Familial Adenomatous Polyposis (FAP)


Familial Adenomatous Polyposis (FAP) is a genetic condition characterized by multiple (>100) adenomatous polyps in the colon and rectum typically developing after the first decade of life. FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner Syndrome. Individuals with FAP have an increased risk of colorectal cancer and other tumours (see risks below).

Most cases of FAP are caused by mutations of the APC gene on chromosome 5q21. FAP is an autosomal dominant condition - this means that affected persons are genetically heterozygous (having both a good and a mutated copy of the APC gene), each offspring of a patient with FAP has a 50% chance of inheriting FAP. Males and females are equally likely to be affected. A diverse range of different mutations APC have been reported in FAP including insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in transcription.

Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (9)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

APC 5q21-q22 GS, DP2, DP3, BTPS2, DP2.5, PPP1R46 -APC and Adenomatous Polyposis Coli
MUTYH 1p34.1 MYH -MUTYH and Adenomatous Polyposis Coli
SMAD4 18q21.1 JIP, DPC4, MADH4, MYHRS -SMAD4 and Adenomatous Polyposis Coli
BMPR1A 10q22.3 ALK3, SKR5, CD292, ACVRLK3, 10q23del -BMPR1A and Adenomatous Polyposis Coli
MCC 5q21 MCC1 -MCC and Adenomatous Polyposis Coli
AXIN2 17q24.1 AXIL, ODCRCS -AXIN2 and Adenomatous Polyposis Coli
PLA2G2A 1p35 MOM1, PLA2, PLA2B, PLA2L, PLA2S, PLAS1, sPLA2 -PLA2G2A and Adenomatous Polyposis Coli
POLD1 19q13.3 CDC2, MDPL, POLD, CRCS10 -POLD1 and Adenomatous Polyposis Coli
CTBP1 4p16 BARS -CTBP1 and Adenomatous Polyposis Coli

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Risk of Cancer in FAP

People who inherit a mutant APC gene have over 90% likelihood of developing colonic adenomas. Age at onset of adenomas in the colon varies: 15% by age 10, 75% by age 20, and 90% by 30. Without intervention, most individuals with FAP will develop colon or rectal cancer by the fourth decade of life. APC gene mutation carriers are monitored, typically with regular sigmoidoscopy beginning around puberty.

In addition to increased risk of colorectal cancer, individuals with FAP have increased risk of:

MalignancyRelative RiskAbsolute Lifetime Risk (%)

Source: Genetics of Colorectal Cancer, National Cancer Institute (accessed 31/12/14).

Latest Publications (FAP genetics)

Church J, Xhaja X, LaGuardia L, et al.
Desmoids and genotype in familial adenomatous polyposis.
Dis Colon Rectum. 2015; 58(4):444-8 [PubMed] Related Publications
BACKGROUND: Desmoid disease can be a serious, life-threatening complication of familial adenomatous polyposis. The ability to predict patients at increased desmoid risk is important, but a convincing genotype-phenotype correlation for desmoid formation has not yet been described.
PURPOSE: The aim of this study is to assess the relationship between desmoid disease and genotype in patients with familial adenomatous polyposis.
DESIGN: This is a cohort study.
PATIENTS: All patients with familial adenomatous polyposis and a documented pathogenic APC mutation in themselves or a first-degree relative were selected.
MAIN OUTCOMES MEASURES: The comparison of genotype and the presence, stage, and site of desmoid disease are the primary end points of this study.
RESULTS: Three hundred twenty-three patients from 219 families were identified. Mutations spanned the length of the gene, from codon 213 to codon 2051. Desmoid disease was diagnosed in 77 patients from 68 families. Desmoid disease was found in 14.9% of patients with a mutation 5' of codon 400, 23.2% of patients with a mutation from codon 401 to 1400, and in 37.1% of those with a mutation 3' of 1400. All patients with 5' mutations had stage I or II abdominal desmoid disease, and all tumors were stable or shrinking. Twelve percent of patients who had desmoid disease with mutations between codons 400 and 1400 had stage III or IV desmoid disease, and 5 of 42 (12%) tumors were growing at the time of the study. There had been 2 desmoid-related deaths. Almost half (44%) of patients who had desmoid disease with mutations 3' of codon 1400 had stage III or IV disease. Three of 14 tumors were growing (21%), and there were 4 desmoid-related deaths.
LIMITATIONS: This study was conducted at a tertiary referral center, and there was no systematic surveillance for desmoids.
CONCLUSION: Desmoid disease occurs in patients who have familial adenomatous polyposis with almost any APC mutation, although there is an increased propensity in those with a 3' mutation. The incidence and severity of the desmoid disease are related to the site of the mutation.

Weren RD, Venkatachalam R, Cazier JB, et al.
Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.
J Pathol. 2015; 236(2):155-64 [PubMed] Related Publications
Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC.

Syngal S, Brand RE, Church JM, et al.
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
Am J Gastroenterol. 2015; 110(2):223-62; quiz 263 [PubMed] Related Publications
This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Zhang M, Wang Z, Lin Y, et al.
[Analysis of APC gene mutation in a familial adenomatous polyposis pedigree].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(6):757-60 [PubMed] Related Publications
OBJECTIVE: To analyze mutation of adenomatous polyposis coli (APC) gene in a family affected with familial adenomatous polyposis.
METHODS: The diagnosis was made based on clinical manifestations, family history, presence of numerous polyps in the colon as well as pathological examination. Peripheral blood samples were collected, and genomic DNA was extracted. Potential mutation of the APC gene was detected by polymerase chain reaction (PCR) and DNA sequencing. After finding the mutation in the proband, the same mutation was screened among other family members. The mutation was also confirmed with PCR-restriction fragment length polymorphism (RFLP), with which 100 unrelated healthy controls were examined.
RESULTS: A novel heterozygous nonsense mutation c.2891T>G (L964X) of the APC gene was identified in this pedigree. The mutation has led to premature termination of translation. The same mutation was not detected among the 100 healthy controls.
CONCLUSION: The c.2891T>G (L964X) of the APC gene probably underlies the familial adenomatous polyposis in this pedigree. The combined DNA sequencing and PCR-RFLP method is efficient and accurate for the diagnosis.

Yamaguchi T, Koizumi K, Arai M, et al.
A large deletion of chromosome 5q22.1-22.2 associated with sparse type of familial adenomatous polyposis: report of a case.
Jpn J Clin Oncol. 2014; 44(12):1243-7 [PubMed] Related Publications
The proband was a 32-year-old man with sparse type of familial adenomatous polyposis with fundic gland and duodenal polyps and congenital hypertrophy of the retinal pigment epithelium without osteoma, dental abnormalities and desmoid tumors. Direct DNA sequencing did not detect germline mutations in any APC exon. However, using the multiplex ligation-dependent probe amplification method, we detected germline deletions of all APC exons. Using dual-color fluorescence in situ hybridization, we identified germline deletion of locus 5q22.1-22.2 that includes APC. Analysis of colorectal tumors identified somatic APC mutations in the cluster region in all polyps, but no loss of heterozygosity was detected in any polyp.

Horpaopan S, Spier I, Zink AM, et al.
Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis.
Int J Cancer. 2015; 136(6):E578-89 [PubMed] Related Publications
To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (β-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant.

Russo A, Catania VE, Cavallaro A, et al.
Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.).
Int J Surg. 2014; 12 Suppl 2:S125-9 [PubMed] Related Publications
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported. In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment. We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP.

Modica S, Cariello M, Morgano A, et al.
Transcriptional regulation of the intestinal nuclear bile acid farnesoid X receptor (FXR) by the caudal-related homeobox 2 (CDX2).
J Biol Chem. 2014; 289(41):28421-32 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Farnesoid X receptor (FXR, NR1H4) is a bile acid-activated transcription factor that belongs to the nuclear receptor superfamily. It is highly expressed in the enterohepatic system, where it senses bile acid levels to consequently reduce their synthesis while inducing their detoxification. Bile acids are intestinal tumor promoters and their concentrations have to be tightly regulated. Indeed, reduced expression of FXR in the intestine increases colorectal cancer susceptibility in mice, whereas its activation can promote apoptosis in genetically modified cells. Notably, despite the broad knowledge of the FXR enterohepatic transcriptional activity, the molecular mechanisms regulating FXR expression in the intestine are still unknown. Herein, by combining both gain and loss of function approaches and FXR promoter activity studies, we identified caudal-related homeobox 2 (CDX2) transcription factor as a positive regulator of FXR expression in the enterocytes. Our results provide a putative novel tool for modulating FXR expression against bile acid-related colorectal cancer progression.

Abbruzzese C, Diodoro MG, Sperduti I, et al.
Detection of phosphorylated insulin receptor in colorectal adenoma and adenocarcinoma: implications for prognosis and clinical outcome.
J Cell Physiol. 2015; 230(3):562-7 [PubMed] Related Publications
Colorectal carcinoma remains among the most frequent causes of cancer death. Besides the well-known genetic predisposition, a key role in colorectal adenoma and adenocarcinoma etio-pathogenesis, mainly in sporadic cases, is played by definite risk factors, such as obesity, type 2 diabetes, insulin resistance, hyper-insulinemia, and insulin therapy. These epidemiological data motivated us to determine, by means of immunohistochemistry, the amount of activated (phosphorylated) insulin receptor in archival samples from 22 colorectal adenoma and 117 adenocarcinoma patients, with the objective to estimate the role of this factor in colorectal epithelium transformation and cancer progression. Statistical analysis of the results clearly showed that positive staining for phosphorylated insulin receptor was significantly more frequent in adenomas than adenocarcinomas (P < 0.0001) and, within the adenocarcinoma cohort, it was more frequent in low-grade tumors (P = 0.005). In adenomas, staining was exclusively cytoplasmic, while in adenocarcinomas it was cytoplasmic and/or nuclear (P < 0.0001). Interestingly, disease-free survival in colorectal adenocarcinoma patients pointed out a significantly better prognosis for those bearing a positive staining for phosphorylated insulin receptor (P = 0.02). From these data, we can argue that activated insulin receptor plays a fundamental role at the early stages of tumorigenesis, where late stages could be characterized by a shift toward more active oncogenic drivers. Determining the amount of phosphorylated insulin receptor could thus represent a novel prognostic/predictive tool in colorectal adenocarcinoma patients.

Siraj AK, Bu R, Prabhakaran S, et al.
A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.
Mol Cancer. 2014; 13:168 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
BACKGROUND: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group.
METHODS: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing.
RESULTS: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen).
CONCLUSION: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.

Pope JL, Ahmad R, Bhat AA, et al.
Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis.
Mol Cancer. 2014; 13:167 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
BACKGROUND: The tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this regard, we have demonstrated that claudin-1 expression in colon cancer cells potentiates their tumorigenic ability while in vivo expression of claudin-1 in the intestinal epithelial cells (IECs) promotes Notch-activation, inhibits goblet cell differentiation and renders susceptibility to mucosal inflammation. Notably, a key role of inflammation in colon cancer progression is being appreciated. Therefore, we examined whether inflammation plays an important role in claudin-1-dependent upregulation of colon carcinogenesis.
METHODS: APCmin mice were crossed with Villin-claudin-1 transgenic mice to generate APC-Cldn1 mice. H&E stained colon tissues were assessed for tumor number, size and histological grade. Additionally, microarray and qPCR analyses of colonic tumors were performed to assess molecular changes due to claudin-1 expression. APC-Cldn1 and APCmin controls were assessed for colonic permeability via rectal administration of FITC-dextran, and bacterial translocation via qPCR analysis of 16S rDNA.
RESULTS: Claudin-1 overexpression in APCmin mice significantly increased (~4-fold) colonic tumor growth and size, and decreased survival. Furthermore, transcriptome analysis supported upregulated proliferation, and increased Wnt and Notch-signaling in APC-Cldn1 mice. APC-Cldn1 mice also demonstrated inhibition of mucosal defense genes while expression of pro-inflammatory genes was sharply upregulated, especially the IL-23/IL-17 signaling. We predict that increased Notch/Wnt-signaling underlie the early onset of adenoma formation in APC-Cldn1 mice. An increase in mucosal permeability due to the adenomas and the inherent barrier defect in these mice further facilitate bacterial translocation into the mucosa to induce inflammation, which in turn promote the tumorigenesis.
CONCLUSION: Taken together, these results confirm the role of claudin-1 as a promoter of colon tumorigenesis and further identify the role of the dysregulated antigen-tumor interaction and inflammation in claudin-1-dependent upregulation of colon tumorigenesis.

Pavicic W, Nieminen TT, Gylling A, et al.
Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.
Genes Chromosomes Cancer. 2014; 53(10):857-64 [PubMed] Related Publications
n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.

Kitahara S, Suzuki Y, Morishima M, et al.
Vasohibin-2 modulates tumor onset in the gastrointestinal tract by normalizing tumor angiogenesis.
Mol Cancer. 2014; 13:99 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
BACKGROUND: Vasohibin-2 (VASH2) has been identified as an endogenous and vascular endothelial growth factor (VEGF)-independent angiogenic factor that is highly expressed in tumor cells. In the present study, we aimed to determine whether pre-existing vascular changes can be used to predict tumor transformation as benign or malignant. We sought to characterize microvascular changes and tumor development in the intestinal tract of ApcMin/+ mice and ApcMin/+/Vash2-/- mice.
METHODS: ApcMin/+ mice provide a unique orthotopic model for the development of spontaneous adenomatous polyposis and subsequent carcinomas, a phenomenon termed the adenoma-carcinoma sequence. ApcMin/+ mice were mated with Vash2-/- mice with a mixed C57BL/6 background and the resulting pups were screened for the Min mutation and for the Vash2-/- gene by PCR. Intestinal tumors from ApcMin/+ mice and ApcMin/+/Vash2-/- mice were removed and either frozen or epon-embedded for subsequent analyses. For 3-dimensional imaging using confocal laser-scanning microscopy and transmission electron microscopy, cryosections were made, and immunofluorescent staining for various markers was performed.
RESULTS: We found that structural abnormalities in tumor vessels from benign tumors resembled those in malignant tumors. In addition, a novel angiogenic factor, vasohibin-2 (VASH2) protein, was detected around tumor blood vessels in late-stage adenomas and adenocarcinomas, but was absent from early-stage adenomas in ApcMin/+ mice. Tumors used to examine endogenous VASH2 (derived from CMT93 colon carcinomas) were less vascularized in Vash2-/- mice and were more regular than those seen in wild-type (WT) mice. In addition, tumors in Vash2-/- mice were smaller than those in WT mice. Furthermore, cross-breeding of mice homozygous for a deletion of Vash2 with mice heterozygous for the APC mutation resulted in animals that showed a significant decrease in the number of polyps in the small intestine.
CONCLUSION: We propose that VASH2 may modulate the onset of tumors in the gastrointestinal tract by regulating tumor angiogenesis.

Nie Y, Zhang R, Fan K, Liang H
[Familial adenomatous polyposis:a report of 10 cases in 3 generations of a family and literature review].
Zhonghua Nei Ke Za Zhi. 2014; 53(4):290-2 [PubMed] Related Publications
OBJECTIVE: To investigate the clinical characteristic, diagnosis and treatment of familial adenomatous polyposis (FAP).
METHODS: According to family history of the proband, we surveyed the pedigree and retrospectively analyzed the clinical characteristics of 10 FAP patients in 3 generations of the family.
RESULT: Among all 10 cases, 3 died of colorectal cancer including two of whom had history of intestinal obstruction.Seven people of the third generation were all diagnosed as FAP. Among them, only 2 patients had clinical symptoms. Colonoscopy was done in all 7 patients before 35 years old. However, none of them had polyps or evidence of cancer.Surgical operation was performed on 1 patient and high frequency electric cutting under endoscopy was performed on 6 patients.
CONCLUSIONS: The early clinical manifestations of FAP are nonspecific. Pedigree investigation and colonoscopy screening for high-risk population are important to find early asymptomatic FAP patients.

Chen C, Peng Y, Peng Y, et al.
miR-135a-5p inhibits 3T3-L1 adipogenesis through activation of canonical Wnt/β-catenin signaling.
J Mol Endocrinol. 2014; 52(3):311-20 [PubMed] Related Publications
MicroRNAs are endogenous, conserved, and non-coding small RNAs that function as post-transcriptional regulators of fat development and adipogenesis. Adipogenic marker genes, such as CCAAT/enhancer binding protein α (Cebpa), peroxisome proliferator-activated receptor γ (Pparg), adipocyte fatty acid binding protein (Ap2), and fatty acid synthase (Fas), are regarded as the essential transcriptional regulators of preadipocyte differentiation and lipid storage in mature adipocytes. Canonical Wnt/β-catenin signaling is recognized as a negative molecular switch during adipogenesis. In the present work we found that miR-135a-5p is markedly downregulated during the process of 3T3-L1 preadipocyte differentiation. Overexpression of miR-135a-5p impairs the expressions of adipogenic marker genes as well as lipid droplet accumulation and triglyceride content, indicating the importance of miR-135a-5p for adipogenic differentiation and adipogenesis. Further studies show that miR-135a-5p directly targets adenomatous polyposis coli (Apc), contributes to the translocation of β-catenin from cytoplasm to nucleus, and then activates the expressions of cyclin D1 (Ccnd1) and Cmyc, indicating the induction of canonical Wnt/β-catenin signaling. In addition, inhibition of APC with siRNA exhibits the same effects as overexpression of miR-135a-5p. Our findings demonstrate that miR-135a-5p suppresses 3T3-L1 preadipocyte differentiation and adipogenesis through the activation of canonical Wnt/β-catenin signaling by directly targeting Apc. Taken together, these results offer profound insights into the adipogenesis mechanism and the development of adipose tissue.

Kattentidt-Mouravieva AA, den Heijer M, van Kessel I, Wagner A
How harmful is genetic testing for familial adenomatous polyposis (FAP) in young children; the parents' experience.
Fam Cancer. 2014; 13(3):391-9 [PubMed] Related Publications
Predictive genetic testing for familial adenomatous polyposis (FAP) is routinely offered to children at-risk from the age of 10 years onwards. Predictive testing for FAP at a younger age is debatable, because of absence of medical benefits. However, circumstances may arise when testing at a younger age (<10 years) is appropriate. Currently, there is a lack of published experience with predictive testing of children at this young age. We evaluated 13 children who were tested for FAP at the age younger than 10 years; 7 mutation-carriers and 6 non-carriers. Parents of these children were re-contacted and open-ended semi-structured interviewed. None of the contacted parents regretted the timing of genetic testing. The major reasons for testing at the young age were (1) testing of all children in the family at the same moment; (2) certainty for the future; and (3) preparing the child for future surveillance. None of the parents observed changes in mental or physical health in their child after testing. Also, young genetic testing did not lead to colon surveillance before it was indicated. Genetic testing for FAP at a young age is experienced as causing no harm by parents. Future studies should evaluate children's own experiences with early genetic testing.

Taki K, Sato Y, Sato Y, et al.
A case of a child with an APC pathogenic mutation, aberrant expression of splice variants and positive family history of FAP.
Jpn J Clin Oncol. 2014; 44(6):602-6 [PubMed] Related Publications
Familial adenomatous polyposis is an autosomal dominant hereditary disease characterized by the appearance of hundreds to thousands of colorectal adenomatous polyps; if left untreated, there is nearly a 100% lifetime risk of colorectal cancer. In the present case, adenomatous polyps were observed at 6 years of age. Unlike our previous assumption, adenomatous polyps were detected by colonoscopy at <10 years of age. Considering the clinical importance of early diagnosis, we report this case involving germline adenomatous polyposis coli mutation (c.1958G > C, GenBank: M74088.1) that caused an increase in the isoform without exon 15. Although this isoform has been reported previously, it remains controversial whether the variant is pathogenic or not because it was observed both in patients with familial adenomatous polyposis and in normal controls. Nonetheless, due to quantitative distortion of splice variants in adenomatous polyposis coli transcripts and the early development of adenomatous polyps, we believe that this variant may be pathogenic.

Lozyns'ka MR, Plavski A, Lozyns'kyĭ IuS
[Clinical and genetic features of APC- and MYH-mutation-negative patients with multiple polyposis of large bowel that tested by conventional methods].
Tsitol Genet. 2014 Jan-Feb; 48(1):18-24 [PubMed] Related Publications
The genealogic analysis, molecular and clinical investigations has been carried out in 19 probands with multiple colorectal adenomas (approximately 100 or more). Twelve of these patients (63.1%) were APC and MYH mutation-negative. Three (25%) probands have positive family history. The median of the disease manifestation age in APC-negative patients was intermediate between the median of the disease manifestation age in APC- and MYH-positive patients. Extraintestinal manifestations in the APC-negative probands are more rare than in APC-positive patients. A half of APC- and MYH-negative probands with multiple polyposis had colorectal cancer. APC- and MYH-negative patients formed a genetically heterogenous group.

Ponz de Leon M, Bianchini MA, Reggiani-Bonetti L, et al.
An unusual case of familial adenomatous polyposis with very early symptom occurrence.
Fam Cancer. 2014; 13(3):375-80 [PubMed] Related Publications
We report the clinical case of a patient who showed an "accelerated" form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family-already described in 2001-featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient.

Schürmanns K, Gelos M, Felder G, et al.
[Can an online risk assessment tool for identification of hereditary colorectal cancer reach the at-risk population and influence screening compliance?].
Dtsch Med Wochenschr. 2014; 139(18):935-40 [PubMed] Related Publications
BACKGROUND AND AIM: Lynch syndrome is a frequent autosomal dominant cancer predisposition leading to an estimated incidence of 3000-4000 new cancer diagnoses of colorectal and endometrial cancer in Germany per year. The underlying hereditary condition is largely underestimated and underrecognized by physicians. The usually young at-risk population, feeling insecure about their personal risk assessment, seeks information online. The aim of this study was to evaluate whether this online risk assessment tool for identification of increased risk for hereditary cancer predisposition reaches the target population and whether it succeeds in positively influencing intensified screening compliance.
METHODS: The underlying algorithm for the test is based on the Bethesda and Amsterdam criteria and recent literature on polyposis syndromes. In the context of interrogating family and personal history, a total of five risk categories were defined. In addition to the cancers as defined in the above mentioned criteria, precursor lesions (polyps) were integrated into the risk estimate. Prior to launching, the algorithm was validated in family pedigrees of 102 mutation carriers with identified MLH-1 or MSH-2 mutations.
RESULTS: During the time interval analysed, which was between October 2008 and April 2011 a total of 656 participants were included. Among these 19.1 % (125/656) belonged to the target population at increased familial or hereditary risk. 72.8 % (91/125) were yet healthy with known cancer-affected relatives. Merely 34.4 % (11/32) of the high-risk population were currently participating in a risk adjusted screening program. After completion of the online test 62.5 % (20/32) felt motivated to reconsider and adjust accordingly with increased surveillance. The test received an overall "good" evaluation (83 %) based on handling, performance and information content.
CONCLUSION: This online risk-assessment tool was mainly completed by healthy (not cancer-affected) individuals with an increased risk for familial or hereditary colorectal cancer predisposition. The family pedigrees were comparable to these of known mutation carriers. The at-risk population was positively motivated to intensify screening strategies and the test received an overall positive evaluation.

Schneikert J, Ruppert JG, Behrens J, Wenzel EM
different Roles for the axin interactions with the SAMP versus the second twenty amino acid repeat of adenomatous polyposis coli.
PLoS One. 2014; 9(4):e94413 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Wnt signalling is prevented by the proteosomal degradation of β-catenin, which occurs in a destruction complex containing adenomatous polyposis coli (APC), APC-like (APCL), Axin and Axin2. Truncating mutations of the APC gene result in the constitutive stabilisation of β-catenin and the initiation of colon cancer, although tumour cells tolerate the expression of wild-type APCL. Using the colocalisation of overexpressed Axin, APC and APCL constructs as a readout of interaction, we found that Axin interacted with the second twenty amino acid repeat (20R2) of APC and APCL. This interaction involved a domain adjacent to the C-terminal DIX domain of Axin. We identified serine residues within the 20R2 of APCL that were involved in Axin colocalisation, the phosphorylation of truncated APCL and the down-regulation of β-catenin. Our results indicated that Axin, but not Axin2, displaced APC, but not APCL, from the cytoskeleton and stimulated its incorporation into bright cytoplasmic dots that others have recognised as β-catenin destruction complexes. The SAMP repeats in APC interact with the N-terminal RGS domain of Axin. Our data showed that a short domain containing the first SAMP repeat in truncated APC was required to stimulate Axin oligomerisation. This was independent of Axin colocalisation with 20R2. Our data also suggested that the RGS domain exerted an internal inhibitory constraint on Axin oligomerisation. Considering our data and those from others, we discuss a working model whereby β-catenin phosphorylation involves Axin and the 20R2 of APC or APCL and further processing of phospho-β-catenin occurs upon the oligomerisation of Axin that is induced by binding the SAMP repeats in APC.

Shirts BH, Salipante SJ, Casadei S, et al.
Deep sequencing with intronic capture enables identification of an APC exon 10 inversion in a patient with polyposis.
Genet Med. 2014; 16(10):783-6 [PubMed] Related Publications
PURPOSE: Single-exon inversions have rarely been described in clinical syndromes and are challenging to detect using Sanger sequencing. We report the case of a 40-year-old woman with adenomatous colon polyps too numerous to count and who had a complex inversion spanning the entire exon 10 in APC (the gene encoding for adenomatous polyposis coli), causing exon skipping and resulting in a frameshift and premature protein truncation.
METHODS: In this study, we employed complete APC gene sequencing using high-coverage next-generation sequencing by ColoSeq, analysis with BreakDancer and SLOPE software, and confirmatory transcript analysis.
RESULTS: ColoSeq identified a complex small genomic rearrangement consisting of an inversion that results in translational skipping of exon 10 in the APC gene. This mutation would not have been detected by traditional sequencing or gene-dosage methods.
CONCLUSION: We report a case of adenomatous polyposis resulting from a complex single-exon inversion. Our report highlights the benefits of large-scale sequencing methods that capture intronic sequences with high enough depth of coverage-as well as the use of informatics tools-to enable detection of small pathogenic structural rearrangements.

Liao DX, Li B, Du XM, et al.
Two Chinese pedigrees for adenomatous polyposis coli: new mutations at codon 1309 and predisposition to phenotypic variations.
Fam Cancer. 2014; 13(3):361-8 [PubMed] Related Publications
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease caused by a mutation in the adenomatous polyposis coli (APC) gene. Some studies have attempted to correlate mutations at codon 1309 with classic FAP (≥100 colorectal polyps). We report two Chinese FAP pedigrees with new frameshift mutations at codon 1309, in which affected individuals manifest phenotypic variations. Comprehensive physical examinations were performed for all living individuals and the medical data of deceased patients were collected. Screening of the APC and human mutY homolog (MUTYH) genes for germline mutations was conducted by direct polymerase chain reaction (PCR) sequencing. In two pedigrees, a heterozygous deletion in exon 16 of the APC gene was present in all FAP patients but absent in the unaffected individuals. There were no changes to the MUTYH gene. The first pedigree, with a new frameshift mutation at c.3926_3930 del AAAAG (p. Glu1309Aspfs X4), exhibited obvious differences in the polyp number such that the proband manifested only three colorectal polyps, whereas another patients showed the symptoms of classic FAP. The second pedigree, also traced a new mutation at c.3922_3925 del AAAG (p. Glu1309Argfs X11). Although all of the patients presented with classic polyposis, one of them exhibited a delayed onset of colorectal cancer in his 50s. Two novel mutations at codon 1309 in two Chinese families suffering from FAP could enrich the germline mutation spectrum of the APC gene. Families of individuals might manifest different phenotypes, even with an identical codon 1309 mutation, unlike in previous studies.

Sereno M, Merino M, López-Gómez M, et al.
MYH polyposis syndrome: clinical findings, genetics issues and management.
Clin Transl Oncol. 2014; 16(8):675-9 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the most frequent cancer in first world. Two hereditary CCR syndrome have been described: familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer. A recently described biallelic mutation of MYH, is responsible for adenomatous polyposis with an increased risk of CRC and is responsible for 30-40 % of adenomatous polyposis cases in which an APC mutation cannot be found. However, there is no clear consensus in the literature as whether a monoallelic mutation increases the risk for colorectal cancer. In addition, some authors have indicated that the spectrum of extracolonic lesions in MYH associated polyposis (MAP) might be far different from that observed in FAP and could be more similar to Lynch syndrome spectrum. In this review we are going to describe some general and specific aspects of MAP, including genetic topics, clinical features, different phenotypes and strategies to reduce CCR risk.

Grandval P, Blayau M, Buisine MP, et al.
The UMD-APC database, a model of nation-wide knowledge base: update with data from 3,581 variations.
Hum Mutat. 2014; 35(5):532-6 [PubMed] Related Publications
Familial adenomatous polyposis (FAP) is a rare autosomal-inherited disease that highly predisposes to colorectal cancer, characterized by a diffuse duodenal and colorectal polyposis associated with various extradigestive tumors and linked to germline mutations within the APC gene. A French consortium of laboratories involved in APC mutation screening has progressively improved the description of the variation spectrum, inferred functional significance of nontruncating variations, and delineated phenotypic characteristics of the disease. The current version of the UMD-APC database is described here. The total number of variations has risen to 5,453 representing 1,473 distinct variations. The published records initially registered into the database were extended with 3,581 germline variations found through genetic testing performed by the eight licensed laboratories belonging to the French APC network. Sixty six of 149 variations of previously unknown significance have now been classified as (likely) causal or neutral. The database is available on the Internet (http://www.umd.be/APC/) and updated twice per year according to the consensus rules of the network. The UMD-APC database is thus expected to facilitate functional classification of rare synonymous, nonsynonymous, and intronic mutations and consequently improve genetic counseling and medical care in FAP families.

Grasso F, Giacomini E, Sanchez M, et al.
Genetic instability in lymphoblastoid cell lines expressing biallelic and monoallelic variants in the human MUTYH gene.
Hum Mol Genet. 2014; 23(14):3843-52 [PubMed] Related Publications
The MUTYH DNA glycosylase counteracts mutagenesis by removing adenine misincorporated opposite DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Biallelic germline mutations in MUTYH cause the autosomal recessive MUTYH-associated polyposis (MAP). The impact on genetic instability of the p.Tyr179Cys and p.Arg245His MUTYH variants was evaluated in lymphoblastoid cell lines (LCLs) derived from MAP patients and their relatives in comparison to wild-type LCLs. No difference in MUTYH expression was identified between wild type and LCLs with the p.Tyr179Cys, while the p.Arg245His mutation was associated with an unstable MUTYH protein. LCLs homozygous for the p.Tyr179Cys or the p.Arg245His variant contained increased DNA 8-oxodG levels and exhibited a mutator phenotype at the PIG-A gene. The extent of the increased spontaneous mutation frequency was 3-fold (range 1.6- to 4.6-fold) in four independent LCLs carrying the p.Tyr179Cys variant, while a larger increase (6-fold) was observed in two p.Arg245His LCLs. A similar hypermutability and S-phase delay following treatment with KBrO3 was observed in LCLs homozygous for either variant. When genetic instability was investigated in monoallelic p.Arg245His carriers, mutant frequencies showed an increase which is intermediate between wild-type and homozygous cells, whereas the mutator effect in heterozygous p.Tyr179Cys LCLs was similar to that in homozygotes. These findings indicate that the type of MUTYH mutation can affect the extent of genome instability associated with MUTYH inactivation. In addition, the mild spontaneous mutator phenotype observed in monoallelic carriers highlights the biological importance of this gene in the protection of the genome against endogenous DNA damage.

Ibrahim A, Barnes DR, Dunlop J, et al.
Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer.
Eur J Hum Genet. 2014; 22(11):1330-3 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ≥70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.

Church JM
Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition.
Dis Colon Rectum. 2014; 57(3):396-7 [PubMed] Related Publications
Germline mutations in the exonuclease (proofreading) domains of 2 DNA polymerases (POLE and POLD1) have been associated with a dominantly inherited, highly penetrant syndrome of oligo adenomatous polyposis and early-age-of-diagnosis colorectal cancer and endometrial cancer. The loss of proofreading capability causes multiple mutations throughout the genome and is manifest as microsatellite-stable, chromosomal unstable cancers. This is an important addition to the range of dominantly inherited syndromes of colorectal cancer predisposition.

Valle L, Hernández-Illán E, Bellido F, et al.
New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.
Hum Mol Genet. 2014; 23(13):3506-12 [PubMed] Related Publications
Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.

Wang L, Liu X, Gusev E, et al.
Regulation of the phosphorylation and nuclear import and export of β-catenin by APC and its cancer-related truncated form.
J Cell Sci. 2014; 127(Pt 8):1647-59 [PubMed] Related Publications
We report the first direct analysis of the endogenous β-catenin phosphorylation activity in colon cancer SW480 cells. By comparing parental SW480 cells that harbor a typical truncated adenomatous polyposis coli (APC) form, cells expressing full-length APC and APC-depleted cells, we provide the formal demonstration that APC is necessary for β-catenin phosphorylation, both for priming of the protein at residue serine 45 and for the subsequent phosphorylation of residues 33, 37 and 41. Truncated APC still sustains a surprisingly high phosphorylation activity, which requires the protein to bind to β-catenin through the APC 20-amino-acid (20AA) repeats, thus providing a biochemical explanation for the precise truncations found in cancer cells. We also show that most of the β-catenin phosphorylation activity is associated with a dense insoluble fraction. We finally examine the impact of full-length and truncated APC on β-catenin nuclear transport. We observe that β-catenin is transported much faster than previously thought. Although this fast translocation is largely insensitive to the presence of wild-type or truncated APC, the two forms appear to limit the pool of β-catenin that is available for transport, which could have an impact on β-catenin nuclear activities in normal and cancer cells.

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