Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation

Familial adenomatous polyposis (FAP) is a rare syndrome characterized by the presence of hundreds to thousands of colorectal adenomas and is responsible for less than 1% of all colorectal cancers. The syndrome is also characterized by extra-colorectal features including amongst others upper gastrointestinal tract polyps and desmoid tumors. The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene. We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors.     

Novel germline APC mutations in Swedish patients with familial adenomatous polyposis and Gardner syndrome

BACKGROUND: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. METHODS: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. RESULTS: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. CONCLUSIONS: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.     

Novel Germline APC Mutations in Swedish Patients with Familial Adenomatous Polyposis and Gardner Syndrome

Background: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. Methods: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. Results: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. Conclusions: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.     

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.     

Desmoid tumours in familial adenomatous polyposis.

Desmoids are rare, benign fibromatous lesions, which can arise in patients with familial adenomatous polyposis (FAP), a disorder caused by germline adenomatous polyposis coli (APC) gene mutation. This study investigated the risk of desmoids in FAP, the relation between specific APC gene mutations and desmoid formation, and the clinical characteristics of FAP patients with desmoids. Eighty three of 825 FAP patients (10%) from 49 of 161 kindreds (30%) had desmoids. The absolute risk of desmoids in FAP patients was 2.56/1000 person years; comparative risk was 852 times the general population. APC gene mutations were similar in families with and without desmoids. The female/male ratio was 1.4 (p = NS). Previous abdominal surgery was noted in 68% of patients with abdominal desmoids (55% developed within five years postoperatively). Desmoid risk in FAP family members of a desmoid patient was 25% in first degree relatives v 8% in third degree relatives. Desmoids are a comparatively common complication of FAP associated with surgical trauma and familial aggregation. Desmoid development was not linked to specific APC gene mutations and was not found predominantly in women. Studies of chemopreventive therapy, given within five years after abdominal surgery, should be considered in FAP patients with a family history of desmoid disease.     

Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature

Mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP). Disease severity and the presence of extracolonic manifestations seem to be correlated with the location of the mutation on the APC gene. In this review, large studies describing genotype-phenotype correlations in FAP were evaluated and categorized. Attenuated FAP (AFAP, <100 colorectal adenomas) is correlated with mutations before codon 157, after codon 1595 and in the alternatively spliced region of exon 9. Severe polyposis (>1000 adenomas) is found in patients with mutations between codons 1250 and 1464. Mutations in the remainder of the APC gene cause an intermediate phenotype (hundred to thousands of adenomas). Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and desmoid tumours are associated with mutations between codons 311 and 1444 and after codon 1444, respectively. No consistent correlations were found for upper gastrointestinal tumours. Genotype-phenotype correlations in FAP will be useful in decisions concerning screening and surgical management of FAP.     

3' Mutation of the APC gene and family history of FAP in a patient with apparently sporadic desmoid tumors

Desmoid tumors may occur sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis. Different phenotypes have been described and some genotype-phenotype correlations have been raised, associated with different sites of germline mutations in the adenomatous polyposis coli (APC) gene. We report on a 42-year-old woman ascertained for a large desmoid tumor of the anterior chest wall with pleural involvement, which persistently recurred despite a decade of treatment including hormone therapy, chemotherapy, and surgery. Spontaneous disappearance of the tumor was later noted after 1 year without any treatment and confirmed after 4 years of regular follow-up. Repeated colonoscopies were normal in the proband and DNA sequencing showed a frameshift mutation due to a single adenosine deletion at position 5772 (codon 1924). This mutation, located in the exon 15 at the 3' end of the APC gene, leads to an unusual and late onset phenotype. The pedigree revealed other isolated or familial adenomatous polyposis-associated cases of desmoid tumors. This family report shows that a molecular analysis of the APC gene should be performed in familial desmoid tumors for accurate genetic counseling and follow-up.     

An unexpected Cowden syndrome case found among members of a large familial adenomatous polyposis kindred

Genetic testing is now considered the standard of care in the management of familial adenomatous polyposis (FAP). Non-carriers of mutations are excluded from endoscopic surveillance. During the systematic screening of the relatives of an affected member with FAP, one non-carrier of APC mutations was unexpectedly found with the typical Cowden syndrome phenotype. One large Algerian family with FAP was screened for an APC germline mutation. Moreover, we also performed a mutation search in the Cowden syndrome member for PTEN, BMPR1A or MADH4 (SMAD4) germline mutations. We identified a mutation in the APC gene that results in a truncated protein (Y935X) in the FAP proband, and subsequently in 12 FAP-affected members. Among the 12 APC mutation-negative members of this family, we found one member with the Cowden disease phenotype. However, the mutation analysis in the PTEN gene and the two other genes involved in juvenile polyposis, namely BMPR1A and MADH4 (SMAD4), in the Cowden syndrome patient failed to show any pathogenic mutation. Genetic testing is a powerful tool that can provide a definitive diagnosis for FAP. However, not all polyposes in the FAP family are adenomatous polyposes.     

Hepatoblastoma and APC gene mutation in familial adenomatous polyposis.

BACKGROUND: Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An association between hepatoblastoma and familial adenomatous polyposis (FAP), which is due to germline mutation of the APC (adenomatous polyposis coli) gene, has been confirmed, but correlation with site of APC mutation has not been studied. AIM: To analyse the APC mutational spectrum in FAP families with hepatoblastoma as a possible basis to select kindreds for surveillance. PATIENTS: Eight patients with hepatoblastoma in seven FAP kindreds were compared with 97 families with identified APC gene mutation in a large Registry. METHODS: APC gene mutation was evaluated by RNase protection assay or in vitro synthesis protein assay. The chi 2 test and correlation were used for data analysis. RESULTS: APC gene mutation was identified in all seven FAP kindreds in which an at risk member developed hepatoblastoma. A male predominance was noted (six of eight), similar to literature cases (18 of 25, p < 0.01. Mutations were restricted to codons 141 to 1230, but no significant difference in site of mutation between pedigrees with and without hepatoblastoma was identified. CONCLUSIONS: Hepatoblastoma occurs primarily in boys in FAP kindreds and is associated with germline APC mutation in the 5' end of the gene. However, the site of APC mutation cannot be used to predict occurrence of this extracolonic cancer in FAP pedigrees.     

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a...     

Analysis of Wnt/Beta catenin signalling in desmoid tumors

Desmoid tumors are fibromatous lesions occurring both sporadically and in patients with familial adenomatous polyposis (FAP). Because of the association of these tumors with the hereditary colorectal cancer syndrome FAP we set out to define the molecular events driving desmoid tumorigenesis, hypothezising these might be identical to events driving colorectal tumorigenesis. We found that whereas FAP-associated desmoid tumors are caused by germline APC mutations followed by somatic inactivation of the wild-type APC allele, sporadic desmoids are usually characterized by oncogenic mutations in the b-catenin gene, both identical molecular alterations to those found in the vast majority of colorectal cancers. Next we set out to investigate the cellular pathways activated by these mutations, and identified activation of the Wnt signaling pathway in desmoid tumors. Wnt signaling modulates expression of developmental genes and cell fate via beta-catenin, and has been implicated in many cancer types. Currently we are investigating tissue-specific downstream effectors of the Wnt pathway that might be responsible for the behaviour of these invasive fibrous tumors. Our findings also point to a role for this pathway in the regulation of normal myofibroblast proliferation and suggest novel treatments in desmoid tumors and other fibrous proliferative disorders.     

Characterization of APC exon 15 germ-line mutation in FAP family with severe phenotype showing extracolonic symptoms

The adenomatous polyposis coli (APC) gene plays a crucial role in colorectal carcinogenesis. Germ-line mutations of APC gene give rise to familial adenomatous polyposis coli (FAP) - autosomal dominant syndrome manifesting hundreds to thousands of colorectal polyps, if untreated with malignant progression. We have used the techniques of heteroduplex analysis (HDA), protein truncation test (PTT), single strand conformation polymorphism (SSCP) and DNA sequencing for the identification and detailed positional analysis of mutations in IFAP family with the expressive phenotype characterized by polyposis and extracolonic lesions. Detailed analysis revealed a 5bp deletion in a mutation cluster region (MCR) in exon 15 of APC gene in codon 1308. Two screened members of the FAP family exhibited this novel mutation.     

Familial adenomatous polyposis: genetics and epidemiology

Familial adenomatous polyposis (FAP) is a rare genetic disease characterised by the development of hundreds to thousands of adenomatous polyps along the colon-rectum leading to cancer at a young age, if left untreated. In 1991, the gene responsible for the vast majority of FAP cases, the adenomatous polyposis coli (APC) gene, was identified. In 5-30% of FAP patients, no APC mutation is identifiable by current genetic testing. In 2003, it was shown that 'APC-negative' FAP patients may carry biallelic mutations in a different gene, the MYH gene. Genetics of FAP will be discussed in relation to its present clinical applications. If the hereditable mutation(s) is/are known in a family, it is possible to plan endoscopic surveillance only for those who actually inherited the mutation(s). Also, genetic testing may be of help in the diagnosis of atypical adenomatous polyposis cases and in the clinical management of affected individuals.     

Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression

OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS: APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.     

五个家族性腺瘤性息肉病家系分析

目的分析5个家族性腺瘤性息肉病（FAP）家系,总结常染色体显性遗传规律。 方法对5个FAP家系进行调查分析,取外周血、粪便行全外显子组测序（WES）筛查大肠癌基因,行结肠镜检查并取活体组织进行病理分析。 结果5个家系中,连续几代发生FAP,当父亲或者母亲患FAP后,其子代发生FAP的概率均等（50%）,无性别差异,发病者均存在腺瘤样结肠息肉病基因（APC）突变,未成年人中未见发病,部分患者患有2种以上肿瘤。 结论在有FAP病史的家系中,未成年人一般不发病,成年后均需要进行APC基因检测及结肠镜检查,一旦发现腺瘤需要尽早进行内镜下治疗,避免结直肠癌的发生。     

Familial desmoids in association with adrenal and ovarian masses and leiomyomas

PURPOSE: Desmoid tumors are rare occurrences. However, they are more commonly seen in patients with familial adenomatous polyposis. The purpose of this article is to review three cases of abdominal desmoids in association with adrenal, ovarian masses, leiomyoma, and neurologic involvement in three sisters with familial adenomatous polyposis. METHOD: A case study was done of these sisters, their siblings, and their parents. RESULTS: All three sisters had desmoid tumors and no evidence of familial adenomatous polyposis. All three sisters had ovarian pathology, two had adrenal masses, one had a fibroadenoma of the breast, one had a leiomyoma of the stomach, and two had neurologic involvement. Additionally, male siblings, parents, and grandparents had no evidence of desmoids or familial adenomatous polyposis. CONCLUSION: This constellation of symptoms in the affected sisters may reflect a separate gene defect predisposing to desmoid tumors or a varying expression of the adenomatous polyposis coli gene.     

Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In the present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of desmoid neoplasms) associated with an unusual mutation of the adenomatosis polyposis coli gene. If confirmed by other investigations, these findings might help to understand the biologic mechanisms by which specific adenomatosis polyposis coli mutations predispose to desmoid tumors. METHODS: The family with familial adenomatous polyposis, living in southern Italy, was studied from 1985 to the end of 1999; at this date, 15 individuals have been affected by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors. A total of 19 family members were studied for adenomatosis polyposis coli gene mutations; 13 of them tested positive and 6 negative. The analytical procedure-previously described-consisted of the extraction of peripheral blood cell DNA, amplification of exon 15 by polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing of the DNA fragment containing the mutation. RESULTS: The main clinical features of the family were 1) a high frequency of desmoid tumors and, consequently, a high penetrance of the desmoid trait in all branches of the family and in 11 (73.3 percent) of 15 affected individuals and 2) severity of desmoids in at least 4 family members, 2 of whom died for causes related to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting of a large deletion of 310 base pairs at codon 1,464, with duplication of the breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the adenomatosis polyposis coli gene at the beginning of the region frequently associated with desmoids induced a familial adenomatous polyposis phenotype featured by a high penetrance of the desmoid trait, with severe disease in several affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli.     

Clinicopathological features of familial adenomatous polyposis in Korean patients

AIM: To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations. METHODS: One hundred thirty-five patients who underwent surgical procedures for familial adenomatous polyposis(FAP) were included. FAP was diagnosed when the number of adenomatous polyps was 100. Data related to patient, extracoloic manifestations, cancer characteristics, operative procedure, follow up and surveillance were collected. APC mutation testing was performed in the 30 most recent patients. DNA was extracted from peripheral blood and polymerase chain reaction products using 31 primer pairs on APC gene were sequenced. A retrospective study was performed to investigate a causal relationship between prognosis and feature of patient.RESULTS: The mean age of the 51 patients with colorectal cancer(CRC) was older than that of those without CRC(30.5 vs 36.9, P = 0.002). Older individuals were more likely to have colon cancer at the time of FAP diagnosis [odds ratio, 4.75(95%CI: 1.71-13.89) and 5.91(1.76-22.12) for 40-49 years and age 50 vs age 30). The number of confirmed deaths was 13 and the median age at death was 40 years(range, 27 to 85 years). Ten of the deaths(76.9%) were from CRC. Another cause of two cases of death were desmoid tumors(15.4%). Development of cancer on remnant rectal or ileal mucosa after surgery was not observed. The APC mutation testing revealed 23 pathogenic mutations and one likely pathogenic mutation, among which were four novel mutations. The correlation between mutational status and clinical manifestations was investigated. Mutations that could prodict poor prognosis were at codon 1309 which located on mutation cluster region, codon 1465 and codon 1507.CONCLUSION: Identification of APC mutations should aid in the diagnosis and counseling of family members in terms of early diagnosis and management of FAP.     

APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. AIMS: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. METHODS: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. RESULTS: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. CONCLUSIONS: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).