Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Stevurková,; Adamcikova, Zuzana; Holec,; Zajac,

doi:10.4149/neo_2009_06_486

Cited by 15 publications

(13 citation statements)

References 17 publications

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“…The severity of polyposis and early onset CRC is dependent on the location of APC mutations [7,13]. The Dutch FAP patients with mutations in the APC MCR develops CRC 13 years earlier than patients with mutations in the rest of the APC gene, while patients with mutations in APC AFAP regions develops CRC later compared to individuals with mutations in the rest of the APC gene (log-rank p ≤ 0.0001, see Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Even though haplotype reconstructions from pedigrees found no evidence for a specific APC haplotype associated with disease severity [10], genotype-phenotype correlations have been associated with the location of germline mutations within APC that are related to the severity of polyposis and expression of extra-colonic features [7,11]. Patients with mutations in the mutation cluster region (MCR), located between codons 1286 to 1513 [12], have generally a worse prognosis with earlier onset of disease [13]. Most severe disease is associated with germline mutations at codon 1309 [14], while milder forms of disease with less than 100 adenomas and later ages of onset (attenuated FAP (AFAP)) is associated with codons <157, 312–412 and >1595 [11,15].…”

Section: Introductionmentioning

confidence: 99%

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The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

Talseth‐Palmer

Wijnen

Andreassen

et al. 2013

Hered Cancer Clin Pract

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BackgroundFamilial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into CRC with close to 100% penetrance. Germline mutations in the APC gene, which plays an integral role in the Wnt-signalling pathway, have been found to be responsible for 70-90% of FAP cases. Several studies suggest that modifier genes may play an important role in the development of CRC and possible modifiers for FAP have been suggested. Interestingly, a study has found that SNPs within ATP5A1 is associated with raised levels of ATP5A1 expression and high expression levels may facilitate CRC development. We aimed to determine if SNPs in ATP5A1 modify the risk of developing CRC/adenomas in FAP patients.MethodsGenomic DNA from 139 Australian FAP patients with a germline APC mutation underwent genotyping at the Australian Genome Research Facility (AGRF) utilising iPLEX GOLD chemistry with Sequenom MassArray on an Autoflex Spectrometer for 16 SNPs in the ATP5A1 gene. Association between ages of diagnosis/risk of CRC/adenomas was tested with Kaplan-Meier estimator analysis, logistic regression and cox proportional hazard regression.ResultsAn association between age of diagnosis of CRC and genotypes was observed for SNP rs2578189 (p = 0.0014), with individuals harbouring the variant genotype developing CRC 29 years earlier than individuals harbouring the wildtype genotype. Individuals harbouring the variant genotype of SNP rs2578189 were also at increased risk of CRC (HR = 13.79, 95% CI = 2.36-80.64, p = 0.004). We used an independent Dutch FAP cohort (n = 427) to validate our results; no association between SNP rs2578189 and CRC was observed.ConclusionThese results highlight the difficulties in studying a disease that has a high degree of intervention and also emphasize the importance of large sample sizes when searching for modifier genes in patients with an inherited predisposition to disease. To fully determine if there are genetic modifiers of disease in FAP we would encourage people that are interested in collaborating in future studies into the role of modifier genes in disease expression in FAP to join forces.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

Talseth‐Palmer

Wijnen

Andreassen

et al. 2013

Hered Cancer Clin Pract

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“…We think that although the number of cases analyzed was relatively small, the above three findings will contribute to establishing relationships between germline APC abnormalities and clinical phenotypes in (A)FAP patients and to better characterizing the differences between APC-related polyposis and MutYH-associated polyposis in the future. However, since many examples of deviations from observed APC genotype-FAP phenotype correlations and highly variable phenotypic traits have been reported [16,32-34], it has been pointed out that the family history is important in (A)FAP genotype-phenotype analyses and the factors other than the APC genotype may be involved in producing the (A)FAP phenotype.…”

Section: Discussionmentioning

confidence: 99%

Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis

et al. 2010

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BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps and frequent extracolonic manifestations. An attenuated form of FAP (AFAP) is diagnosed based on a milder colorectal phenotype, and the colorectal phenotype of (A)FAP has been linked to germline APC mutations. The relationships between the spectrum of mutations and extracolonic manifestations are quite well known, but they need to be further defined.FindingsNine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.ConclusionsNine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.

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“…Genotype-phenotype correlations have been associated with the location of germline mutations within APC that are related to disease severity and the expression of extra-colonic disease [40–42], see figures in Half et al [8] and Macrae [10]. Patients with mutations in the mutation cluster region (MCR), located between codons 1286 and 1513 [43], have generally a worse prognosis with earlier disease onset than those with mutations outside this region [44]. Germline mutations at codon 1309 is associated with most severe disease [45], while milder forms with less than 100 adenomas and later ages of onset (AFAP) are associated with codons <157, 312–412 and >1595 [33, 41].…”

Section: Familial Adenomatous Polyposis (Fap) Geneticsmentioning

confidence: 99%

The genetic basis of colonic adenomatous polyposis syndromes

Talseth‐Palmer

2017

Hered Cancer Clin Pract

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Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs. Adenomatous polyposis syndromes can be divided into; familial adenomatous polyposis (FAP) -classic FAP and attenuated familial adenomatous polyposis (AFAP), MUTYHassociated polyposis (MAP), NTHL1-associated polyposis (NAP) and polymerase proofreading-associated polyposis (PPAP). The polyposis syndromes genetics and clinical manifestation of disease varies and cases with clinical diagnosis of FAP might molecularly show a different diagnosis. This review examines different aspects of the adenomatous polyposis syndromes genetics and clinical manifestation of disease; in addition the genotype-phenotype and modifier alleles of FAP will be discussed. New technology has made it possible to diagnose some of the APC mutation negative patients into their respective syndromes. There still remain many molecularly undiagnosed adenomatous polyposis patients indicating that there remain causative genes to be discovered and with today's technology these are expected to be identified in the near future. The knowledge about the role of modifier alleles in FAP will contribute to improved pre-symptomatic diagnosis and treatment. New novel mutations will continually be discovered in genes already associated with disease and new genes will be discovered that are associated with adenomatous polyposis. The search for modifier alleles in FAP should be made a priority.

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Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Cited by 15 publications

References 17 publications

The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis

The genetic basis of colonic adenomatous polyposis syndromes

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