The genetic landscape of the FAS pathway deficiencies

Increased frequency of endometrial cancer (EC) since the beginning of this century exceeds that of breast cancer and to a large extent can be attributed to dynamics of parameters, which characterize hormonal and metabolic status of ill women and molecular genetic landscape of transforming endometrium. During the past few years there are suggested several options for a personalized assessment of the risk of EC. The aim of this article is to propose and justify own version of this score with the idea of its further not only retrospective but also prospective testing both in relation to the risk of developing endometrial cancer as well as an additional marker helping to predict tumor response to treatment.

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Neoadjuvant Chemotherapy Induces the Appearance of New Copy Number Aberrations in Breast Tumor and is Associated with Metastasis

Current Cancer Drug Targets ◽

10.2174/1568009620666200506104523 ◽

2020 ◽

Vol 20 (9) ◽

pp. 681-688

Author(s):

Nikolai V. Litviakov ◽

Marina K. Ibragimova ◽

Matvey M. Tsyganov ◽

Artem V. Doroshenko ◽

Eugeniy Y. Garbukov ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Copy Number ◽

Breast Cancer Patients ◽

Free Survival ◽

Luminal B ◽

Cell Clones ◽

Genetic Landscape ◽

Intelligent Approach

Background: In this study, we examined the CNA-genetic landscape (CNA – copy number aberration) of breast cancer prior to and following neoadjuvant chemotherapy (NAC) and correlated changes in the tumor landscape with chemotherapy efficiency as well as metastasis-free survival. Objective: Breast cancer patients (n = 30) with luminal B molecular subtypes were treated with anthracycline- based therapy. Methods: To study CNAs in breast tumors, microarray analysis was performed. Results: Three effects of NAC on tumor CNA landscape were identified: 1 – the number of CNA-bearing tumor clones decreased following NAC; 2 – there were no alterations in the number of CNA-containing clones after NAC; 3 – the treatment with NAC increased the number of CNA-bearing clones (new clones appeared). All NAC-treated patients who had new tumor clones with amplification (20%) had a 100% likelihood of metastasis formation. In these cases, NAC contributed to the emergence of potential metastatic clones. Our study identified the following loci – 5p, 6p, 7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 18Chr and 19p – that were amplified during the treatment with NAC and may be the markers of potential metastatic clones. In other patients who showed total or partial elimination of CNA-bearing cell clones, no new amplification clones were observed after NAC, and no evidence of metastases was found with follow-up for 5 years (р = 0.00000). Conclusion: Our data suggest that the main therapeutic result from NAC is the elimination of potential metastatic clones present in the tumor before treatment. The results showed the necessity of an intelligent approach to NAC to avoid metastasis stimulation.

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Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Cancers ◽

10.3390/cancers13040731 ◽

2021 ◽

Vol 13 (4) ◽

pp. 731

Author(s):

Renáta Váraljai ◽

Susanne Horn ◽

Antje Sucker ◽

Daniela Piercianek ◽

Verena Schmitt ◽

...

Keyword(s):

Brain Metastases ◽

Genetic Variants ◽

Genetic Alterations ◽

Metastasis Formation ◽

Driver Genes ◽

Targeted Next Generation Sequencing ◽

Paired Samples ◽

Melanoma Metastases ◽

Frequent Event ◽

Genetic Landscape

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

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Genetic landscape of recessive diseases in the Vietnamese population from large‐scale clinical exome sequencing

Human Mutation ◽

10.1002/humu.24253 ◽

2021 ◽

Author(s):

Ngoc Hieu Tran ◽

Thanh‐Huong Nguyen Thi ◽

Hung‐Sang Tang ◽

Le‐Phuc Hoang ◽

Trung‐Hieu Le Nguyen ◽

...

Keyword(s):

Exome Sequencing ◽

Large Scale ◽

Clinical Exome Sequencing ◽

Genetic Landscape ◽

Vietnamese Population

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Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules ◽

10.3390/biom11040496 ◽

2021 ◽

Vol 11 (4) ◽

pp. 496

Author(s):

Alessandra Maresca ◽

Valerio Carelli

Keyword(s):

Optic Nerve ◽

Mitochondrial Dysfunction ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Mitochondrial Dynamics ◽

Unmet Need ◽

Deep Understanding ◽

Genetic Landscape ◽

Innovative Therapies ◽

Energy Dependent

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

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