Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment

Rocca, Valentina; Blandino, Giovanni; D’Antona, Lucia; Iuliano, Rodolfo; Agostino, Silvia Di

doi:10.3390/cancers14153664

Cited by 21 publications

(13 citation statements)

References 108 publications

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“…Inherited germline TP53 pathogenic and likely pathogenic mutations (TP53) cause autosomal dominant multicancer predisposition 33,34 . And one of the most iconic diseases is Li-Fraumeni syndrome (LFS) [35][36][37] . A study found that LFS men have a 25-fold increased risk of PCa compared with the general population 38 .…”

Section: Discussionmentioning

confidence: 99%

Integrative analyses of DNA methylase expression and related immune landscape in Prostate Cancer

Zhang,

Huang,

Wang

2024

Preprint

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Objectives DNA methylation is a common in epigenetics process which plays important roles in the initiation and progression of prostate cancer (PCa). However, the underlying mechanism remains poorly understood. Methods and Results In this study, we systematically analyzed expression level of DNA methylase in prostate cancer and their correlation with immune infiltration and patient outcomes. We enrolled the transcription data of 52 normal and 502 prostate cancer tissues for the study. First, we systematically analyzed data pertaining to patient clinical information and mRNA gene expression data. We found that 5 out of 8 key regulators of DNA methylase significantly increased in PCa. Subsequently, we identified two subgroups (clusters 1 and 2) via consensus clustering based on the expression of 8 DNA methylase. Cluster 2 had worse prognosis, higher histological grade and pathological stage compared with cluster 1. Moreover, cluster 2 was remarkably enriched for cancer-related pathways. We further constructed a robust risk signature based on the expression of DNA methylase. Further analysis indicated that this risk signature could be an independent prognostic factor for PCa. Moreover, the efficacy of this three-gene risk signature was validated in external dataset. We also show that the model is highly correlated with immune cell infiltration. Conclusions In summary, we in this study uncovered the vital roles of DNA methylase in PCa and developed a risk signature as a promising prognostic marker in PCa patients. At the same time, it provides a reliable basis for the choice of treatment.

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Section: Discussionmentioning

confidence: 99%

Integrative analyses of DNA methylase expression and related immune landscape in Prostate Cancer

Zhang,

Huang,

Wang

2024

Preprint

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“…Therefore, these clinical data suggested that tumors with PSMD14 overexpression in BC patients were significantly correlated with aggressive tumor characteristics. Multiple studies have confirmed that there are noticeable family genetic characteristics in the tumorigenesis of malignant tumors, such as ovarian cancers (BRCA1 and BRCA2 mutations) ( Heemskerk-Gerritsen et al, 2022 ), Li-Fraumeni syndrome (TP53 mutation) ( Rocca et al, 2022 ) and hereditary nonpolyposis colorectal cancer (DNA mismatch repair deficient) ( Liotta et al, 2021 ). Similarly, our study showed that patients with a family history of cancer were more likely to have high PSMD14 expression.…”

Section: Discussionmentioning

confidence: 99%

Depletion of PSMD14 suppresses bladder cancer proliferation by regulating GPX4

Jia

Zhang

et al. 2023

PeerJ

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Objective The aim of this study was to investigate the role of deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in patients with bladder cancer. Methods From 2016 to 2018, 181 patients diagnosed with primary bladder cancer at the Affiliated Hospital of Qingdao University were recruited. The expression of PSMD14 in bladder cancer tissues was tested by immunochemistry. The association between PSMD14 expression and clinical and pathological data and outcomes of bladder cancer patients was determined. Overexpression and knockdown cells were constructed to evaluate the effects of PSMD14 on proliferation of bladder cancer cells. Results Our results showed that PSMD14 was significantly overexpressed in bladder cancer tissues compared to adjacent non-tumor tissues (76.24% vs 23.76%, P = 0.02). The expression of PSMD14 was significantly higher in patients with larger tumor diameters (85.14% vs 70.09%, P = 0.019) and patients with a family history of cancer (92.16% vs 70.00%, P = 0.002). Patients with high expression of PSMD14 had poor disease-free survival (DFS) (HR = 2.89, 95% CI [1.247–6.711], P = 0.013). Gain and loss of function experiments demonstrated that PSMD14 deficiency inhibited bladder cancer cell proliferation. Additionally, depletion of PSMD14 suppressed bladder cancer cell growth via down-regulation of GPX4, and the promotion of PSMD14-induced cell growth was observably reversed by the GPX4 inhibitor RSL3. Conclusion We determined that PSMD14 is highly expressed in bladder cancer tissues, and that PSMD14 expression correlated with poor disease-free survival. Depletion of PSMD14 could inhibit the proliferation of bladder cancer cells through the downregulation of GPX4. Therefore, PSMD14 may be an effective target for the treatment of bladder cancer.

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“…Germline mutations in genes involved in DNA repair pathways are associated with genome instability and an increased risk of cancer development. For example, individuals with Li-Fraumeni syndrome are predisposed to various cancers, including leukemia, sarcomas, brain tumors, adrenocortical carcinoma, and other solid tumors, often manifesting at a young age ( 9 ). While TP53 germline mutations are frequently associated with Li-Fraumeni syndrome, some individuals with TP53-negative Li-Fraumeni syndrome harbor germline mutations in CHEK2 ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Case report: A germline CHEK1 c.613 + 2T>C leads to a splicing error in a family with multiple cancer patients

Qian,

Peng,

et al. 2024

Front. Oncol.

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BackgroundGenome instability plays a crucial role in promoting tumor development. Germline mutations in genes responsible for DNA repair are often associated with familial cancer syndromes. A noticeable exception is the CHEK1 gene. Despite its well-established role in homologous recombination, germline mutations in CHEK1 are rarely reported.Case presentationIn this report, we present a patient diagnosed with ovarian clear cell carcinoma who has a family history of cancer. Her relatives include a grandfather with esophageal cancer, a father with gastric cancer, and an uncle with a brain tumor. The patient carried a typical genomic profile of clear cell carcinoma including mutations in KRAS, PPP2R1A, and PIK3R1. Importantly, her paired peripheral blood cells harbored a germline CHEK1 mutation, CHEK1 exon 6 c.613 + 2T>C, which was also found in her father. Unfortunately, the CHEK1 status of her grandfather and uncle remains unknown due to the unavailability of their specimens. Further evaluation via RT-PCR confirmed a splicing error in the CHEK1 gene, resulting in truncation at the kinase domain region, indicative of a loss-of-function mutation.ConclusionThis case highlights a rare germline CHEK1 mutation within a family with a history of cancer. The confirmed splicing error at the mRNA level underscores the functional consequences of this mutation. Documenting such cases is vital for future evaluation of inheritance patterns, clinical penetrance of the mutation, and its association with specific cancer types.

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Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment

Cited by 21 publications

References 108 publications

Integrative analyses of DNA methylase expression and related immune landscape in Prostate Cancer

Integrative analyses of DNA methylase expression and related immune landscape in Prostate Cancer

Depletion of PSMD14 suppresses bladder cancer proliferation by regulating GPX4

Case report: A germline CHEK1 c.613 + 2T>C leads to a splicing error in a family with multiple cancer patients

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