Three submicroscopic deletions at the APC locus and their rapid detection by quantitative-PCR analysis

Rosa, Marina De; Scarano, Maria I.; Panariello, Luigia; Carlomagno, Nicola; Rossi, Giovanni Battista; Tempesta, Alfonso; Borgheresi, P.; Renda, Andrea; Izzo, Paola

doi:10.1038/sj.ejhg.5200344

Cited by 29 publications

(15 citation statements)

References 39 publications

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“…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. Our study on Italian patients suggested gene deletion in 3 of 10 cases.…”

Section: Discussionmentioning

confidence: 87%

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: 87%

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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“…Exon 14 of APC was chosen as target for the assay, as it is encompassed by the majority of submicroscopic APC germ-line deletions reported to date (10)(11)(12)(13). Exon 12 of human serum albumin (Alb), another single-copy gene, was chosen as internal control.…”

Section: Methodsmentioning

confidence: 99%

“…By analogy, such submicroscopic deletions may be missed in a substantial fraction of APC mutation-negative patients with classical polyposis or AAPC͞multiple adenomas. So far, only limited data are available, and no comprehensive studies have been performed to establish the frequency of germ-line APC deletions in these patients (10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas

Sieber

Lamlum

Crabtree

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

129

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Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called ''multiple'' adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC͞multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC͞multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

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“…11 In one family,10 linkage analysis with flanking and intragenic markers followed by in situ hybridisation with intragenic cosmid clones showed that the deletion was approximately 200 kb and included more than the 3′ half of the APC gene and the 3′ adjacent D5S346 microsatellite. A recent report11 described a quantitative PCR assay to detect submicroscopic deletions which included the entire APC gene and the adjacent D5S346 microsatellite in three unrelated Italian FAP families. These submicroscopic deletions do not appear to be associated with mental retardation.…”

mentioning

confidence: 99%

Submicroscopic deletions of the APC gene: a frequent cause of familial adenomatous polyposis that may be overlooked by conventional mutation scanning

Flintoff¹,

Sheridan²,

Turner³

et al. 2001

Journal of Medical Genetics

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Three submicroscopic deletions at the APC locus and their rapid detection by quantitative-PCR analysis

Cited by 29 publications

References 39 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

Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas

Submicroscopic deletions of the APC gene: a frequent cause of familial adenomatous polyposis that may be overlooked by conventional mutation scanning

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