Familial polyposis coli and its extracolonic manifestations.

A detailed clinical study of 30 families with familial polyposis coli is presented. Seven 'isolated' cases are also described. It was found that some families did not exhibit any extracolonic manifestations, but the majority of families showed various numbers of members who had these manifestations of differing types and degrees. In view of the great variability within the members of a family, polyposis coli and the Gardner syndrome are probably both produced by one pleiotropic gene. The occurrence of other neoplastic phenomena in association with polyposis coli has been considered. Many types of malignancy can occur in these patients and their families and the majority are probably fortuitous. The consistent finding of an association with medulloblastoma is such as to make this association of significance, but no reason is known for this. It is suggested that the term 'Turcot syndrome' should be used in a more restrictive manner than at present.     

Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli

The analysis of APC and MYH mutations in adenomatous polyposis coli patients should provide clues about the genetic heterogeneity of the syndrome in human populations. The entire coding region and intron-exon borders of the APC and MYH genes were analyzed in 60 unrelated Italian adenomatous polyposis coli patients. APC analysis revealed 26 point mutations leading to premature termination, one missense variant and one deletion spanning the entire coding region in 32 unrelated patients. Novel truncating point mutations included c.1176_1177insT (p.His393_PhefsX396), c.1354_1355del (p.Val452_SerfsX458), c.2684C>A (p.Ser895X), c.2711_2712del (p.Arg904_LysfsX910), c.2758_2759del (p.Asp920_CysfsX922), c.4192_4193del (p.Ser1398_SerfsX1407), c.4717G>T (p.Glu1573X) and a novel cryptic APC exon 6 splice site. MYH analysis revealed nine different germline variants in nine patients, of whom five were homozygotes or compound heterozygotes. The mutations included 4 novel MYH missense variants (c.692G>A, p.Arg231His; c.778C>T, p.Arg260Trp; c.1121T>C, p.Leu374Pro; and c.1234C>T, p.Arg412Cys) affecting conserved amino acid residues in the ENDO3c or NUDIX domains of the protein and one novel synonymous change (c.672C>T, p.Asn224Asn). Genotype-phenotype correlations were found in carriers of APC mutations but not in carriers of biallelic MYH mutations, except for a negative correlation with low number of polyps. A distinctive characteristic of patients negative for APC and MYH mutations was a significantly (p<0.0001) older age at diagnosis compared to patients with APC mutations. Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations.     

Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli

Patients with familial adenomatous polyposis coli (FAP) carry heterozygous mutations of the APC gene. At a young age, these patients develop multiple colorectal adenomas that consistently display a second somatic mutation in the remaining APC wild-type allele. Inactivation of APC leads to impaired degradation of beta-catenin, thereby promoting continuous cell-cycle progression. The role of APC inactivation in rare extracolonic tumors of FAP patients has not been characterized sufficiently. Among tissue specimen from 174 patients with known APC germ-line mutations, we identified 8 tumors infrequently seen in FAP. To investigate the pathogenic role of APC pathway deregulation in these lesions, they were analyzed for second-hit somatic mutations in the mutational cluster region of the APC gene. Immunohistochemistry was performed to compare the expression pattern of beta-catenin to the mutational status of the APC gene. Exon 3 of the beta-catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated beta-catenin concentration. Although CTNNB1 mutations were not observed, second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of beta-catenin. No APC mutations were seen in focal nodular hyperplasia of the liver, angiofibrolipoma, and seborrheic wart. This is the first study reporting second somatic APC mutations in FAP-associated uterine adenocarcinoma and epidermal cysts. Furthermore, our data strengthen a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients.     

Mutation analysis of the adenomatous polyposis coli (APC) gene in Danish patients with familial adenomatous polyposis (FAP)

Development of one hundred or more adenomas in the colon and rectum is diagnostic for the dominantly inherited, autosomal disease Familial Adenomatous Polyposis (FAP). It is possible to identify a mutation in the Adenomatous Polyposis Coli (APC) gene in approximately 80% of the patients, and almost 1,000 different pathogenic mutations have been identified in the APC gene up till now. We report 12 novel and 24' previously described germline APC mutations from 48 unrelated Danish families. Four families with the mutation localized in the 3' region of the gene showed great variance in phenotypic presentation.     

Hypertrophic and polypoid gastropathy associated with juvenile adenomatous polyposis coli

Juvenile Polyposis is a syndrome with gastrointestinal polyps and increased cancer risk. The commonest form of this syndrome is inherited as autosomal dominant trait and presents as Familial Juvenile Polyposis Coli. Another variant involves mainly the stomach and another is generalized throughout the gastrointestinal tract. We present the case of two brothers with polyposis coli complicated by colonic cancer. The polyps were of juvenile, adenomatous and mixed types. The two patients after a decade of colonic endoscopic polypectomies presented gastric involvement by polyps and needed multiple endoscopic gastric resections. One brother underwent total gastrectomy. This stomach showed diffuse polyposis of hyperplastic and fundic gland types within an unexpected background of foveolar and glandular hypertrophic gastropathy. The patients at present are followed up with endoscopic procedures.     

Mutation analysis of the adenomatous polyposis coli (APC) gene in northwest Spanish patients with familial adenomatous polyposis (FAP) and sporadic colorectal cancer

Germline mutations in the tumor‐suppresor APC gene are associated with hereditary familial adenomatous polyposis (FAP) and somatic mutations are common in sporadic colorectal cancer. In this study, we report the identification of three novel germline mutations: 1682‐1683insA, 3252‐3253insAT, 3544A>T and a new somatic mutation 4130‐4131delTT, all giving rise to truncated APC proteins. The majority of the mutations we found originate a truncated APC protein and cause the FAP phenotype. However, special attention must be given to the missense mutations Asp1822Val and Ser2621Cys since their segregation with the FAP phenotype is questionable. In our FAP families we did not find any genetical alterations at codon 1309, being this mutation the most frequent reported in APC. Differences in the recurrence of pathological mutations in APC could exist among populations. However, epidemiological studies must be performed to confirm this hypothesis. Hum Mutat 18:355, 2001. © 2001 Wiley‐Liss, Inc.     

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.     

家族性结肠息肉病患者的诊断及治疗

目的探讨家族性结肠息肉病的临床表现规律，为其早期诊断及正确治疗提供依据。方法总结家族性结肠息肉病患者的临床资料，对其病因、癌变、早期诊断及治疗等方面进行探讨。结果家族性结肠息肉病是由于基因突变所致，突变谱的不同决定了其临床表现的多样性。家族性结肠息肉病是一种癌前期病变，具有较高的癌变率；纤维结肠镜检查是家族性结肠息肉病早期诊断的一种行之有效的方法；合理的手术治疗可以取得满意的疗效。结论家族性结肠息肉病是一种遗传性疾病，癌变率较高，早期诊断、合理治疗可以取得满意的疗效。     

Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients

The authors of the above paper wish to note that the codon correspondingto the mutation at the nucleotide 4921 is given incorrectlyin the text and in the legend to Figure 1; it should read 1641(not 1841).     

Del(10)(q22.3q24.1) associated with juvenile polyposis

Juvenile polyps are the most frequent gastrointestinal polyps with a malignant potential for which the genetic basis is unknown. Juvenile polyps, with a normal epithelium but hypertrophic lamina propria, are histologically quite distinct from adenomatous polyps which have dysplastic changes in epithelial nuclei. Furthermore, the adenomatous polyposis coli (APC) gene on Chr 5, mutated somatically in adenomatous polyps and mutated in the germline of patients with familial adenomatous polyposis, is not linked to hereditary juvenile polyposis. We provide the first report indicating that a tumor suppressor gene associated with juvenile polyposis may be located at 10q22.3q24.1. Cytogenetic studies of a patient with juvenile polyposis and multiple congenital abnormalities of the head, extremities, and abdomen revealed a de novo interstitial deletion of Chr 10 as the only defect, del(10)(10q22.3q24.1). Am. J. Med. Genet. 70:361–364, 1997. © 1997 Wiley-Liss, Inc.     

Increased chromosome breakage by N-methyl-N1-nitro-N-nitrosoguanidine in patients with adenomatous polyposis coli

In a search for hypersensitivity to chromosome breaking agents, lymphocytes and fibroblasts from patients with the precancerous condition adenomatous polyposis coli (APC) were treated with N-methyl-N1-nitro-N-nitrosoguanidine (MNNG) and bleomycin. The APC cells showed a significantly increased level of chromatid-type damage following MNNG treatment (5 micrograms/ml for lymphocytes, 1 or 2 micrograms/ml for fibroblasts). No such differential effect was noted for bleomycin, but a threefold increase in "pulverized" cells was seen in APC lymphocyte cultures treated in G0, that is before cells have entered the cell cycle. Increased spontaneous and induced chromosome instability appears to be an important effect of the APC mutant gene as molecular evidence suggests that chromosomal mechanisms are likely to play a major role in tumorigenesis both in this condition and in sporadic colorectal cancer.     

Frequent mutation in North African patients with MUTYH‐associated polyposis

Lefevre JH, Colas C, Coulet F, Baert‐Desurmont S, Mongin C, Tiret E, Frebourg T, Soubrier F, Parc Y. Frequent mutation in North African patients with MUTYH‐associated polyposis. MUTYH‐associated polyposis (MAP) has been characterized as an autosomal recessive disease predisposing to a variable number of colorectal adenomas with a high risk of cancer. Numerous studies have indicated that two missense mutations (Y179C and G396D) account for about 80% of MUTYH allelic variants in Europeans. Ethnic and geographic differences in the mutation spectrum have been observed. The aim of this study was to report mutations in patients from North Africa, determine the incidence of the c.1227_1228dup mutation in our cohort of MUTYH patients and to evaluate the existence of a founder effect. Within a group of 36 families with MAP, 11 were shown to have a homozygous c.1227_1228dup mutation. These families came from Algeria (n = 5), Tunisia (n = 4), Morocco (n = 1) and Portugal (n = 1). Probands belonging to families of North African origin showed a significantly higher frequency of c.1227_1228dup (78.6% vs 4.5%, p < 0.0001). Haplotype analyses were performed using 10 microsatellite markers surrounding the MUTYH gene spanning a region of 4.4 cM. We identified a common haplotype of at least 1.3 cM in all families suggesting a founder effect for this mutation.     

Familial adenomatous polyposis coli: five novel mutations in exon 15 of the adenomatous polyposis coli (APC) gene in Italian patients. Mutations in brief no. 225. Online

Germline mutations within the adenomatous polyposis coli (APC) gene, a tumor suppressor gene, are responsible for most cases of familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer. To date, more than 300 germ-line causative mutations within this gene have been described (Beroud and Soussi, 1996). Of these, about 95% are chain-terminating mutations, and more than 60% have been localized within exon 15 (Nagase and Nakamura, 1993, Beroud and Soussi, 1996). Using polymerase chain reaction-single strand conformation polymorphism, protein truncation test (PTT) and DNA sequencing we have identified five new frameshift mutations (2523insCTTA, 2638delA, 2803insA, 3185delAA, 4145delTCATGT), all occurring within exon 15 and giving rise to truncated protein products. Two of these new mutations are of particular interest because of the unusual phenotypic features shown by probands. The phenotype of the proband bearing the 2523insCTTA mutation at codon 842 was very aggressive with onset of the symptoms at 12 years, while the patient bearing the 3185delAA mutation at codon 1062 exhibited features of an attenuated form of FAP (AAPC). Our data reiterate the great heterogeneity of the mutational spectrum in FAP that gives rise to an extreme variability of the clinical expression.     

Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene.

The APC gene was investigated in 31 unrelated polyposis coli families by SSCP analysis and the protein truncation test. Twenty-three germline mutations were identified which gave rise to a variety of different phenotypes. Some of these mutations have already been described; however we report six previously unpublished mutations. Typical disease symptoms were observed in families who harboured mutations between exon 4 (codon 169) and codon 1393 of exon 15. Mutations beyond codon 1403 were associated with more varied phenotype with respect to the development of extracolonic symptoms. In this report we provide support for the notion that there appears to be a correlation between the location of an APC mutation (beyond codon 1403) and extracolonic manifestations of familial adenomatous polyposis.     

Association of adenomatous polyposis coli (APC) gene polymorphisms with autism spectrum disorder (ASD).

We serendipitously identified a single nucleotide polymorphism (SNP), 8636C>A (rs1804197) in the 3'-untranslated region of the adenomatous polyposis coli (APC) gene to be associated with autism spectrum disorder (ASD). In order to gain further evidence for the association between the APC locus and ASD, we genotyped four additional adjacent common SNPs (rs2229992, rs42427, rs459552, and rs465899) in the coding regions within the APC gene in a set of Swedish ASDs and controls. One common haplotype TGAG was found to be associated with ASD after haplotype analysis using both Haploview v3.1.1 (P = 0.006) and COCAPHASE v2.403 (P = 0.030). This result is the first to suggest that the genomic locus at APC is associated with ASD, and that the APC gene itself is a good predisposing candidate to be evaluated in future studies due to its important role in neuronal development and function.     

Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia

The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in most sporadic colorectal tumors. During both embryonic and postnatal periods, APC is widely expressed in a variety of tissues, including the brain and gastrointestinal tract. The APC gene product (APC) is a large multidomain protein consisting of 2843 amino acids. APC downregulates the Wnt signaling pathway through its binding to β-catenin and Axin. Most mutated APC proteins in colorectal tumors lack the β-catenin-binding regions and fail to inhibit Wnt signaling, leading to the overproliferation of tumor cells. Several mouse models (APC ^580D , APC ^Δ716 , APC ¹³⁰⁹ , APC ^Min , APC ^1638T ) have been established to investigate carcinogenesis caused by APC mutations. APC also binds to APC-stimulated guanine nucleotide exchange factor, the kinesin superfamily-associated protein 3, IQGAP1, microtubules, EB1, and discs large (DLG). APC has both nuclear localization signals and nuclear export signals in its molecule, suggesting its occasional nuclear localization and export of β-catenin from the nucleus. APC is highly expressed in the intestinal and colorectal epithelia and may be involved in homeostasis of the enterocyte renewal phenomena, in which proliferation, migration, differentiation, and apoptosis are highly regulated both temporally and spatially. Through the many binding proteins mentioned, APC can exert multiple functions involved in epithelial homeostasis.     

Adenomatous polyposis coli (APC) protein expression in primary and metastatic serous ovarian carcinoma

The aim of this study was to investigate protein expression of adenomatous polyposis coli (APC) in primary and metastatic serous ovarian carcinoma. The expression of beta-catenin and E-cadherin was additionally analyzed. One hundred and thirteen primary (n = 56) and metastatic (n = 57) lesions were immunohistochemically stained for APC, E-cadherin, and beta-catenin. Staining extent was scored. Possible differences in immunoreactivity in primary and metastatic sites and the association between the proteins analyzed were evaluated statistically. Cytoplasmic immunoreactivity for APC was found in 67/113 (59%) tumors, most often in the majority (> 50%) of cells. E-cadherin was detected in 102/113 (90%) carcinomas, while beta-catenin was expressed in 109/113 (97%) specimens. Nuclear expression of beta-catenin was seen in 3/113 (3%) specimens, all negative for APC. APC and beta-catenin were often coexpressed, but this finding failed to reach statistical significance (p = 0.11). A significant association was seen between E-cadherin and beta-catenin expression (p = 0.001). APC expression was comparable in primary and metastatic tumors (p > 0.05). In conclusion, APC expression is absent in a considerable number of both primary and metastatic ovarian carcinomas, but this finding is only rarely coupled to nuclear accumulation of beta-catenin. These findings support the role for beta-catenin signaling via the Wingless/Wnt pathway in ovarian carcinoma. The mechanism behind the down-regulated expression of APC in serous ovarian carcinoma and its significance has yet to be elucidated.     

Toll-like receptor (TLR) 4 polymorphism Asp299Gly is not associated with disease course in Dutch sarcoidosis patients

The aetiology of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas in variable organs, remains enigmatic. Clarification is hampered by heterogeneity in disease phenotypes and course, due partly to the influence of a variety of genetic and environmental factors. Multiple studies have pointed towards bacteria as possible causative agents. Toll-like receptors (TLR) are innate immunity receptors important in the immune response against pathogens. TLR-4, together with CD14 and MD-2, is an essential receptor for the recognition of lipopolysaccharide (LPS), unique to the cell wall of Gram-negative bacteria. Recently, an association between TLR-4 polymorphism Asp299Gly, leading to a change in the extracellular domain of the receptor and possible hyporesponsiveness to LPS, and a chronic course of sarcoidosis was found in German patients. In the present study this polymorphism was genotyped in 156 Dutch sarcoidosis patients and 200 healthy Dutch controls using dual-labelled fluorescent oligonucleotides. No differences were found in allelic distributions between patients and controls (P = 0.79) or within the different clinical entities of the sarcoidosis group (P = 0.44). Importantly, there were no differences between the Dutch and German sarcoidosis patients (P = 0.62). However, the allelic distribution of the Asp299Gly polymorphism differed significantly between both control groups (P = 0.04). This study highlights the importance of testing a reported gene association in a distinct population when performing genetic association studies.