is familial or occurred de novo.     

Subject-reported compliance in a chemoprevention trial for familial adenomatous polyposis

A high level of compliance with an assigned treatment regimen is fundamental to accurate assessment of treatment effectiveness in any clinical trial. If compliance is poor, an effective treatment may be confounded by inadequate delivery of the regimen. Although much research has focused on broad aspects of compliance dealing with clinical therapeutic situations, there was a need for further research dealing specifically with adherence issues in a long-term chemoprevention trial since subject motivation in the latter is likely to differ from that of the former. Examining subject-reported compliance over the first 2-year treatment periods of a long-term chemoprevention trial for familial adenomatous polyposis, it was found that (1) compliance decreased over time, (2) fiber compliance was lower than vitamin compliance, and (3) four explanatory variables which may be amenable to individualized study-team interventions emerged as useful prognosticators of fiber compliance.     

家族性腺瘤样息肉病中APC基因的胚系突变分析

目的 探索有效的突变检测技术，系统分析家族性腺瘤样息肉病(familial adenomatous polyposis，FAP)相关基因结肠腺瘤病(adenomatous polyposis coli，APC)基因的胚系突变，及其与疾病表型的关系。方法 从22例临床确诊的FAP患者，外周静脉血中提取基因组DNA。变性高效液相色谱、蛋白截短检测、测序技术结合应用进行全基因分析。根据患者临床资料，进行基因型-表型分析。结果 22例FAP患者中13例检出APC基因胚系突变，均为无义或移码突变。基因型-表型关系的初步分析表明，在基因5′端或3′端发生突变的患者临床症状较轻，在基因中段发生突变的患者临床症状典型或严重。结论 本研究中所采用的技术体系可敏感、高效地检出APC基因突变，APC基因的突变型与FAP患者的临床表型存在关联，所采用的技术体系适用于FAP症状出现前的基因诊断。     

应用变性高效液相色谱检测31例家族性腺瘤性息肉病家系结肠腺瘤性息肉病基因突变

目的 应用变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)技术检测我国家族性腺瘤性息肉病(familial adenomatons polyposis,FAP)家系的结肠腺瘤性息肉病(adenoinatous pelyposis coli,APC)基因变异特征,研究其病因机制.方法 采集31个家系的先证者、患者和家系成员的外周血淋巴细胞,抽提DNA并以降落式PCR扩增APC基因各外显子和启动子.基因突变检测先由DHPLC进行筛选,发现异常峰者进行测序鉴定并TA克隆鉴定,结果与网络数据进行比对.结果 31个家系中共有15个家系检出了12种不同的突变类型,FAP家系APC基因的突变检出率为48.39%.发现了4种新的突变及3例不同的内含子突变.4个新的突变分别位于255、677、1192、1403密码子,均为移码突变.证明了DHPLC能检出APC基因的突变.在APC基因的突变中,移码突变占86.67%,无义突变占13.33%,说明移码突变是中国人APC基因突变的主要方式.在突变位点上,第15外显子突变最常见,约占86.67%.结论 FAP家系APC基因的突变检出率为48.39%,发现了4种新的导致蛋白编码改变的突变.证实中国人FAP家系中APC基因突变位点以第15外显子最常见,类型以移码突变为主.     

Predictive testing for familial adenomatous polyposis in a rural South Indian community

During the course of genome studies in a rural community in the South Indian state of Karnataka, DNA-based investigations and counselling for familial adenomatous polyposis (FAP) were requested via the community physician. The proposita died in 1940 and FAP had been clinically diagnosed in 2 of her 5 children, both deceased. DNA samples from 2 affected individuals in the third generation were screened for mutations in the APC gene, and a frame-shift mutation was identified in exon 15 with a common deletion at codon 1061. Predictive testing for the mutation was then organized on a voluntary basis. There were 11 positive tests, including confirmatory positives on 2 persons diagnosed by colonoscopy, and to date surgery has been successfully undertaken on 3 previously undiagnosed adults. The ongoing success of the study indicates that, with appropriate access to the facilities offered by collaborating centres, predictive testing is feasible for diseases such as FAP and could be of significant benefit to communities in economically less developed countries.     

Lung adenocarcinoma associated with familial adenomatous polyposis. Clear cell carcinoma with beta-catenin accumulation accompanied by atypical adenomatous hyperplasia

A 46-year-old man presented with a lung tumor 17 years after a subtotal colectomy and 13 years after a partial duodenectomy for familial adenomatous polyposis (FAP). There had been no malignant transformation in the specimens from his colectomy and duodenectomy, and a current gastrointestinal investigation revealed no evidence of malignancy. Pathological analysis of the lung tumor demonstrated adenocarcinoma with clear cells and a papillary structure, accompanied by tiny tumorous nodules in the background lung parenchyma. Many of the nodules were multifocal adenocarcinoma; however, some of the nodules demonstrated atypical adenomatous hyperplasia (AAH). This is the first case report of a lung adenocarcinoma accompanied by AAH in a FAP patient. Immunohistochemical and loss of heterozygosity studies revealed unique features of the lesions reflecting a disruption of the adenomatous poliposis coli–beta-catenin pathway.     

家族性腺瘤性息肉病与高脂血症的关系

家族性腺瘤性息肉病（familial adenomatous polyposis,FAP）是由APC（adenomatous polyposis coli）基因突变引起的常染色体显性遗传病。高脂血症作为FAP的肠外伴随症状逐渐被关注,同时在FAP的经典模型Apc基因突变的Min小鼠上也出现了高血脂症状。本文从高脂血症、FAP以及APC基因突变的角度,阐述三者的相互联系,期望对病人的预防与治疗提供有价值的参考。     

APC promoter 1B deletion in seven American families with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation‐dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele‐specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42–98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States.     

Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis

A small fraction of families with familial adenomatous polyposis (FAP) display an attenuated form of FAP (AFAP). We aimed to assess the presence of germline mutations in the MUTYH and adenomatous polyposis coli (APC) genes in AFAP families and to compare the clinical features between the two causative genes. Families with clinical AFAP were selected from the Dutch Polyposis Registry according to the following criteria: (a) at least two patients with 10-99 adenomas diagnosed at age >30 years or (b) one patient with 10-99 adenomas at age >30 years and a first-degree relative with colorectal cancer (CRC) with a few adenomas, and, applying for both criteria, no family members with more than 100 polyps before the age of 30 years. All probands were screened for germline mutations in the APC and MUTYH genes. Twenty-five of 315 Dutch families with FAP (8%) met our criteria for AFAP. These families included 146 patients with adenomas and/or CRC. Germline APC mutations were identified in nine families and biallelic MUTYH mutations in another nine families. CRC was identified at a mean age of 54 years (range 24-83 years) in families with APC and at 50 years (range 39-70 years) in families with MUTYH (p = 0.29). APC and biallelic MUTYH mutations are responsible for the majority of AFAP families. Based on our results and those reported in the literature, we recommend colonoscopy once every 2 years in AFAP families, starting surveillance from the late teens in APC mutation carriers and from age 20-25 years in biallelic MUTYH mutation carriers.     

APC germline mutations identified in Czech patients with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited predisposition to colorectal cancer, which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. The APC mutations have been investigated in 46 Czech unrelated FAP families and 9 suspected FAP families using DGGE analysis and direct DNA sequencing. We found 25 germline APC mutations and identified 11 which were not previously reported. Of the identified mutations, 10 were 1 to 5 bp deletions, four were 1 bp insertions and six were nonsense, all leading to the formation of premature stop codon. In addition, we detected two mutations in the splice-donor region of APC intron 11, one missense and two samesense mutations. Phenotypes of patients with known and novel types of mutations are presented and discussed.     

The expression of E-cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with beta-catenin and gamma-catenin and APC mutations are believed to play a role in the altered levels of beta-catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E-cadherin and catenins in colorectal neoplasms and non-neoplastic mucosa from FAP patients. The expression and cellular distribution of E-cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non-neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E-cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E-cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non-neoplastic mucosa.     

Undifferentiated columnar cells in colorectal adenomas and familial adenomatous polyposis

We have observed and defined morphometrically and histochemically groups of undifferentiated columnar cells within the surface epithelium in colorectal mucosa. They were present within both non-polypoid and polypoid mucosa in familial adenomatous polyposis, and within non-hereditary adenomatous polyps of the colon and rectum. The cells show some evidence of proliferative activity and appear similar to cells previously described in the stomach which were proposed as precursors to type 3 sulphomucin-secreting intestinal metaplasia in atrophic gastritis. To our knowledge, these observations have not been previously described. It is possible that the cells represent the cellular basis of the shift in the proliferative zone from the normal site at the crypt base to the colorectal mucosal surface, which is known to precede adenomatous polyp formation. The cells may therefore be involved in the early stages of colorectal adenoma formation.     

Cell proliferation and ultrastructural changes of the duodenal mucosa of patients affected by familial adenomatous polyposis

Patients affected by familial adenomatous polyposis (FAP) are at risk of developing duodenal neoplasia. Our objective was to detect early abnormalities of the epithelial cell proliferation and ultrastructure of apparently normal duodenal mucosa of FAP patients. Biopsy specimens were taken from the duodenal mucosa. Cell proliferation was studied by immunohistochemistry with proliferating cell nuclear antigen (PCNA), and ultrastructure, by transmission electron microscopy. We found that the PCNA labeling index for duodenal mucosa of patients with FAP was higher in comparison to the case of hospital controls without cancer risk (P = 0.019). Moreover, ultrastructural changes related to an impairment of cell adhesion function were found in all biopsies of FAP patients but not in the duodenal mucosa of the controls. We conclude that alterations of cell proliferation kinetics and epithelial adherens junction structures were phenotypic characteristics of histologically normal duodenal mucosa of FAP patients. These abnormalities may be considered as intermediate biomarkers of neoplasia and potential surrogate endpoints in chemoprevention studies.