Tumor Suppressors Having Oncogenic Functions: The Double Agents

Datta, Neerajana; Chakraborty, Subhradeep; Basu, Mausumi; Ghosh, Mrinal K.

doi:10.3390/cells10010046

Cited by 63 publications

(47 citation statements)

References 198 publications

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“…In the verrucous lesion of patient Ia, the wild-type allele was also found to be regularly transcribed, with no allelic imbalance clearly detected, and translated, therefore a significant reduction of the PTEN protein is not supported. These results confirm that PTEN fails to follow the Knudson two-hit mechanism expected for classical tumor-suppressor genes and support the hypothesis of a haploinsufficiency mechanism for this gene (15,16). To the best of our knowledge, evidence supporting this hypothesis are mainly based on experimental models (17)(18)(19)(20), and therefore the verification on real patients, as performed in this and in our previous works, is fundamental to better understand the pathogenic mechanism of PTEN.…”

Section: Discussionsupporting

confidence: 84%

“…Even though the biological roles of this gene have been extensively studied, the link between the dysfunction caused by germline variants and the clinical manifestations remains largely elusive. It is known that although PTEN is considered a tumor-suppressor gene, its behavior differs from that of classical tumor-suppressor genes, which act in accordance with Knudson's "two-hit" hypothesis (14,15). Indeed, evidence showing that the loss of a single PTEN allele is enough to promote cancer development has led to the hypothesis of a haploinsufficiency mechanism for this gene (16).…”

Section: Introductionmentioning

confidence: 99%

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PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

et al. 2021

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Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

et al. 2021

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“…However, extensive research over the last few years has elucidated that certain tumor suppressor genes might act as "double agents" with both oncogenic and tumor-suppressor functions. Therefore, in some cases heterozygous pathogenic variations can lead to manifest disease with a dominant inheritance pattern [59]. Legius syndrome is a demonstrative example.…”

Section: Nf1-like Syndromes With Unclarified Tumor Predisposing Effectmentioning

confidence: 99%

Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

et al. 2021

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Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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“…It is also possible that fibronectin internalization mediated by LRP1 is the result of specific signalling activated by eHSP90. Indeed, AKT and NF-κB activation (eHSP-LRP1 mediated signalling pathways) has been reported to be involved in fibronectin turnover [ 69 , 96 , 97 ].…”

Section: Ehsps Tune Cancer Hallmarksmentioning

confidence: 99%

The dark-side of the outside: how extracellular heat shock proteins promote cancer

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et al. 2021

Cell. Mol. Life Sci.

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In addition to exerting several essential house-keeping activities in the cell, heat shock proteins (HSPs) are crucial players in a well-structured molecular program activated in response to stressful challenges. Among the different activities carried out by HSPs during emergency, they reach the extracellular milieu, from where they scout the surroundings, regulate extracellular protein activity and send autocrine and paracrine signals. Cancer cells permanently experience stress conditions due to their altered equilibrium and behaviour, and constantly secrete heat shock proteins as a result. Other than supporting anti-tumour immunity, extracellular heat shock proteins (eHSPs), can also exacerbate cancer cell growth and malignancy by sustaining different cancer hallmarks. eHSPs are implicated in extracellular matrix remodelling, resistance to apoptosis, promotion of cell migration and invasion, induction of epithelial to mesenchymal transition, angiogenesis and activation of stromal cells, supporting ultimately, metastasis dissemination. A broader understanding of eHSP activity and contribution to tumour development and progression is leading to new opportunities in the diagnosis and treatment of cancer.

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Tumor Suppressors Having Oncogenic Functions: The Double Agents

Cited by 63 publications

References 198 publications

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

The dark-side of the outside: how extracellular heat shock proteins promote cancer

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