The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management

Leoz, Maria Liz; Carballal, Sabela; Moreira, Leticia; Ocaña, Teresa; Balaguer, Francesc

doi:10.2147/tacg.s51484

Cited by 79 publications

(68 citation statements)

References 92 publications

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“…The site of germline mutation in the APC gene is known to correlate with the disease phenotype [1]. Our family 42 with pseudoexon 6/7 was associated with classical FAP in agreement with genotype-phenotype expectations.…”

Section: Discussionsupporting

confidence: 87%

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

et al. 2016

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Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.

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Section: Discussionsupporting

confidence: 87%

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

et al. 2016

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“…FAP is an autosomal dominant polyposis syndrome characterized by hundreds of adenomas in the large intestine as well as in the upper gastrointestinal tract (Leoz et al 2015, Waller et al 2016. It is due to germline mutations in APC gene located on long (q) arm of chromosome 5 at position 22.2.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Apart from colorectal cancer, patients with Gardner syndrome most often have small bowel cancer. The other cancers included pancreatic (Leoz et al 2015). Type 2 Turcot's syndrome is a very rare form of mutation of APC gene in which there is an association of intestinal polyposis and brain tumours -most often medulloblastoma (Gadish et al 2005, Skomorowski et al 2012.…”

Section: Clinical Featuresmentioning

confidence: 99%

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer

Lam¹,

Saremi²

2017

Endocrine-Related Cancer

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The aim of this systematic review is to study the features of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) by analysing the 129 documented cases in the English literature. The disease occurred almost exclusively in women. The median age of presentation for CMV-PTC was 24 years. Slightly over half of the patients with CMV-PTC had familial adenomatous polyposis (FAP). CMV-PTC presented before the colonic manifestations in approximately half of the patients with FAP. Patients with FAP often have multifocal tumours in the thyroid. Microscopic examination of CMV-PTC revealed predominately cribriform and morular pattern of cancer cells with characteristic nuclear features of papillary thyroid carcinoma. Psammoma body is rare. On immunohistochemical studies, β-catenin is diffusely positive in CMV-PTC. The morular cells in CMV-PTC are strongly positive for CD10, bcl-2 and E-cadherin. Pre-operative diagnosis of CMV-PTC by fine-needle aspiration biopsy could be aided by cribriform architecture, epithelial morules and β-catenin immunostaining. Mutations of APC gene are found in the patients with CMV-PTC associated with FAP. In addition, mutations in CTNNB1, RET/PTC rearrangement and PI3K3CA mutations have been reported. BRAF mutation is negative in all CMV-PTC tested. Compared to conventional papillary thyroid carcinoma, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patients' mortality rates (2%). To conclude, patients with CMV-PTC have distinctive clinical, pathological and molecular profiles when compared to conventional papillary thyroid carcinoma.

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“…Given the extent of his polyposis, the patient was advised to undergo definitive surgical management; he ultimately underwent total colectomy 8 months following his initial presentation. Subsequent genetic testing revealed that the patient was positive for the mutated APC gene thereby confirming the diagnosis of FAP [23]. …”

Section: Case Presentationmentioning

confidence: 99%

Familial Adenomatous Polyposis Manifesting asLactococcusEndocarditis: A Case Report and Review of the Association ofLactococcuswith Underlying Gastrointestinal Disease

Bazemore

Zietlow

Hendershot

et al. 2016

Case Reports in Infectious Diseases

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A 45-year-old male with a prosthetic aortic valve presented to the hospital with several months of generalized malaise. On admission, he was noted to have anemia of unclear etiology and subsequently became febrile with multiple blood cultures growing Lactococcus garvieae. Inpatient workup was concerning for infectious endocarditis (IE) secondary to Lactococcus. The patient was discharged home with appropriate antimicrobial therapy; however, he was readmitted for persistent, symptomatic anemia and underwent colonoscopy, which revealed innumerable colonic polyps consistent with Familial Adenomatous Polyposis (FAP) that was later confirmed with genetic testing. Surveillance computed tomography (CT) imaging of the aortic repair later demonstrated valve dehiscence with surrounding fluid collection; he underwent redo surgery and was found to have destruction of the aortic annulus and a large pseudoaneurysm. Histopathology of the valve prosthesis confirmed IE. It is suspected that the patient developed Lactococcus IE from enteric translocation. Review of the literature provides several reports of Lactococcus infections in association with underlying gastrointestinal disease, including colorectal cancer. Given this association, we raise the question of whether the diagnosis of Lactococcus IE should evoke suspicion and encourage evaluation for gastrointestinal pathology, as occurs with Streptococcus bovis.

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The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management

Cited by 79 publications

References 92 publications

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer

Familial Adenomatous Polyposis Manifesting asLactococcusEndocarditis: A Case Report and Review of the Association ofLactococcuswith Underlying Gastrointestinal Disease

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