Genetic and clinical characterisation of familial adenomatous polyposis: a population based study

Al, Moisio; Järvinen, Heikki; Peltomäki, Païvi

doi:10.1136/gut.50.6.845

Cited by 93 publications

(69 citation statements)

References 36 publications

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“…These patients were from different European origin. No deletions were detected in 18 APC mutation-negative FAP kindreds from Finland (Moisio et al, 2002). On the contrary, De Rosa et al (1999) reported gene deletions in three (33%) of nine mutation-negative FAP families of Italian origin.…”

Section: Discussionmentioning

confidence: 94%

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APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

Venesio

Balsamo

Rondo-Spaudo

et al. 2003

Laboratory Investigation

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SUMMARY:Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (Ͼ95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein.We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (␤-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression. (Lab Invest 2003, 83:1859 -1866.

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Section: Discussionmentioning

confidence: 94%

“…Despite the mutation strategy we used, we could have missed gene alterations in these cases (20% of all tested cases). Moisio et al (2002), by using a comprehensive mutation detection strategy, could not identify APC alterations in 28% of Finnish FAP kindreds, including deletions and imbalance in allelic expression.…”

Section: Discussionmentioning

confidence: 99%

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

Venesio

Balsamo

Rondo-Spaudo

et al. 2003

Laboratory Investigation

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“…The two most common germline mutations, 5 bp deletions in codons 1061 and 1309, occur in the mutation cluster region of exon 15, and correlate with a high number of adenomas at an early age (Soravia et al, 1998;Wallis et al, 1999;Friedl et al, 2001). Retinal lesions are commonly associated with alterations between codons 463 and 1387 Moisio et al, 2002). Desmoid tumours and mandibular osteomas, as seen in the Gardner variant, occur with mutations between codons 1403 and 1578 (Wallis et al, 1999;Moisio et al, 2002).…”

Section: Familial Adenomatous Polyposismentioning

confidence: 99%

“…Desmoid tumours and mandibular osteomas, as seen in the Gardner variant, occur with mutations between codons 1403 and 1578 (Wallis et al, 1999;Moisio et al, 2002). In contrast, the attenuated FAP phenotype results from mutations either in the 5 0 part of the APC gene (5 0 to codon 158), the alternatively spliced exon 9, or in the far 3 0 part of the gene beyond codon 1595 (Spirio et al, 1993;van der Luijt et al, 1995;Friedl et al, 1996;Walon et al, 1997;Soravia et al, 1998;Moisio et al, 2002). A mutation discovered at codon 1307 of the APC gene generates a hypermutable polyadenine tract among the Ashkenazim (Laken et al, 1997).…”

Section: Familial Adenomatous Polyposismentioning

confidence: 99%

Highly penetrant hereditary cancer syndromes

2004

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The past two decades have brought many important advances in our understanding of the hereditary susceptibility to cancer. Approximately 5-10% of all cancers are inherited, the majority in an autosomal dominant manner with incomplete penetrance. While this is a small fraction of the overall cancer burden worldwide, the molecular genetic discoveries that have resulted from the study of families with heritable cancer have not only changed the way these families are counselled and managed, but have shed light on molecular regulatory pathways important in sporadic tumour development as well. In this review, we consider 10 of the more highly penetrant cancer syndromes, with emphasis on those predisposing to breast, colon, and/or endocrine neoplasia. We discuss the prevalence, penetrance, and tumour spectrum associated with these syndromes, as well as their underlying genetic defects.

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“…These findings are consistent with a previous report in which the mutation was proven to affect splicing in a family with an attenuated phenotype. 36 …”

Section: Variant C531 ϩ 5gͼc In Intronmentioning

confidence: 99%

Analysis of Rare APC Variants at the mRNA Level

Kaufmann

Vogt

Uhlhaas

et al. 2009

The Journal of Molecular Diagnostics

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In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 ؉ 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father , suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants , particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms , and could lead to better treatment modalities. Determining the pathogenicity of a germline mutation in an inherited disease is crucial for diagnostics and counseling and is particularly relevant for predictive testing in persons at risk. Generally, nonsense and frameshift mutations, large exonic deletions, and mutations in the conserved splice sequences in a gene are considered as pathogenic. In contrast, the pathological significance of rare variants predicted to result in amino acid substitutions (missense mutations), small in-frame deletions, or even same-sense mutations (silent variants) is often unclear. Similarly, the functional effect of DNA variants at less conserved positions in introns is difficult to predict. As a consequence, a growing number of single bp substitutions identified in routine diagnostics are denoted as unclassified variants (UVs) or variants of uncertain significance, respectively.Based on functional analysis, it has become evident in recent years that a substantial proportion of so-called UVs, particularly those located close to exon-intron boundaries, affect splicing because of the disruption of putative regulatory elements such as exonic splicing enhancer and silencer motifs, or composite exonic regulatory elements of splicing.1-8 Aberrant splicing as the underlying mechanism of presumed missense or silent variants has been detected in a number of genes involved in cancer predisposition such as MLH1, MSH2, BRCA1, BRCA2, RB1, NF1, and ATM. -17Familial adenomatous polyposis (FAP) (MIM no. 175100) is an autosomal-dominant precancerous condition characterized by the appearance of numerous colorectal adenomas, which, if not detected early and removed, invariably result in colorectal cancer. In classic FAP, patients develop hundreds to thousands of adenomatous poly...

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Genetic and clinical characterisation of familial adenomatous polyposis: a population based study

Cited by 93 publications

References 36 publications

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

Highly penetrant hereditary cancer syndromes

Analysis of Rare APC Variants at the mRNA Level

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