TP53 - tumor protein p53
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Publication
Journal: Best practice & research. Clinical endocrinology & metabolism
May/16/2020
Abstract
Cushing syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.
Publication
Journal: Clinical Lung Cancer
May/16/2020
Abstract
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC) harboring mutations in many canonical NSCLC-driver genes (eg, TP53, KRAS, MET). Protection of telomeres 1 (POT1) mutations are observed in angiosarcoma and chronic lymphocytic leukemia, but their frequency in other solid tumors, including NSCLC subtypes, has not been rigorously explored.We analyzed next-generation sequencing data from 62,368 tumors, including 11,134 NSCLCs and 100 PSCs. We performed logistic regression to identify associations between POT1 mutation frequency and tumor histology across 184 tumor categories, adjusting for tumor mutational burden. We further explored co-occurring gene mutations in genes previously reported to underlie PSC tumorigenesis.

RESULTS
Across 184 tumor categories, POT1 mutations were most frequent in PSC and were 14 times more common in PSC (28%) than in other tumor types (P = 1.23 × 10-31) and 6.7 times more common in PSC than other NSCLCs (P = 5.1 × 10-17). PSCs harboring KRAS mutations were significantly more likely to harbor POT1 mutations (P = 1.3 × 10-3), whereas those with TP53 mutations were less likely to harbor POT1 mutations (P = .037). One-fourth of POT1-mutated PSCs harbored a second POT1 mutation. Across all PSCs, 83% of POT1 mutations were in the OB1/OB2 (DNA-binding) domain (P = 1.5 × 10-5), an enrichment not observed in other tumor types.

We report an unanticipated association between POT1 mutation and PSC. Unlike other molecular alterations that are frequent across NSCLC subtypes, POT1 mutations are largely unique to PSC. This finding may help to develop disease-defining molecular subgroups within PSC and presents opportunities for molecularly stratified prognostication and therapy.
Publication
Journal: Cancers
May/16/2020
Abstract
Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n = 42) and European American (EA, n = 33) women. RNA sequencing data were analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like two tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.
Publication
Journal: American Journal of Pathology
May/16/2020
Abstract
Prognosis for young patients with breast cancer is generally poor, yet considerable differences in clinical outcome between individual patients exist. To understand the genetic basis of the disparate clinical courses, we collected tumors from 34 younger women, 17 with good and 17 with poor outcomes, as determined by disease-specific survival during a follow-up period of 17 years. The clinicopathological parameters of the tumors were complemented with DNA image cytometry profiles, enumeration of copy numbers of eight breast cancer genes by multicolor fluorescence in situ hybridization, and targeted sequence analysis of 563 cancer genes. Both groups included diploid and aneuploid tumors. The degree of intratumor heterogeneity was significantly higher in aneuploid versus diploid cases, and so were gains of the oncogenes MYC and ZNF217. We observed significantly more copy number alterations in the group with poor outcome. Almost all tumors in the group with long survival were classified as luminal A, whereas triple-negative tumors predominantly occurred in the short survival group. Mutations of PIK3CA were more common in the group with good outcome, whereas TP53 mutations were more frequent in patients with poor outcomes. We show that TP53 mutations and the extent of genomic imbalances are associated with poor outcome in younger breast cancer patients and thus emphasize the central role of genomic instability vis-a-vis tumor aggressiveness.
Publication
Journal: International Journal of Molecular Sciences
May/16/2020
Abstract
TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.
Publication
Journal: Nature Communications
May/16/2020
Abstract
Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).
Publication
Journal: Gynecologic Oncology
May/15/2020
Abstract
Uterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated.In this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing.In 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC.In conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.
Publication
Journal: Thoracic Cancer
May/15/2020
Abstract
TP53 is a crucial tumor suppressor gene. However, the mutation pattern of TP53 in Chinese patients with breast cancer has not yet been determined.A total of 411 untreated patients with invasive breast cancer diagnosed at Guangdong Provincial People's Hospital (GDPH) between June 2017 to September 2018 were recruited into the study. Mutational alterations in TP53 were detected and correlations between TP53 mutations and clinicopathological features analyzed. Comparative analysis of the data in the GDPH cohort with those in the METABRIC cohort were carried out.A significantly higher rate of TP53 mutations was detected in the GDPH cohort (51.3%) compared with the METABRIC cohort (34.4%) (P < 0.01). In the GDPH cohort, 77.8% of the mutations were located in the conserved areas across exons 5-8 of TP53; among these, 112 were identified as missense mutations and mainly clustered in the DNA-binding region. R273C/H (n = 11) and R248Q/W (n = 10) were two of the most common mutation sites of TP53 detected in the cohort of GDPH patients. Logistic regression multivariate analysis showed that histological grade III, ki-67 > = 25%, HR- and Her2+ in breast cancer had higher mutation probability of TP53 (P < 0.001 in the GDPH cohort). Furthermore, receiver operating characteristic (ROC) model combining molecular typing and Ki-67 was established to predict the mutation of TP53, and the AUC was 0.846.A significantly higher rate of TP53 mutation was detected in the Chinese cohort compared with the METABRIC. Correlation analysis revealed a significant association of TP53 mutation with HR- and HER2+, higher Ki-67 and histological grade in breast cancer patients.
Publication
Journal: Scientific Reports
May/15/2020
Abstract
Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of PTCH1 and TP53 and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcription levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 58.6% and TP53 in 31.4% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59.2% and 38.2% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. Increased reverse transcriptase subunit expression was observed in tumors with TERT promoter mutations and not with THOR methylation. Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter.
Publication
Journal: International Immunopharmacology
May/15/2020
Abstract
The STK11 mutation defined a special subtype for patients with lung adenocarcinoma. The cBioPortal data platform was applied to analyze STK11 mutation frequency and the relationship between STK11 mutation and immune prognostic markers. The TIMER database was used to analyze the relationship between STK11 mutation and immune cell infiltration. The survival difference for lung adenocarcinoma patients harbored STK11 mutation who received immunotherapy also used the cBioPortal database. The results showed that STK11 mutation co-occurrence more KRAS and KEAP1 mutation and fewer TP53 and EGFR mutation (all, P < 0.05); the patients harbored STK11 mutation had a lower expression of PDL1 (P = 0.002), higher TMB score (P = 0.002), higher proportion of males and smoking history; the patients harbored STK11 mutation had fewer immune cell infiltration including B cell (P < 0.01), CD8+ T cell (P < 0.001), CD4+ T cell (P < 0.001), Macrophage (P < 0.001), Neutrophil (P < 0.001) and Dendritic cell (P < 0.001). Importantly, we found the patients harbored STK11 mutation who received immune checkpoint inhibitors have worse overall survival (OS) with median survival only 6 months. In conclusion, our study demonstrated that STK11 mutation defined a special subtype for lung adenocarcinoma patients with different co-occurrence gene mutation, lower PDL1 expression, fewer immune cell infiltration and worse OS benefit from immune checkpoint inhibitors.
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