Role of somatic mutations and chromosomal aberrations in the prognosis of uveal melanoma in a Spanish patient cohort

Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtained by fine needle aspiration (FNA). GEP has demonstrated high accuracy in distinguishing class I and II tumors, both having different metastatic potential. Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ and GNA11, detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathway and the development of uveal melanoma (UM). The role of these mutations in treatment selection and possible benefit from targeted therapy are somewhat unclear. However, until the discovery of novel agents, local versus systemic therapies remain options for treatment that can still be considered for disease control in certain cases. We report a series of patients with metastatic UM with distinct mutational profiles. One had significant liver metastases with proven GNQ-209P mutation on tissue biopsy while peripheral blood molecular profiling did not show these mutations. The other three cases had no GNQ-209P mutation. All cases received nab-paclitaxel (Abraxane) as a treatment drug, and we record their responses to treatment and their molecular-profiling results.

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THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

Problems in oncology ◽

10.37469/0507-3758-2017-63-4-545-556 ◽

2017 ◽

Vol 63 (4) ◽

pp. 545-556

Author(s):

Natalya Oskina ◽

Aleksandr Shcherbakov ◽

Maksim Filipenko ◽

Nikolay Kushlinskiy ◽

L. Ovchinnikova

Keyword(s):

Genetic Disease ◽

Intracellular Signaling ◽

Somatic Mutations ◽

Pi3k Pathway ◽

Genetic Alterations ◽

Phosphatidylinositol 3 Kinase ◽

Intracellular Signaling Pathway ◽

Metabolic Activities ◽

Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

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The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma

Cancers ◽

10.3390/cancers13071700 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1700

Author(s):

Melissa Chalada ◽

Charmaine A. Ramlogan-Steel ◽

Bijay P. Dhungel ◽

Christopher J. Layton ◽

Jason C. Steel

Keyword(s):

Risk Factors ◽

Ultraviolet Radiation ◽

Uveal Melanoma ◽

World Health Organisation ◽

World Health ◽

Genetic Mutations ◽

High Incidence ◽

The World ◽

The Impact

Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM.

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Histologic Findings of Choroidal Vasculopathy in Eyes Enucleated following Radiation Therapy for Uveal Melanoma: Radiation Choroidopathy

Klinische Monatsblätter für Augenheilkunde ◽

10.1055/a-1275-0626 ◽

2021 ◽

Author(s):

Sean Platt ◽

Diva R. Salomao ◽

Jose Pulido

Keyword(s):

Radiation Therapy ◽

Uveal Melanoma ◽

Malignant Tumors ◽

Vitreous Hemorrhage ◽

Radiation Retinopathy ◽

Radiation Induced ◽

Histopathologic Analysis ◽

Choroidal Vessels ◽

Choroidal Vasculopathy

Abstract Introduction Little has been published about the choroidal vascular changes that occur years after radiation exposure. The aim of this study was to review the histological changes observed in the choroidal vasculature following radiotherapy for uveal melanoma. Methods Records from a single institution were retrospectively reviewed from June 7, 2007 to June 7, 2017; 101 patients with a diagnosis of uveal melanoma that underwent enucleation had their records reviewed. Out of these, a total of 26 eyes had undergone plaque brachytherapy prior to enucleation, which had been performed at a mean time of 7.2 years (range from 0 years to 30 years) after the initial plaque placement. A histopathologic analysis was conducted on all 26 eyes with special emphasis on the choroidal changes. Of these 26 eyes, 18 demonstrated evidence of radiation-induced vasculopathy. Results Of the 18 eyes, 10/18 (55%) had radiation retinopathy and 16/18 (89%) had radiation choroidal vasculopathy. One patient had a phthisical eye, and the choroid could not be evaluated because the characteristics of the vasculature could not be determined. Nine cases had vitreous hemorrhage (50%), all cases had radiation retinopathy, and 8/9 (89%) had radiation choroidopathy. Of the 16 cases with radiation choroidal vasculopathy, 3/16 (19%) had only intratumoral radiation choroidal vasculopathy, 3/16 (19%) had only extratumoral radiation choroidal vasculopathy, and, thus, 10/16 (32%) had both intratumoral and extratumoral radiation choroidal vasculopathy. In patients with radiation choroidal vasculopathy, 2/16 (13%) had hyalinization of the choroidal vessels. Another 3/16 (19%) cases with radiation choroidal vasculopathy had ectatic vessels. The other 11/16 (68%) had evidence of both hyalinization of the choroidal vessels as well as ectatic vessels in the choroid. Histological evidence of radiation retinopathy and choroidopathy were seen in 69% of eyes enucleated after receiving radiation therapy, which, in some cases, also had vitreous hemorrhage. Polypoidal choroidal vasculopathy, choroidal neovascularization, and retinal choroidal anastomoses (RAP-type lesions) were seen in 12 of the 16 eyes (75%). Discussion/Conclusion Irradiation of malignant tumors of the eye causes not only radiation retinopathy but also radiation choroidopathy. The role of radiation choroidopathy in the subsequent visual loss following radiotherapy and the role of anti-VEGF therapy needs to be recognized and distinguished from radiation retinopathy. Our data adds to the prior limited knowledge that radiation affects the choroid and can induce specific phenotypes similar to the clinical spectrum of CNV, PCV, and RAP.

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Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-02842-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

M. Janusz Mezynski ◽

Angela M. Farrelly ◽

Mattia Cremona ◽

Aoife Carr ◽

Clare Morgan ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Lines ◽

Somatic Mutations ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Erbb Family ◽

Gastric Tumour ◽

Pi3k Signalling ◽

Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

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Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3

Nature Genetics ◽

10.1038/ng.2674 ◽

2013 ◽

Vol 45 (8) ◽

pp. 933-936 ◽

Cited By ~ 257

Author(s):

Marcel Martin ◽

Lars Maßhöfer ◽

Petra Temming ◽

Sven Rahmann ◽

Claudia Metz ◽

...

Keyword(s):

Exome Sequencing ◽

Uveal Melanoma ◽

Somatic Mutations

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Role of epigenetic deregulation in hematogenous dissemination of malignant uveal melanoma

Neoplasma ◽

10.4149/neo_2018_180420n261 ◽

2018 ◽

Vol 65 (06) ◽

pp. 840-854 ◽

Cited By ~ 2

Author(s):

B. Smolkova ◽

V. Horvathova Kajabova ◽

I. Zmetakova ◽

L. Kalinkova ◽

G. Czanner ◽

...

Keyword(s):

Uveal Melanoma ◽

Hematogenous Dissemination ◽

Malignant Uveal Melanoma

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The Structural Basis of Repertoire Shift in an Immune Response to Phosphocholine

Journal of Experimental Medicine ◽

10.1084/jem.191.12.2101 ◽

2000 ◽

Vol 191 (12) ◽

pp. 2101-2112 ◽

Cited By ~ 26

Author(s):

McKay Brown ◽

Maria A. Schumacher ◽

Gregory D. Wiens ◽

Richard G. Brennan ◽

Marvin B. Rittenberg

Keyword(s):

Immune Response ◽

Light Chain ◽

Indirect Effects ◽

Somatic Mutations ◽

Variable Region ◽

Primary Response ◽

Structural Basis ◽

Antibody Repertoire ◽

High Affinity

The immune response to phosphocholine (PC)–protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high affinity to PC–protein. The somatically mutated memory hybridoma, M3C65, possesses high affinity for PC–protein and the phenyl-hapten analogue, p-nitrophenyl phosphocholine (NPPC). Affinity measurements using related PC–phenyl analogues, including peptides of varying lengths, demonstrate that carrier determinants contribute to binding affinity and that somatic mutations alter this recognition. The crystal structure of an M3C65–NPPC complex at 2.35-Å resolution allows evaluation of the three light chain mutations that confer high-affinity binding to NPPC. Only one of the mutations involves a contact residue, whereas the other two have indirect effects on the shape of the combining site. Comparison of the M3C65 structure to that of T15, an antibody dominating the primary response, provides clear structural evidence for the role of carrier determinants in promoting repertoire shift. These two antibodies express unrelated variable region heavy and light chain genes and represent a classic example of the effect of repertoire shift on maturation of the immune response.

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Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

10.1101/2020.09.14.20190538 ◽

2020 ◽

Author(s):

Irene Lobon ◽

Manuel Solis-Moruno ◽

David Juan ◽

Ashraf Muhaisen ◽

Federico Abascal ◽

...

Keyword(s):

Parkinson Disease ◽

Somatic Mutations ◽

Amplicon Sequencing ◽

Brain Regions ◽

Single Nucleotide Variants ◽

Validation Rate ◽

Synaptic Functions ◽

Whole Exome ◽

Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease.

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