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Pathways of tumorigenesis in attenuated familial adenomatous polyposis (AFAP) polyps with ''three hits'', illustrating the possible sequences in which somatic mutations/allelic loss may occur in AFAP polyps with ''three hits'' as well as the possible functional effects of these changes. Two truncating somatic mutations are shown. In a ''kick-start'' model (i), these changes can occur in either order and tumour growth ensues once both somatic changes have occurred; in a ''step wise'' model (ii), somatic mutation of the germline wild-type allele causes limited clonal expansion and is followed by somatic mutation of the germline mutant allele which promotes further tumour growth. The expected ratio of the two somatic alleles is 1:1 for the ''kick-start model'' but lies between 1:4 and 1:1 for the ''step wise'' model with the minimum estimate (*) assuming a mutation detection sensitivity of 20%.
Source publication
Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein.
We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have...
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Papillary thyroid carcinoma (PTC) is a rare extracolonic manifestation of familial adenomatous polyposis, determined by germline mutations of the adenomatous polyposis coli (APC) gene. The aim of this study was to assess the presence of loss of heterozygosity of APC in the thyroid tumoral tissue. Specimens from six female patients, aged 20-36, were...
Background
Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary syndrome characterised by the development of hundreds to thousands of adenomatous colonic polyps during the second decade of life. FAP is caused by germ line mutations in the adenomatous polyposis coli (APC) gene located on chromosome 5q21–22.
Case presentation
A 3...
Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members...
Citations
... Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by germline mutations in the adenomatous polyposis coli (APC) gene and is characterized by the development of numerous adenomatous polyps throughout the colon and rectum. FAP is classified into the following three phenotypes according to the number of colorectal adenomatous polyps: profuse (>1,000), sparse (100-1,000), and attenuated ; the phenotypes are known to be correlated with mutations in the APC gene [1,2]. The pattern of onset and development of colorectal cancer (CRC) in FAP patients is also correlated with the FAP phenotypes; the development of colorectal polyps and CRC in the attenuated type occurs later than that in the profuse and sparse types [1,3,4]. ...
... FAP is classified into the following three phenotypes according to the number of colorectal adenomatous polyps: profuse (>1,000), sparse (100-1,000), and attenuated ; the phenotypes are known to be correlated with mutations in the APC gene [1,2]. The pattern of onset and development of colorectal cancer (CRC) in FAP patients is also correlated with the FAP phenotypes; the development of colorectal polyps and CRC in the attenuated type occurs later than that in the profuse and sparse types [1,3,4]. ...
... The reason why superficial depressed CRC lesions were observed only in attenuated FAP patients in this study remains unclear, although the lower density of polyps in attenuated FAP patients might have made it easier to identify depressed superficial lesions. The development of superficial depressed CRC lesions in older patients can be explained by the fact that CRC in patients with attenuated FAP develops later than in those with profuse and sparse FAP [1,3]. ...
Objectives:
This retrospective study was conducted to clarify the morphological characteristics of colorectal cancer (CRC) in Japanese familial adenomatous polyposis (FAP) patients.
Methods:
This study was carried out by the study group for FAP of the Japanese Society for Cancer of the Colon and Rectum. FAP patients who underwent surgical resection between 2000 and 2012 were included in the study.
Results:
Of the 303 patients enrolled, 119 patients without CRC were excluded. Of 523 lesions, 49 lesions with missing morphological information were excluded; hence, only 474 CRC lesions in 178 patients (328 superficial lesions in 122 patients and 146 non-superficial lesions in 92 patients) were included in the study. Depressed lesions accounted for 3.0% of superficial lesions and ulcerated lesions accounted for 84.9% of non-superficial lesions. The depressed superficial lesions were observed only in patients with sparse and attenuated FAP (P = 0.003). The age of the patients at surgery differed between the two groups, with patients with depressed superficial lesions being significantly older than those with non-depressed superficial lesions (P = 0.009). Moreover, the age of the patients at FAP diagnosis differed between the two groups, with patients with ulcerated non-superficial lesions being significantly older than those with protruded non-superficial lesions (P = 0.006).
Conclusions:
In patients with FAP, depressed superficial CRC lesions rarely developed but were detected in our study group, and ulcerated non-superficial CRC lesions were also present with similar ratios. Clinicians should pay attention to depressed superficial lesions during endoscopic surveillance of FAP patients.
... [12]. Overall, there appears to be a genotype-phenotype correlation in patients with FAP (for review, see Nieuwenhuis and Vasen 2006 [13]), with severe disease being associated with variants occurring in the mutation cluster region (MCR) of APC [14] and attenuated FAP being linked to variants 5' of codon 157 [15] and 3' of codon 1581 [16]. Notwithstanding, there are significant exceptions to the notion of a genotype/ phenotype correlation in FAP, which is more readily explained by other factors that impact adenoma multiplicity. ...
Background
Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5’ and 3’ ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36 . We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort.
Methods
In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression.
Results
Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression.
Conclusions
This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.
... AFAP has in several studies been associated with truncating pathogenic variants in the 5′ and 3′ end of the APC gene as well as exon 9, although the codons involved have varied slightly. A clear genotype-phenotype correlation is still controversial [5][6][7]. ...
... The variant carriers in this study all have phenotypes consistent with AFAP; most had polyp count < 100 and onset of cancer at age 46-88, and although individual II-II in family 1 and individual III-I in family 2 both had large numbers of adenomas, they both developed cancer at a relatively high age (62-years-old and 78-years-old, respectively). This is in accordance with the association of a less severe phenotype and pathogenic variants in APC codons 1-177 [5][6][7]. On the other hand, an increasing amount of evidence suggests that modifier variants in other genes, low risk single nucleotide polymorphisms (SNPs) and non-genetic factors such as lifestyle influence the cancer risk and possibly also account for some of the intrafamilial variation [13]. Further research will help to elucidate the possible clinical implications of both the genotype and the role of modifying variants. ...
Background:
We report the first case of a missense variant in the APC gene that interrupts splicing by creating a new cryptic acceptor site. The variant, c.289G>A, p.(Gly97Arg), is located in exon 3, and qualitative and semi-quantitative RNA splicing analysis reveal that the variant results in skipping of the last 70 nucleotides of the exon, which leads to the introduction of a frameshift and a premature stop codon.
Case presentation:
The variant was detected in two, apparently unrelated, Danish families with an accumulation of colorectal cancers, colonic adenomas and other cancers. The families both have an attenuated familial adenomatous polyposis phenotype, which is consistent with the association of pathogenic variants in the 5' end of the gene.One variant-carrier also had Caroli Disease and a Caroli Disease associated hepatic mucinous cystadenocarcinoma. This is the first description of a person with both Caroli Disease and a pathogenic APC variant, and although the APC variant is not known to be connected to the development of the hepatic malformations in Caroli Disease, it remains unclear whether the variant could have contributed to the carcinogenesis of the liver tumour.
Conclusions:
Based on functional and co-segregation data we classify the APC c.289G>A, p.(Gly97Arg) variant as pathogenic (class 5). Our findings emphasize the importance of a functional evaluation of missense variants although located far from the exon-intron boundaries.
... The b-catenin accumulation, in turn, predisposes the tissue to the development of colon tumors [20]. Generally, the bi-allelic loss of the APC function is a mechanism of tumorigenesis in colorectal cancer [17,21]. Depending on the location of the germline variant in APC, the second allele is sporadically mutated or exhibits allelic loss. ...
Patient: Male, 80-year-old
Final Diagnosis: Attenuated APC-associated polyposis
Symptoms: Colon polyps • renal carcinoma
Medication: —
Clinical Procedure: —
Specialty: Genetics
Objective
Unusual clinical course
Background
The diagnoses of adenomatous polyposis coli (APC)-associated polyposis conditions are typically based on suggestive personal features and/or family history, and the identification of a pathogenic variant in the APC gene. However, with large-scale genome sequencing, it is now possible to identify pathogenic variants before or even without the presentation of the expected clinical features. This case describes a novel pathogenic APC variant.
Case Report
We report the unexpected identification of a rare, pathogenic germline APC variant, p.S2627Gfs*12 in an 80-year-old man with a diagnosis of renal cell carcinoma, without any family history of APC-associated polyposis or personal history of colorectal cancer. After the identification of the APC variant, a review of the patient’s medical records showed a personal history of 15 adenomatous polyps over a decade ago, with no follow-up genetic testing at the time.
Conclusions
This novel APC variant has not been characterized to date. The presence of the APC-p.S2627Gfs*12 variant in this patient led to the recommendation of additional cascade genetic testing and surveillance measures for any family members who tested positive for this variant. This report highlights the broad spectrum of the APC-associated polyposis features, and a mild phenotype associated with the pathogenic APC p.S2627Gfs*12 variant.
... Classic FAP patients develop 100s to 1000s of premalignant adenomas which further supports the Cancers 2020, 12 [6,7]. Three hits at APC have also been shown to occur in tumors from attenuated FAP (AFAP) patients who have a milder phenotype with fewer colon polyps (average of 30) and a later age of colon cancer development [8][9][10]. Two hits at the APC locus also occur as acquired mutations in the development of most sporadic CRCs [11]. ...
... While FAP is relatively uncommon (incidence = 1.90 × 10 −6 ; prevalence = 4.65 × 10 −5 ) [14]), results reported here should have wider implications for understanding mechanisms involved in the development of commonly occurring sporadic adenomatous polyps (1 in 2 individuals) and sporadic CRC (1 in 20 individuals) [15]. As noted above, in both FAP and sporadic cases, mutations of APC genes are known events in the development of colonic tumors [6][7][8][9][10][11][12]. Study of the in vivo rate of somatic APC mutation also supports the theory that FAP and sporadic CRC follow the same genetic pathway [16]. ...
The goal of our study was to measure the kinetics of human colorectal cancer (CRC) development in order to identify aberrant mechanisms in tissue dynamics and processes that contribute to colon tumorigenesis. The kinetics of tumor development were investigated using age-at-tumor diagnosis (adenomas and CRCs) of familial adenomatous coli (FAP) patients and sporadic CRC patients. Plots of age-at-tumor diagnosis data as a function of age showed a distinct sigmoidal-shaped curve that is characteristic of an autocatalytic reaction. Consequently, we performed logistics function analysis and found an excellent fit (p < 0.05) of the logistic equation to the curves for age-at-tumor diagnoses. These findings indicate that the tissue mechanism that becomes altered in CRC development and growth involves an autocatalytic reaction. We conjecture that colonic epithelium normally functions as a polymer of cells which dynamically maintains itself in a steady state through an autocatalytic polymerization mechanism. Further, in FAP and sporadic CRC patients, mutation in the adenomatous polyposis coli (APC) gene increases autocatalytic tissue polymerization and induces tumor tissues to autocatalyze their own progressive growth, which drives tumor development in the colon.
... Heterozygous APC germline mutations have been associated with AP predisposition in a gene location-dependent manner [29] . Most of the germline APC mutations are truncating variants lying between codons 178 and 1580, and give rise to stable mutant peptides that exert a dominant-negative effect on the wild-type protein [30,31] . These mutations lead to classical forms of the disease called familial AP (FAP), whereas germline mutations located at both the 5' and 3' ends of the transcript, as well as splicing mutations that lead to exon 9 skipping, give rise to attenuated forms of the disease called attenuated familial AP (AFAP) ( Figure 1A). ...
... These mutations lead to classical forms of the disease called familial AP (FAP), whereas germline mutations located at both the 5' and 3' ends of the transcript, as well as splicing mutations that lead to exon 9 skipping, give rise to attenuated forms of the disease called attenuated familial AP (AFAP) ( Figure 1A). Germline mutations at the 3' end give rise to stable proteins with a certain capability to regulate β-catenin levels [30] , and 5' end mutations upstream of codon 177 produce functional proteins by initiation of translation at codon 184 [31,32] . This internal initiation of translation is relatively inefficient, leading to a haploinsufficient phenotype rather than a dominant-negative phenotype. ...
Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk factor in CAP due to mutations in the known high predisposition genes APC and MUTYH. However, the contribution of genetic susceptibility to AAP is lower and less understood. New predisposition genes have been recently proposed, and some of them have been validated, but their scarcity hinders accurate risk estimations and prevalence calculations. AAP is a heterogeneous condition in terms of severity, clinical features and heritability. Therefore, clinicians do not have strong discriminating criteria for the recommendation of the genetic study of known predisposition genes, and the detection rate is low. Elucidation and knowledge of new AAP high predisposition genes are of great importance to offer accurate genetic counseling to the patient and family members. This review aims to update the genetic knowledge of AAP, and to expound the difficulties involved in the genetic analysis of a highly heterogeneous condition such as AAP.
... A genotype-phenotype correlation is documented in FAP, but it is not consistent. Classical or severe polyposis is associated with mutations between codons 1250-1464 and desmoids with mutations throughout the whole gene, but probably more severe after codon 1444 [11][12][13]. AFAP is associated with mutations before codon 157, in the alternatively spliced region of exon 9 and after codon 1595 [11][12][13]. There is considerable phenotypic variability within and between families. ...
... Classical or severe polyposis is associated with mutations between codons 1250-1464 and desmoids with mutations throughout the whole gene, but probably more severe after codon 1444 [11][12][13]. AFAP is associated with mutations before codon 157, in the alternatively spliced region of exon 9 and after codon 1595 [11][12][13]. There is considerable phenotypic variability within and between families. ...
Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.
... An attenuated form of FAP (AFAP) is distinguished from classical FAP by fewer (between 20 and 100) colorectal adenomas and a slightly reduced risk (80%) and later onset (mean age 56 years) of CRC. 75 In addition to colorectal polyps, most FAP patients develop gastric and duodenal polyps. 76 Duodenal cancer is the second leading cause of death after CRC in FAP. ...
Recognition of hereditary forms of gastrointestinal cancer is of great importance for patients and their families and pathologists play a crucial role in this. This review recapitulates the clinical, pathological and molecular aspects of Hereditary Diffuse Gastric Cancer and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, as well as hereditary colorectal cancer syndromes such as Lynch syndrome and gastrointestinal polyposis syndromes (including Familial Adenomatous Polyposis, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome). Histopathological clues to recognize hereditary forms of gastrointestinal cancer and possible ancillary studies that can support an underlying syndrome and guide genetic testing are discussed.
... This is consistent with data we compiled from previous reports in which this mutation accounted for 17/35 mutations (49%). Although very uncommon in FAP colorectal adenomas (1/296 mutations in the reports we identified; Supplementary Table S4), this mutation has been seen recurrently in colorectal adenomas from patients with attenuated FAP (43)(44)(45) where it appears to occur as a "third hit" further reducing the activity of the attenuated germline mutant allele. We did not find any evidence for third hits affecting APC in duodenal adenomas. ...
Purpose:
Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.
Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared to each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.
Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006) and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2 and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P=0.0017).
Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease.
... Due to the unusual genomic structure of Apc, in which 75% of its coding sequence is contained within a single exon, it has been challenging to produce Cre-conditional alleles that represent the most frequent CRC-associated mutations. As mentioned above, the majority of Apc mutations in human CRC lie between amino acids 1250 and 1450 in the "Mutation Cluster Region," and there is a strong correlation between the type of APC truncation, level of Wnt signaling and disease severity in familial cases [75][76][77]. Inducible CRISPR/Cas9-based genome editing now provides an avenue to assess the impact of specific Apc alterations on tumor initiation, progression, and response. ...
The WNT signaling pathway is a critical mediator of tissue homeostasis and repair, and frequently co-opted during tumor development. Almost all colorectal cancers (CRC) demonstrate hyperactivation of the WNT pathway, which in many cases is believed to be the initiating and driving event. In this short review, we provide a focused overview of recent developments in our understanding of the WNT pathway in CRC, describe new research tools that are enabling a deeper understanding of WNT biology, and outline ongoing efforts to target this pathway therapeutically.
