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1.
Asian Pac J Cancer Prev ; 24(9): 3165-3168, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37774068

ABSTRACT

OBJECTIVE: Study the frequency of codon 7 (c.747 G>T, p. R249S) mutation associated with Aflatoxin B1 (AFB1) exposure in Egyptian patients with hepatocellular carcinoma (HCC). METHODS: We utilized restriction fragment polymorphism and direct sequencing to assess codon 7 mutations in 104 hepatocellular carcinomas. The expression of TP53 protein in the tumors were assessed in 44 tumors by a monoclonal rabbit antibody. RESULTS: We identified a single 1/104 (1%) with c.747 G>T, p. R249S variant. 28/44 (63.6%) tumors showed no or occasional (less than < 5%) nuclear staining; 9/44 (20.4%) showed mild to moderate (5-49%) and 7/44 (15.9%) showed strong ≥ 50% staining. CONCLUSION: We observed much lower frequency of TP53 gene than previously published results suggesting geographical alterations in AFB1 exposure in Egypt.


Subject(s)
Aflatoxins , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Rabbits , Animals , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Aflatoxins/adverse effects , Genes, p53 , Egypt/epidemiology , Liver Neoplasms/chemically induced , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mutation , Aflatoxin B1/adverse effects , Codon/genetics , Tumor Suppressor Protein p53/genetics
2.
J Gastrointest Cancer ; 54(1): 275-281, 2023 Mar.
Article in English | MEDLINE | ID: mdl-34813031

ABSTRACT

We report a case of hepatic lymphoepithelioma-like carcinoma-hepatocellular carcinoma subtype (LEL-HCC) in a 41-year-old man with chronic hepatitis C virus (HCV) infection. The patient presented with abdominal pain and further assessment revealed a hypoechoic mass on ultrasonography. Serum alpha-fetoprotein (AFP) was 13·6 ng/dl. The patient was diagnosed as hepatocellular carcinoma based on the established triphasic computed tomography (TCT) diagnostic criteria and he underwent a surgical resection of the mass. Microscopic examination showed sheets and cords of malignant epithelial cells intermixed with heavy lymphoid infiltrate, with more than 100 tumor-infiltrating lymphocytes (TILs) per 10 high-power-field (HPF). Based on immunohistochemical studies, the malignant cells were positive for Hep Par 1 and glypican 3, focally positive for cytokeratin 7 (CK7), and negative for cytokeratin 20 (CK20). TILs were diffusely positive for cluster of differentiation 3 CD3 with an approximately equal CD4/CD8 ratio. The patient was recurrence free at 25 months after surgery, as evident by CT and serum alpha-fetoprotein level. LEL-HCC is a rare variant of HCC with a relatively better prognosis. Exploring the potential for immune modulator-based therapy in this subset of tumors is highly recommended.


Subject(s)
Carcinoma, Hepatocellular , Hepatitis C, Chronic , Liver Neoplasms , Male , Humans , Adult , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/diagnosis , Liver Neoplasms/surgery , Liver Neoplasms/pathology , alpha-Fetoproteins , Hepatitis C, Chronic/complications
3.
Fam Cancer ; 22(3): 307-311, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36513904

ABSTRACT

Germline pathogenic variants in the tumor suppressor gene BAP1 are associated with the hereditary tumor predisposition syndrome with susceptibility to uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other cancers. Germline BAP1 pathogenic variants are rare in the non-cancer general population with an estimated carrier frequency of 1:19,898 but more common in cancer patients with a carrier frequency of 1:1299. In the following we present the first report of a family with two unique BAP1 pathogenic variants. Retrospective case report of a family with two unique pathogenic variants in BAP1. A male (proband) was referred to our ocular oncology clinic for second opinion for his multiple independent uveal melanomas at ages 65, 68 and 71. Given his personal history of squamous cell carcinoma at age 61, renal cell carcinoma at age 63, and family history of atypical meningioma, basal cell carcinoma, pancreatic and prostate cancers he was assessed for germline pathogenic variants in BAP1 through our ongoing research study. Sanger sequencing identified the American founder pathogenic variant, c.1717delC, pL573Wfs*3, that was confirmed in a clinical laboratory. Both the proband's brother and nephew tested negative for the familial variant through single site cascade genetic testing. However, based on the personal history of multiple basal cell carcinoma in the nephew and family history of pancreatic and laryngeal cancers (both not known to be associated with BAP1-TPDS), a large cancer panel testing was recommended for the nephew. His panel testing revealed a different BAP1 pathogenic variant, c.605G>A, p. Trp202*. This variant was not detected in the proband or the proband's brother. Based on the frequency of germline BAP1 variants in the cancer population, the chance of occurrence of two different BAP1 variants in a family with cancer history is 5.9 × 10-7. This case report provides support for the importance of offering large panel cascade genetic testing, rather than single site testing for only the family pathogenic variant, for all at risk family members especially when the family variant cannot explain all the cancers in the family.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Melanoma , Neoplastic Syndromes, Hereditary , Skin Neoplasms , Humans , Male , Middle Aged , Melanoma/genetics , Melanoma/pathology , Skin Neoplasms/genetics , Genetic Predisposition to Disease , Retrospective Studies , Tumor Suppressor Proteins/genetics , Germ-Line Mutation , Neoplastic Syndromes, Hereditary/genetics , Ubiquitin Thiolesterase/genetics
5.
Fam Cancer ; 21(1): 1-5, 2022 01.
Article in English | MEDLINE | ID: mdl-33403473

ABSTRACT

Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.


Subject(s)
Melanoma , Nevus , Uveal Neoplasms , Aged , Fanconi Anemia Complementation Group N Protein/genetics , Female , Genetic Predisposition to Disease , Humans , Melanoma/genetics , Melanoma/pathology
6.
Pain Physician ; 25(9): E1405-E1413, 2022 12.
Article in English | MEDLINE | ID: mdl-36608012

ABSTRACT

BACKGROUND: Chronic pain symptoms are distressing conditions that necessitate regular visits to  pain therapists and may require interventions, however, the COVID-19 pandemic has caused patients and their therapists to limit both visits and interventions with the transition to telehealth, with little or no preparation or training. This has resulted in the extensive use of over-the counter analgesia and corticosteroids. OBJECTIVES: Our study aimed to evaluate the effect of the COVID-19 pandemic on the rates of counseling and interventional pain management therapies (IPMT), and determine the effects of implementing an infection control program (ICP) and mandating personal protective equipment (PPE) on these rates. STUDY DESIGN: Prospective multicenter survey, based on an online self-assessed questionnaire. SETTING: Departments of Anesthesia, Pain, Intensive Care Unit, Physical Medicine, Rheumatology, and  Rehabilitation at Egyptian University hospitals. METHODS: A self-assessed questionnaire was uploaded on Google forms and links were sent to enrolled therapists with an identification number to allow self-administration and privacy. Feedback was analyzed by 2 authors who were blinded to the identity of the responders. RESULTS: A total of 57.9% of responders increased their patients' contact by phone and video conference. Within 1-4 months after the outbreak began, 59% stopped in-person contact and 38.2% stopped their IPM practice. Prescriptions of analgesics and oral steroids increased by about 50%. The majority of responders complained of a shortage of ventilation appliances in their workplaces. About 50% of them always use ICP, 85% use surgical masks, 61% use gloves, and 45% wear gowns when meeting with patients. After the application of PPE, 45.5% of responders increased their consultation rate and 40% increased their rate of IPMT. LIMITATIONS: This study is limited to being a national study, and so lacked comparative data. CONCLUSION: The COVID-19 outbreak seriously affected the rates of in-person consultations and IPMT for patients with chronic pain and increased the rates of consumption of analgesia and oral steroids. Most responders reported a shortage of PPE especially ventilation appliances in workplaces. A high percentage of responders lack interest in ICP and PPE, despite the positive effects of its application on consultation and IPMT rates.


Subject(s)
COVID-19 , Chronic Pain , Humans , SARS-CoV-2 , Pain Management , Pandemics/prevention & control , Chronic Pain/therapy , Prospective Studies , Infectious Disease Transmission, Patient-to-Professional , Personal Protective Equipment
7.
J Pers Med ; 11(10)2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34683171

ABSTRACT

Breast cancer is the most prominent type of cancer among women. Understanding the microenvironment of breast cancer and the interactions between cells and cytokines will lead to better treatment approaches for patients. In this study, we developed a data-driven mathematical model to investigate the dynamics of key cells and cytokines involved in breast cancer development. We used gene expression profiles of tumors to estimate the relative abundance of each immune cell and group patients based on their immune patterns. Dynamical results show the complex interplay between cells and molecules, and sensitivity analysis emphasizes the direct effects of macrophages and adipocytes on cancer cell growth. In addition, we observed the dual effect of IFN-γ on cancer proliferation, either through direct inhibition of cancer cells or by increasing the cytotoxicity of CD8+ T-cells.

9.
Am J Ophthalmol ; 224: 172-177, 2021 04.
Article in English | MEDLINE | ID: mdl-33316260

ABSTRACT

PURPOSE: To estimate point prevalence of uveal melanoma in the patients with germline BAP1 pathogenic variant. DESIGN: Cohort study with risk assessment using Bayesian analysis. METHODS: The point prevalence estimate was obtained by Bayes's rule of reverse conditional probabilities. The probability of uveal melanoma given that BAP1 mutation exists was derived from the prevalence of uveal melanoma, prevalence of germline BAP1 pathogenic variants, and the probability of germline BAP1 pathogenic variant given that uveal melanoma is present. Confidence intervals (CIs) for each variable were calculated as the mean of Bernoulli random variables and for the risk estimate, by the delta method. The age at diagnosis and the gender of the uveal melanoma patients with BAP1 germline pathogenic variants obtained from previous publications or from authors' unpublished cohort was compared with those in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The point prevalence of uveal melanoma in patients with the germline BAP1 pathogenic variants in the US population was estimated to be 2.8% (95% CI, 0.88%-4.81%). In the SEER database, the median age at diagnosis of uveal melanomas was 63 (range 3-99 years) with a male-to-female ratio of 1.01:1. In comparison, uveal melanoma cases with BAP1 germline pathogenic variants from the US population (n = 27) had a median age at diagnosis of 50.5 years (range 16-71). CONCLUSIONS: Quantification of the risk of developing uveal melanoma can enhance counseling regarding surveillance in patients with germline BAP1 pathogenic variant.


Subject(s)
Genetic Predisposition to Disease , Melanoma/epidemiology , Melanoma/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/genetics , Uveal Neoplasms/epidemiology , Uveal Neoplasms/genetics , Adolescent , Adult , Aged , Bayes Theorem , Databases, Factual , Female , Humans , Male , Middle Aged , Prevalence , Probability , Risk Assessment , SEER Program , Young Adult
10.
J Cancer Res Clin Oncol ; 147(1): 167-175, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32980960

ABSTRACT

PURPOSE: Long interspersed nuclear element 1 (LINE-1 or L1) is a dominant non-long terminal repeat (non-LTR) retrotransposon in the human genome that has been implicated in the overexpression of MET. Both the canonical MET and L1-MET transcripts are considered to play a role in hepatocellular carcinoma (HCC) development. The aim of this study was to assess the utility of canonical MET, L1-MET, and MET protein expressions as predictive biomarkers for chemo-sensitivity to MET-inhibitors in HCC cell lines in vitro. Additionally, we assessed their expression in tumour tissues from Egyptian HCC patients. METHODS: MET and L1-MET expressions were assessed by qRT-PCR in six liver cancer cell lines (SNU-387, SNU-475, SK-HEP-1, PLC/PRF/5, SNU-449 and SNU-423) and 47 HCC tumour tissues. MET protein expression was measured by western blot in cell lines and immunohistochemistry in the tumours. Cell proliferation assay was used to assess the effect of crizotinib and tivantinib on the six liver cancer cell lines in correlation with the expression of MET, L1-MET and MET. RESULTS: The antitumor effect of crizotinib and tivantinib correlated with MET gene expression but not with L1-MET transcript or MET protein expressions. No significant difference was observed between HCC tumours and non-tumour samples in MET and L1-MET transcripts expression. There were no significant correlations between the 2-year overall survival rate and the MET, L1-MET transcripts and the MET protein expression. CONCLUSION: MET RNA expression could be useful biomarker for tivantinib and crizotinib targeted therapy in HCC. The value of assessment of MET protein expression is limited.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/pathology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Liver Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Cell Proliferation , Crizotinib/pharmacology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Proto-Oncogene Proteins c-met/metabolism , Tumor Cells, Cultured
11.
ESMO Open ; 5(6): e000990, 2020 11.
Article in English | MEDLINE | ID: mdl-33257317

ABSTRACT

BACKGROUND: Uveal melanoma (UM) is the most common primary ocular malignancy of adults. A small group of patients was found to express familial predisposition. Moreover, it may be preceded or followed by other malignancies elsewhere in the body. We aim to compare the incidence of UM and other associated cancers and study the factors that may influence each condition. PATIENTS AND METHODS: We have collected the data from the Surveillance, Epidemiology and End Results database of nine US cancer registries for UM patients between 1973 and 2015. We calculated the standardised incidence ratios for single primary UM, first primary and second primary UM, and compared the groups for multiple factors. RESULTS: A total of 4946 patients were included in the study; 3863 with single primary UM, 646 developed a second primary malignancy following UM, and 437 patients developed second primary UM following a previous primary malignancy. The risk of developing UM increased after leukaemia, melanoma of the skin and prostate. On the other side, the risk of developing melanoma of the skin, thyroid, renal and other eye and orbit malignancies has increased significantly after initial UM. This risk was more evident in the age group between 50 and 70 years old. Cancer-specific survival was significantly higher in UM associated with other malignancies group compared with single primary UM. CONCLUSION: Our study showed a different behaviour of the UM when associated with other tumours that exceed the known spectrum of hereditary UM. Further studies are required to dissect the genetic background of this behaviour.


Subject(s)
Melanoma , Neoplasms, Second Primary , Skin Neoplasms , Uveal Neoplasms , Adult , Aged , Humans , Male , Melanoma/epidemiology , Melanoma/etiology , Middle Aged , Neoplasms, Second Primary/epidemiology , Skin Neoplasms/epidemiology , Skin Neoplasms/etiology , Uveal Neoplasms/epidemiology
12.
Physiol Meas ; 41(8): 085005, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32909548

ABSTRACT

OBJECTIVE: To probe the distribution of electrical properties in tumor-bearing human hepatic tissues with metastatic colorectal cancer. APPROACH: Electrochemical impedance spectroscopy (EIS) and a non-contact electromagnetic probe were used for distinguishing spatial heterogeneities in fresh, unfixed human hepatic tissues ex vivo from patients with metastatic colorectal cancer (CRC). MAIN RESULTS: Point-wise EIS measurements reported over a frequency range of 100 Hz-1 MHz showed that the interface tissue between visible tumor and normal tissue exhibits an electrically different domain (p < 0.05) from both normal tissue (over 100 Hz-100 kHz) and tumor tissue (over 100 Hz-1 MHz). Observations of the microstructure on tumor-bearing hepatic tissue from hematoxylin and eosin stained images and the equivalent circuit modelling were used to validate the impedance measurements and characterize previously unidentified interfacial domain between normal and tumor tissue. Lastly, in a proof of concept study, a new in-house designed non-contact electromagnetic probe, as opposed to the invasive EIS measurements, was demonstrated for distinguishing tumor tissue from the normal tissue in a hepatic tissue specimen from a patient with metastatic CRC. SIGNIFICANCE: EIS measurements, correlated with histological observations, show potential for mapping electrical properties in tumor-bearing human hepatic tissue.


Subject(s)
Colorectal Neoplasms , Dielectric Spectroscopy , Electric Impedance , Liver Neoplasms/secondary , Colorectal Neoplasms/pathology , Humans , Liver/pathology
13.
Nat Rev Dis Primers ; 6(1): 24, 2020 04 09.
Article in English | MEDLINE | ID: mdl-32273508

ABSTRACT

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.


Subject(s)
Melanoma/diagnosis , Melanoma/physiopathology , Uveal Neoplasms/diagnosis , Uveal Neoplasms/physiopathology , Humans , Magnetic Resonance Imaging/methods , Mass Screening/methods , Neoplasm Metastasis/physiopathology , Prognosis , Risk Factors , Slit Lamp Microscopy/methods , Tomography, X-Ray Computed/methods
14.
Ophthalmology ; 127(5): 668-678, 2020 05.
Article in English | MEDLINE | ID: mdl-32081490

ABSTRACT

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.


Subject(s)
Genes, Neoplasm/genetics , Genetic Predisposition to Disease/genetics , Melanoma/genetics , Neoplasm Proteins/genetics , Uveal Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , DNA, Neoplasm/genetics , Female , Germ-Line Mutation/genetics , Humans , Immunohistochemistry , Infant , Male , Middle Aged , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/genetics , Exome Sequencing
15.
Cancer Res ; 80(3): 561-575, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31685543

ABSTRACT

Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in patients with advanced HCC by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC datasets (1,019 samples). Analysis of HCC tumor and cell line RNA-seq data revealed enriched expression of constitutively active, treatment-refractory AR splice variants (AR-SV). HCC cell lines expressed C-terminal-truncated AR-SV; 28 primary HCC samples abundantly expressed AR-SV. Low molecular weight AR species were nuclear localized and constitutively active. Furthermore, AR/AR-SV signaling promoted AR-mediated HCC cell progression and conferred resistance to AR antagonists. Ligand-dependent and -independent AR signaling mediated HCC epithelial-to-mesenchymal transition by regulating the transcription factor SLUG. These data suggest that AR-SV expression in HCC drives HCC progression and resistance to traditional AR antagonists. Novel therapeutic approaches that successfully target AR-SVs may be therapeutically beneficial for HCC. SIGNIFICANCE: Treatment-refractory, constitutively active androgen receptor splice variants promote hepatocellular carcinoma progression by regulating the epithelial-to-mesenchymal transition pathway.


Subject(s)
Alternative Splicing , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic , Liver Neoplasms/pathology , Receptors, Androgen/genetics , Androgen Receptor Antagonists/pharmacology , Androgens/metabolism , Apoptosis , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Cell Proliferation , Disease Progression , Female , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Male , Prognosis , Signal Transduction , Tumor Cells, Cultured
17.
Invest Ophthalmol Vis Sci ; 60(7): 2474-2480, 2019 06 03.
Article in English | MEDLINE | ID: mdl-31173078

ABSTRACT

Purpose: The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM. Methods: Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM. Activation of the MAPK pathway and other potential downstream signals was assessed by immunohistochemistry and/or Western blot analysis. Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines. Results: Somatic mutations in GNAQ/11 were observed in 35/42 (83.3%) of primary UM. Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity. Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively. Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors. Conclusions: Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations. Thus, GNAQ/11 mutational status is not a sufficient biomarker to adequately predict UM patient responses to single-agent selective MEK inhibitor therapy.


Subject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits/genetics , Melanoma/enzymology , Melanoma/genetics , Mitogen-Activated Protein Kinases/metabolism , Mutation , Uveal Neoplasms/enzymology , Uveal Neoplasms/genetics , Blotting, Western , Cell Line, Tumor , Cohort Studies , DNA Mutational Analysis , Humans , Immunohistochemistry , Plasmids , Polymorphism, Restriction Fragment Length , Sequence Analysis, DNA , Signal Transduction , Transfection
19.
Genes Chromosomes Cancer ; 58(9): 650-656, 2019 09.
Article in English | MEDLINE | ID: mdl-30883995

ABSTRACT

Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included. Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification. BAP1 expression in unaffected choroid tissue from a patient with UM was assessed by quantitative RT-PCR and methylation by pyrosequencing. Twenty-eight patients had one or more germline sequence variants in BAP1; seven of these were pathogenic. One hundred forty patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected. In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of ≥2 BAP1-related cancers 6/16 (38%), age of onset <35 years 4/21 (19%) and familial UM 6/34 (18%). One of 19 non-tumor choroid tissues tested showed uncharacteristically low expression as compared to the controls decrease in BAP1 RNA expression but no evidence of constitutional promotor hypermethylation was detected. UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.


Subject(s)
Choroid/metabolism , Gene Deletion , Germ-Line Mutation , Melanoma/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/genetics , Uveal Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Infant , Male , Melanoma/metabolism , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin Thiolesterase/metabolism , Uveal Neoplasms/metabolism
20.
Invest Ophthalmol Vis Sci ; 60(1): 349-357, 2019 01 02.
Article in English | MEDLINE | ID: mdl-30682205

ABSTRACT

Purpose: Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling is neuroprotective in some retinal damage models but its role in neuronal survival during retinal detachment (RD) is unclear. In addition, serous RDs are a prevalent side effect of MEK inhibitors (MEKi), blocking MAPK/ERK signaling for treatment of certain cancers. We tested the hypothesis that MEKi treatment in experimental RD would increase photoreceptor death. Methods: The MEKi selumetinib was delivered daily to C57BL/6 mice at a clinically relevant dose (10 mg/mL) starting 1 day prior to creating RD with subretinal hyaluronic acid injection. Photoreceptor TUNEL and outer nuclear layer (ONL) thickness were analyzed. Phospho-ERK1/2 (pERK) distribution, glial fibrillary acidic protein (GFAP) accumulation, and Iba-1 (microglia/macrophages) were evaluated with immunofluorescence. Results: pERK accumulated in the Müller glia in detached retinas, but this was effectively blocked by selumetinib. Selumetinib did not induce serous RDs at day 1 and did not increase TUNEL positive photoreceptors or further decrease ONL thickness compared to controls. Retinal gliosis was not altered, but selumetinib did block the increase in intraretinal microglia/macrophage Iba-1 fluorescence intensity and acquisition of amoeboid morphology. Conclusions: MAPK/ERK is neuroprotective in some retinal damage models; in RD, selumetinib blocked Müller pERK accumulation and changed the retinal microglia/macrophage phenotype but did not alter photoreceptor survival. This is consistent with the relatively good visual acuity seen in patients developing transient retinal detachments on MEK inhibitor therapy. Compensation by other neuroprotective pathways in the retina during retinal detachment may occur in the presence of MEK inhibition.


Subject(s)
Benzimidazoles/pharmacology , Photoreceptor Cells, Vertebrate/drug effects , Retinal Detachment/pathology , Administration, Oral , Animals , Benzimidazoles/administration & dosage , Calcium-Binding Proteins/metabolism , Cell Survival/physiology , Ependymoglial Cells/drug effects , Ependymoglial Cells/metabolism , Female , Glial Fibrillary Acidic Protein/metabolism , Immunohistochemistry , In Situ Nick-End Labeling , MAP Kinase Kinase Kinases/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Photoreceptor Cells, Vertebrate/metabolism , Retinal Detachment/enzymology
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