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p53 cancer mutation

Ramona Schulz-Heddergott, Nadine Stark, Shelley J Edmunds, Jinyu Li, Lena-Christin Conradi, Hanibal Bohnenberger, Fatih Ceteci, Florian R Greten, Matthias Dobbelstein, Ute M Moll
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q ) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth...
August 13, 2018: Cancer Cell
Wanglei Qu, Yinling Zhao, Xuan Wang, Yaozhi Qi, Clare Zhou, Ying Hua, Jianqing Hou, Shi-Wen Jiang
BACKGROUND: This study aimed to determine the in vitro and in vivo properties of sixteen frequently used endometrial cancer (EC) cell lines, including the cell proliferation rate, morphology, hormone receptor expression patterns, PTEN, hMLH1 expression, p53 mutation, karyotype, and tumorigenicity in mouse xenograt model. METHODS: Twelve type I (AN3, ECC-1, EN, EN-1, EN-11, HEC-1A, HEC1B, Ishikawa, KLE, MFE-280, MFE-296, MFE-319) and four type II (ARK1, ARK2, HEC-155/180, SPEC-2) endometrial cancer cell lines were studied...
August 11, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Hui Zou, Runying Zou, Keke Chen, Chengguang Zhu, Xin Tian, Yalan You, Xiangling He
Burkitt lymphoma is one of the most common lymphatic system cancers with poor outcome in adult patients. p53-induced apoptosis is a critical signaling for preventing tumor development. Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. However, p53 is frequently mutated in Burkitt lymphoma, which gains novel oncogenic properties. Recently, the p53 family member, p63, became an attractive gene for the therapeutic strategies for patients with cancer...
August 13, 2018: Journal of Cellular Biochemistry
Urvi A Shah, Elaine Y Chung, Orsolya Giricz, Kith Pradhan, Keisuke Kataoka, Shanisha Gordon-Mitchell, Tushar D Bhagat, Yun Mai, Yongqiang Wei, Elise Ishida, Gaurav S Choudhary, Ancy Joseph, Ronald Rice, Nadege Gitego, Crystall Parrish, Matthias Bartenstein, Swati Goel, Ioannis Mantzaris, Aditi Shastri, Olga Derman, Adam Binder, Kira Gritsman, Noah Kornblum, Ira Braunschweig, Chirag Bhagat, Jeff Hall, Armin Graber, Lee Ratner, Yanhua Wang, Seishi Ogawa, Amit Verma, B Hilda Ye, Murali Janakiram
Adult T cell leukemia lymphoma (ATLL) is a rare T cell neoplasm, endemic in the Japanese, Caribbean and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared to the Japanese ATLL. To determine genomic differences between these two cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results to the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher whereas the mutation frequency in JAK/STAT and TCR/NF-κB pathway genes was significantly lower in our cohort...
August 13, 2018: Blood
Ana Carolina de Carvalho, Matias Eliseo Melendez, Cristina da Silva Sabato, Edenir Inez Palmero, Lidia Maria Rebolho Batista Arantes, Cristovam Scapulatempo Neto, André Lopes Carvalho
A better understanding of the clinical and molecular features of oropharyngeal squamous cell carcinomas (OPSCC) may help in the development of strategies for a better patient management, improving survival rates. This retrospective study conducted a clinical and molecular characterization of surgically treated OPSCC samples. Paraffin-embedded samples from a series of cases were screened for high-risk (HR) human papillomavirus (HPV) infection, methylation of a 5-gene panel, p53 expression, and TP53 mutation...
August 11, 2018: Pathology Oncology Research: POR
M Janaki Ramaiah, S Vaishnave
BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy...
August 7, 2018: Gene
Juan Jovel, Zhen Lin, Sandra O'keefe, Steven Willows, Weiwei Wang, Guangzhi Zhang, Jordan Patterson, Carlos Moctezuma-Velázquez, David J Kelvin, Gane Ka-Shu Wong, Andrew L Mason
Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants were inferred from whole genome low-pass sequencing data, and a set of 56 cancer-related genes were screened using an oncology panel assay...
August 2018: Hepatology Communications
Fengjun Guo, Haina Zhang, Zanhui Jia, Manhua Cui, Jingyan Tian
Endometrial cancer tends to be an aggressive malignancy. Although the disease prognosis can be good at the early stages of disease, the advanced condition is not curable. Chemotherapy regimens and hormone-based therapy in combination with surgery are major approaches for the management of endometrial cancers. However, intrinsic chemoresistance reduces the success rate and increases the possibility of disease relapse. Investigation of underlying mechanisms revealed altered activation of PI3K/AKT, MAPK, fibroblast growth factor (FGF), mTOR and WNT pathways and reduced gene expression of tumor suppressor p53 in recurrent endometrial cancer...
2018: American Journal of Cancer Research
Yu-Liang Jiang, Zi-Ye Zhao, Bai-Rong Li, Fu Yang, Jing Li, Xiao-Wei Jin, Hao Wang, En-Da Yu, Shu-Han Sun, Shou-Bin Ning
BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by mutations in serine/threonine kinase 11 (STK11) gene. The increased cancer risk has been connected to P53 pathway. METHODS: PJS probands with STK11 mutation were included in the function analysis. P53 activity elevated by STK11 mutants was investigated using dual-luciferase reporter assay in vitro after constructing expression vectors of STK11 wild type and mutants generated by site-directed substitution. The association between the P53 activity and clinicopathological factors was analysis, especially the cancer history...
August 9, 2018: BMC Medical Genetics
Shu-Yuan Cheng, Anayatzinc Vargas, Ji-Young Lee, Cristina C Clement, Elise Champeil
Mitomycin C (MC) is a well-known DNA alkylating agent. MC analog, 10-decarbamoyl mitomycin C (DMC), unlike MC, has stronger effects on cancer with p53 mutation. We previously demonstrated that MC/DMC could activate p21WAF 1/ CIP 1 in MCF-7 (p53-proficient) and K562 (p53-deficient) cells in a p53-independent mode. This study aimed to elucidate the upstream signaling pathway of p21WAF 1/ CIP 1 activation triggered by MC/DMC. Besides p53, Akt plays an important role on deactivating p21WAF 1/ CIP 1 . The results showed that MC/DMC inhibited Akt in MCF-7 cells, but not in K562 cells...
August 9, 2018: Chemical Biology & Drug Design
Nicholas W Fischer, Aaron Prodeus, Jean Gariépy
BACKGROUND: There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS: This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations)...
August 9, 2018: JCI Insight
Patrick Nyman, Darya Buehler, Paul F Lambert
PURPOSE: Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption and high risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. Notch1 is among the most frequently mutated genes in both HPV-positive and HPV-negative HNSCC...
August 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Maria Teresa Valenti, Luca Dalle Carbonare, Monica Mottes
The transcription factor RUNX2 is the osteogenic master gene expressed in mesenchymal stem cells during osteogenic commitment as well as in pre-osteoblasts and early osteoblasts. However, RUNX2 is also ectopically expressed in melanoma and other cancers. Malignant melanoma (MM) is a highly metastatic skin cancer. The incidence of MM has increased considerably in the past half-century. The expression levels and mutation rates of genes such as BRAF , KIT , NRAS , PTEN , P53 , TERT and MITF are higher in melanoma than in other solid malignancies...
July 26, 2018: World Journal of Stem Cells
Audrey Deeken-Draisey, Guang-Yu Yang, Juehua Gao, Borislav A Alexie
Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of thyroid cancer. A single institution thyroid cancer cohort of ATC was identified within the last ten years at our institution. Retrospective analysis revealed that the frequency of ATC was 0.5% (11/2106 thyroid carcinomas). The average age at diagnosis of ATC was 74 years, and the female to male ratio was 1.2:1. ATC presented as a rapidly enlarging neck mass involving predominantly the left thyroid lobe (7/11, 64%). Cervical adenopathy was present in 7/11 (64%) of cases...
July 31, 2018: Human Pathology
Edwige Kasper, Emilie Angot, Elodie Colasse, Lionel Nicol, Jean-Christophe Sabourin, Sahil Adriouch, Yann Lacoume, Camille Charbonnier, Sabine Raad, Thierry Frebourg, Jean-Michel Flaman, Gaëlle Bougeard
INTRODUCTION: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. MATERIALS AND METHODS: We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice...
July 30, 2018: European Journal of Cancer
Dae-Won Lee, Sae-Won Han, Jun-Kyu Kang, Jeong Mo Bae, Hwang-Phill Kim, Jae-Kyung Won, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim
BACKGROUND: There is a close link between Fusobacterium nucleatum and colorectal cancer (CRC) tumorigenesis and chemoresistance. However, the genetic characteristics and clinical significance of CRC related with F. nucleatum remains unclear. This study evaluated the relationship between F. nucleatum, pathway mutation, and patient prognosis. METHODS: Fusobacterium nucleatum amount in the tumor tissue and adjacent normal tissue were measured by quantitative polymerase chain reaction in adjuvant (N = 128) and metastatic (N = 118) cohorts...
July 30, 2018: Annals of Surgical Oncology
Yoon-Sim Yap, Angad P Singh, John H C Lim, Jin-Hee Ahn, Kyung-Hae Jung, Jeongeun Kim, Rebecca A Dent, Raymond C H Ng, Sung-Bae Kim, Derek Y Chiang
Breast cancer is an increasing problem in Asia, with a higher proportion of premenopausal patients who are at higher risk of recurrence. Targeted sequencing was performed on DNA extracted from primary tumor specimens of 63 premenopausal Asian patients who relapsed after initial diagnosis of non-metastatic breast cancer. The most prevalent alterations included: TP53 (65%); PIK3CA (32%); GATA3 (29%); ERBB2 (27%); MYC (25%); KMT2C (21%); MCL1 (17%); PRKDC, TPR, BRIP1 (14%); MDM4, PCDH15, PRKAR1A, CDKN1B (13%); CCND1, KMT2D, STK11 , and MLH1 (11%)...
2018: NPJ Breast Cancer
Vanesa Gottifredi, Lisa Wiesmüller
The tumor suppressor p53 is a transcriptional factor broadly mutated in cancer. Most inactivating and gain of function mutations disrupt the sequence-specific DNA binding domain, which activates target genes. This is perhaps the main reason why most research has focused on the relevance of such transcriptional activity for the prevention or elimination of cancer cells. Notwithstanding, transcriptional regulation may not be the only mechanism underlying its role in tumor suppression and therapeutic responses...
July 28, 2018: Cancers
Zehang Jiang, Zhixian Liu, Mengyuan Li, Cai Chen, Xiaosheng Wang
Although immunotherapy continues to demonstrate efficacy in a variety of refractory cancers, currently, no any immunotherapeutic strategy is clinically used for gastric cancer (GC) except its microsatellite instable subtype. Thus, it is important to identify molecular biomarkers for predicting the responders to GC immunotherapy. TP53 mutations frequently occur in GC and are associated with unfavorable clinical outcomes in GC. We performed a comprehensive characterization of the associations between TP53 mutations and immune activities in GC based on two large-scale GC cancer genomics data...
July 27, 2018: Translational Oncology
Felix Kf Kommoss, Anthony N Karnezis, Friedrich Kommoss, Aline Talhouk, Florin-Andrei Taran, Annette Staebler, C Blake Gilks, David G Huntsman, Bernhard Krämer, Sara Y Brucker, Jessica N McAlpine, Stefan Kommoss
BACKGROUND: The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort...
July 27, 2018: British Journal of Cancer
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