دورية أكاديمية
Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants.
| العنوان: | Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants. |
|---|---|
| المؤلفون: | Pinto EM; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee. emilia.pinto@stjude.org raul.ribeiro@stjude.org gerard.zambetti@stjude.org., Maxwell KN; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania., Halalsheh H; King Hussein Cancer Center, Amman, Jordan., Phillips A; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Powers J; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania., MacFarland S; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania., Walsh MF; Department of Pediatrics and Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Breen K; Department of Pediatrics and Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Formiga MN; Department of Oncogenetics, A.C. Camargo Center, Sao Paulo, Brazil., Kriwacki R; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Nichols KE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Mostafavi R; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Wang J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee., Clay MR; Department of Pathology, University of Colorado, Boulder, Colorado., Rodriguez-Galindo C; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.; Global Pediatric Medicine at St. Jude Children's Research Hospital, Memphis, Tennessee., Ribeiro RC; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. emilia.pinto@stjude.org raul.ribeiro@stjude.org gerard.zambetti@stjude.org., Zambetti GP; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee. emilia.pinto@stjude.org raul.ribeiro@stjude.org gerard.zambetti@stjude.org. |
| المصدر: | Molecular cancer research : MCR [Mol Cancer Res] 2022 Feb; Vol. 20 (2), pp. 207-216. Date of Electronic Publication: 2021 Oct 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002- |
| مواضيع طبية MeSH: | Exons/*genetics , Genetic Variation/*genetics , Introns/*genetics , Tumor Suppressor Protein p53/*genetics, Humans |
| مستخلص: | Germline TP53 splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4-intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACT). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and in silico assays to determine protein stability, splicing, and transcriptional activity of 10 TP53 variants at exon 4-intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of TP53 variants in human cancer and examined individual reports, focusing on family history of cancer. TP53 exon 4-intron 4 junction germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional eight independent TP53 variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project ( n = 5,213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization, and loss of function. Clinical case review of carriers of TP53 exon 4-intron 4 junction variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni syndrome. Germline variants involving TP53 exon 4-intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline TP53 variants on the fidelity of splicing, protein structure, and function must be considered in evaluating cancer susceptibility. IMPLICATIONS: Taken together, the data indicate that splice variants at TP53 codon 125 and surrounding bases differentially impacted p53 gene expression and function. (©2021 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS; P30 CA021765 United States CA NCI NIH HHS |
| سلسلة جزيئية: | ClinicalTrials.gov NCT00700414; NCT00304070 |
| المشرفين على المادة: | 0 (TP53 protein, human) 0 (Tumor Suppressor Protein p53) |
| تواريخ الأحداث: | Date Created: 20211022 Date Completed: 20220330 Latest Revision: 20220802 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8816887 |
| DOI: | 10.1158/1541-7786.MCR-21-0583 |
| PMID: | 34675114 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3125 |
|---|---|
| DOI: | 10.1158/1541-7786.MCR-21-0583 |