APC Germline Mutations in Individuals Being Evaluated for Familial Adenomatous Polyposis

Abstract

Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

“…and splice site changes [129]. It was observed that FAP patients show increased risk for the ACC formation, compared with the general population.…”

“…In its typical form, FAP manifests as hundreds to thousands of colorectal adenomatous polyps and cancer [129], while Gardner syndrome reveals gastrointestinal polyposis and other lesions, such as osteomas, epidermoid cysts, hepatoblastoma, papillary or follicular thyroid cancer, and adrenal adenomas [130]. The molecular cause underlying these syndromes is found at the locus 5q22.2, containing the adenomatous polyposis coli (APC) gene, which acts as a tumour suppressor by decreasing the activity of b-catenin.…”

“…Zazwyczaj FAP charakteryzuje się występowaniem setek do tysięcy polipów gruczolakowatych jelita grubego i jego rakiem [129], zaś zespół Gardnera wiąże się z polipowatością przewodu pokarmowego i takimi zmianami, jak: kostniaki, torbiele epidermoidalne, hepatoblastoma, rak brodawkowaty i pęcherzykowy tarczycy oraz gruczolaki nadnercza [130]. Molekularnej przyczyny leżącej u podstaw tych zespołów doszukano się w locus 5q22.2, które zawiera gen APC (adenomatous polyposis coli), będący supresorem nowotworów poprzez obniżanie aktywności b-kateniny.…”

“…Gdy zabraknie regulacji poprzez APC następuje akumulacja b-kateniny w ją-drze komórkowym, co prowadzi do aktywacji genów zaangażowanych w rozpoczęcie i postępowanie cyklu komórkowego. Zmiany patogenne w genie APC to głównie mutacje przesuwające ramkę odczytu lub nonsensowne, a następnie duże delecje genowe i zmiany splicingu [129]. U pacjentów z FAP zaobserwowano zwiększone ryzyko ACC w porównaniu z ogólną populacją.…”

Hereditary Colorectal Cancer and Polyposis Syndromes

“…The gene encodes a protein that negatively regulates the β-catenin oncoprotein. In the absence of the APC gene, the β-catenin protein interacts with various transcription factors as it accumulates in the nucleus to upregulate genes that propagate the cell cycle progression [ 28 ]. Germline mutations include deletions, insertions, nonsense, and missense mutations.…”