Characterization of cryptic splicing in germline <i>PTEN</i>
 intronic variants in Cowden syndrome

Chen, Hannah Jinlian; Romigh, Todd; Sesock, Kaitlin; Eng, Charis

doi:10.1002/humu.23288

Cited by 35 publications

(30 citation statements)

References 20 publications

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“…In case of the PTEN mutation, nonsynonymous mutations in phosphatase domain and C2 domain (exon6:c.725G>T:p.G251V; exon10:c.89692922T.C:p.C136R) were reported in each case [9,10], which might lead to the reduction of PTEN's membrane affinity, and subsequent loss of suppression of cell growth [14,15]. In our case, the PTEN mutation occurred in the splicing donor site of intron 5 (exon5:c.492+1G>A), resulting in a PTEN splicing mutant ( Figure 6B) [16]. The same mutation has been reported in patents with Cowden syndrome, which causes hamartomatous neoplasms of the skin and mucosa, GI tract, CNS, and genitourinary tract, and an increased risk for malignancies of the breast, thyroid, and endometrium [16].…”

Section: Discussionmentioning

confidence: 62%

“…In our case, the PTEN mutation occurred in the splicing donor site of intron 5 (exon5:c.492+1G>A), resulting in a PTEN splicing mutant ( Figure 6B) [16]. The same mutation has been reported in patents with Cowden syndrome, which causes hamartomatous neoplasms of the skin and mucosa, GI tract, CNS, and genitourinary tract, and an increased risk for malignancies of the breast, thyroid, and endometrium [16]. TP53 mutations have been widely observed in a variety of tumors, including AML, but they are uncommon in GCT [17].…”

Section: Discussionmentioning

confidence: 75%

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TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia

Akizuki

Sekine

Kogure³

et al. 2019

Preprint

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Background: The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated.Methods: We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them.Results: 16 somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. Conclusions: All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 75%

TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia

Akizuki

Sekine

Kogure³

et al. 2019

Preprint

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“…Pathogenic promoter mutations result in decreased PTEN transcription and translation, the latter due to altered mRNA secondary structure (Zhou et al 2003b;Teresi et al 2007). More recently, some unsuspected PTEN intronic variants were shown to result in pathogenic exon skipping, alternative splicing, or the use of cryptic splice sites (Chen et al 2017b). These splicing changes correlate with significantly lower PTEN protein Tan et al (2012) and Bubien et al (2013), and to age 60 by Nieuwenhuis et al (2014).…”

Section: Pten Dysfunction and Heritable Cancermentioning

confidence: 99%

PTEN in Hereditary and Sporadic Cancer

Ngeow

Eng

2019

Cold Spring Harb Perspect Med

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Germline pathogenic phosphatase and tensin homolog (PTEN) mutations cause PTEN hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the thyroid, breast, endometrium, and other organs. Patients with PHTS may present with other clinical features such as macrocephaly, intestinal polyposis, cognitive changes, and pathognomonic skin changes. Clinically, deregulation of PTEN function is implicated in other human diseases in addition to many types of human cancer. PTEN is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Although PTEN can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. It is positively and negatively regulated at the transcriptional level as well as posttranslationally by phosphorylation, ubiquitylation, oxidation, and acetylation. Although most of its tumor-suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. In this review, we highlight our current knowledge of PTEN function and recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically for cancer treatment.

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“…6; see also Additional File 2: Tables S10 and S11). Two variants were classified PS3 or BS3 based on splicing assays [86,87], which we did not . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

Section: Pten Vcepmentioning

confidence: 99%

Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels

Kanavy

McNulty

Jairath

et al. 2019

Preprint

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Background The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that well-established functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays. Methods We evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies. Results Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation. Conclusions Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.

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Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome

Cited by 35 publications

References 20 publications

TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia

TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia

PTEN in Hereditary and Sporadic Cancer

Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels

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