ArticleAmerican journal of human genetics2007
Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation.
Article in American journal of human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 83 citations in OpenAlex.
- Breast-Ovarian Hereditary Cancer Syndrome: BeyondCurrent oncology (Toronto, Ont.) · 2026Review
- Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants.NPJ genomic medicine · 2025Article
- Identification of a germline deep intronic PTEN-deletion leading to exonization through whole genome and targeted RNA sequencing.Familial cancer · 2025Article
- Regional-specific calibration enables application of computational evidence for clinical classification of 5' cis-regulatory variants in Mendelian disease.American journal of human genetics · 2024Article
- Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.American journal of human genetics · 2022Article
- Article
- Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations.NPJ genomic medicine · 2022Article
- An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation.Nature communications · 2021Article
- Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates.Endocrine pathology · 2021Review
- Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes-Considerations for Future Studies.International journal of molecular sciences · 2020Review
- PTEN in Hereditary and Sporadic Cancer.Cold Spring Harbor perspectives in medicine · 2020Review
- Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations.JAMA network open · 2020Article
- PTEN-opathies: from biological insights to evidence-based precision medicine.The Journal of clinical investigation · 2019Review
- MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback loop.Oncotarget · 2017Article
- Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.The Journal of allergy and clinical immunology · 2017Article
- GermlineNPJ genomic medicine · 2017Article
- Exome sequencing reveals germline gain-of-functionCold Spring Harbor molecular case studies · 2016Article
- A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.European journal of human genetics : EJHG · 2016Article
- Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.American journal of human genetics · 2016Article
- Cutaneous manifestation of gastrointestinal disease.Journal of gastrointestinal oncology · 2016Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Germline mutations of PTEN (phosphatase and tensin homolog deleted on chromosome 10) are associated with the multihamartomatous disorder Cowden syndrome (CS). Moreover, patients with CS with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer. Here, we examined the downstream effect of five PTEN promoter variants (-861G/T, -853C/G, -834C/T, -798G/C, and -764G/A) that are not within any known cis-acting regulatory elements. Clinically, all five of these patients have been given diagnoses of breast, thyroid, and/or endometrial cancer. We demonstrated that protein binding to the PTEN promoter (-893 to -755) was not altered in the five variants when compared with the wild-type (WT) promoter. However, reporter assays indicated that three of the variants (-861G/T, -853C/G, and -764G/A) demonstrated an ~50% decrease in luciferase activity compared with the WT construct. PTEN messenger RNA (mRNA) levels were not altered in these variants, whereas secondary structure predictions indicated that different PTEN 5' untranslated region transcript-folding patterns exist in three variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicate that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. These data emphasize the importance of PTEN promoter nucleotide variations and their ability to lead to CS progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid, and endometrial malignancies; thus, understanding of the mechanism of PTEN dysfunction in these patients will lead to more-sensitive molecular diagnostic and predictive testing and, ultimately, to rational targeted therapies to treat or prevent malignancy.
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