A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

2019 ◽  
Vol 52 (1) ◽  
pp. 34-40 ◽  
Author(s):  
K. E. Knickelbein ◽  
M. E. Lassaline ◽  
M. Singer‐Berk ◽  
C. M. Reilly ◽  
A. B. Clode ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Risk Factor ◽  
Dna Binding ◽  
Cell Carcinoma ◽  
Missense Mutation ◽  
Squamous Cell ◽  
Genetic Risk ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Genetic Risk Factor

scholarly journals A missense mutation in damage-specific DNA binding protein 2 is a genetic risk factor for limbal squamous cell carcinoma in horses

2017 ◽  
Vol 141 (2) ◽  
pp. 342-353 ◽  
Author(s):  
Rebecca R. Bellone ◽  
Jiayin Liu ◽  
Jessica L. Petersen ◽  
Maura Mack ◽  
Moriel Singer-Berk ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Risk Factor ◽  
Dna Binding ◽  
Cell Carcinoma ◽  
Missense Mutation ◽  
Squamous Cell ◽  
Genetic Risk ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Genetic Risk Factor

scholarly journals DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1460
Author(s):  
Margo Crausaz ◽  
Thomas Launois ◽  
Kathryn Smith-Fleming ◽  
Annette M. McCoy ◽  
Kelly E. Knickelbein ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Risk Factor ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Genetic Risk ◽  
Mate Selection ◽  
Missense Variant ◽  
Genetic Risk Factor ◽  
Dna Testing ◽  
Gene Damage

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye. A missense variant within the gene damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) was previously identified as a causal recessive genetic risk factor for the development of ocular SCC within Haflingers, Belgian Draft horses, and Rocky Mountain Horses, but not in the Appaloosa or Arabian breeds. This study aimed to evaluate three cases of ocular SCC in additional breeds and determine if DNA testing for the DDB2 variant in warmblood horses and Connemara ponies is warranted. Histopathology confirmed ocular SCC in all three cases and DNA testing confirmed each horse was homozygous for the DDB2 risk factor. The DDB2 risk allele frequency was estimated to be 0.0043 for Holsteiners (N = 115), 0.014 for Belgian Warmbloods (N = 71), and 0.22 for Connemara Ponies (N = 86). Taken together these data support using DNA testing for DDB2 in Connemara Ponies to assist in mate selection and clinical management. Given the low observed allele frequencies in both the Holsteiner and Belgian Warmblood breeds and that the case under investigation was a warmblood cross-bred, evaluating additional SCC affected warmbloods is warranted to fully determine the importance of DDB2 genotyping as a risk factor in warmblood breeds.

scholarly journals Knockdown of Ubiquitin-Specific Protease 53 Enhances the Radiosensitivity of Human Cervical Squamous Cell Carcinoma by Regulating DNA Damage-Binding Protein 2

2020 ◽  
Vol 19 ◽  
pp. 153303382092979
Author(s):  
Qifen Zhou ◽  
Xiongbo Yao ◽  
Chunlin Wu ◽  
Shaohua Chen ◽  
Dage Fan
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Dna Binding ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Binding Protein ◽  
Cervical Squamous Cell Carcinoma ◽  
Dna Binding Protein ◽  
Specific Protein ◽  
Cycle Arrest

Background: Cervical cancer ranks fourth in incidence and mortality among women. Ubiquitin-specific protein 53 binds to damage-specific DNA binding protein 2 and affects the biological properties of colon cancer. Damage-specific DNA binding protein is involved in nucleotide excision repair, which can repair DNA damage. However, the mechanism by which ubiquitin-specific protein 53 regulates the radiosensitivity of cervical cancer through damage-specific DNA binding protein remains unclear. Methods: Tissue samples from 40 patients with cervical squamous cell carcinoma who received radiotherapy were examined by immunohistochemistry to detect the expression of ubiquitin-specific protein 53, and clinical data were collected for statistical analysis. The cell cycle was detected by flow cytometry in Siha cells transfected with Si-USP53 and exposed to 8 Gy irradiation. Cell viability was determined by the CCK8 method in cells transfected with Si-USP53 and exposed to 0, 2, 4, 6, 8, or 10 Gy. The expression of damage-specific DNA binding protein, cyclin-dependent kinase 1, and cell cycle checkpoint kinase 2 was detected in cells transfected with Si-USP53. Results: The expression of ubiquitin-specific protein 53 in the tissues of patients with cervical squamous cell carcinoma was correlated with the sensitivity to radiotherapy. Knockdown of ubiquitin-specific protein 53 in Siha cells downregulated damage-specific DNA binding protein and caused G2/M cell cycle arrest and decreased the survival rate of cells in response to radiation. Conclusion: Ubiquitin-specific protein 53–induced cell cycle arrest and affected the radiotherapy sensitivity of tumors through damage-specific DNA binding protein.

scholarly journals Additional Evidence for DDB2 T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Moriel H. Singer-Berk ◽  
Kelly E. Knickelbein ◽  
Zachary T. Lounsberry ◽  
Margo Crausaz ◽  
Savanna Vig ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Genetic Risk ◽  
High Throughput Sequencing ◽  
Risk Allele ◽  
Dna Binding Protein ◽  
Sequencing Data ◽  
High Throughput Sequencing Data ◽  
Better Than

Squamous cell carcinoma (SCC) is the most common periocular cancer in horses and the second most common tumor of the horse overall. A missense mutation in damage-specific DNA-binding protein 2 (DDB2, c.1012 C>T, p.Thr338Met) was previously found to be strongly associated with ocular SCC in Haflinger and Belgian horses, explaining 76% of cases across both breeds. To determine if this same variant in DDB2 contributes to risk for ocular SCC in the Arabian, Appaloosa, and Percheron breeds and to determine if the variant contributes to risk for oral or urogenital SCC, histologically confirmed SCC cases were genotyped for the DDB2 variant and associations were investigated. Horses with urogenital SCC that were heterozygous for the DDB2 risk allele were identified in the Appaloosa breed, but a significant association between the DDB2 variant and SCC occurring at any location in this breed was not detected. The risk allele was not identified in Arabians, and no Percherons were homozygous for the risk allele. High-throughput sequencing data from six Haflingers were analyzed to ascertain if any other variant from the previously associated 483 kb locus on ECA12 was more concordant with the SCC phenotype than the DDB2 variant. Sixty polymorphisms were prioritized for evaluation, and no other variant from this locus explained the genetic risk better than the DDB2 allele (P=3.39×10−17, n=118). These data provide further support of the DDB2 variant contributing to risk for ocular SCC, specifically in the Haflinger and Belgian breeds.

Su1821 A Risk Factor Predictive of Serious Laryngeal Edema During Endoscopic Resection for Squamous Cell Carcinoma of the Esophagus

2013 ◽  
Vol 144 (5) ◽  
pp. S-482
Author(s):  
Nobuyuki Ara ◽  
Kaname Uno ◽  
Naoki Asano ◽  
Katsunori Iijima ◽  
Tomoyuki Koike ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Risk Factor ◽  
Cell Carcinoma ◽  
Endoscopic Resection ◽  
Squamous Cell ◽  
Laryngeal Edema ◽  
Carcinoma Of The Esophagus

PS02.024: PRIMA-1 INDUCES P53-MEDIATED APOPTOSIS BY UPREGULATING NOXA IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH TP53 MISSENSE MUTATION

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 126-127
Author(s):  
Haruna Furukawa ◽  
Tomoki Makino ◽  
Makoto Yamasaki ◽  
Koji Tanaka ◽  
Yasuhiro Miyazaki ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Missense Mutation ◽  
Cell Lines ◽  
Squamous Cell ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Wild Type ◽  
Massive Apoptosis

Abstract Background TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore wild type activity to mutant p53 and induce massive p53-dependent apoptosis. APR-246 (methylated PRIMA-1) has been tested in a phase I/II clinical trial with promising results; however, the effects and mechanism in ESCC remain unknown. This study was designed to assess the antitumor effect of PRIMA-1 treatment in both ESCC cell lines with different TP53 status and an ESCC xenograft model and uncover the molecular mechanism of PRIMA-1. Methods After evaluating the TP53 mutation status of a panel of eleven ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different p53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in TP53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1’s function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. Results PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with a TP53 missense mutation, whereas no apoptosis was induced in ESCC with wild type TP53 and with TP53 frameshift and nonsense mutations. Importantly, the knockdown of Noxa cancelled the apoptosis induced by PRIMA treatment in ESCC cell lines with a TP53 missense mutation. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. Conclusion PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with a TP53 missense mutation. Disclosure All authors have declared no conflicts of interest.

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