scholarly journals Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma

2020 ◽  
Vol 102 ◽  
Author(s):  
Yael Laitman ◽  
Shay Tzur ◽  
Ruben Attali ◽  
Amit Tirosh ◽  
Eitan Friedman
Keyword(s):  
Allelic Imbalance ◽  
Chromosomal Region ◽  
Cancer Susceptibility ◽  
Functional Studies ◽  
Cancer Susceptibility Genes ◽  
Whole Exome ◽  
Familial Pheochromocytoma ◽  
The Family ◽  
Recombination Processes

Abstract Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.

Prostate cancer susceptibility genes: lessons learned and challenges posed.

2003 ◽  
pp. 225-259 ◽  
Author(s):  
J Simard ◽  
M Dumont ◽  
D Labuda ◽  
D Sinnett ◽  
C Meloche ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Genetic Variants ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Screening Methods ◽  
Cancer Susceptibility Genes ◽  
Prostate Cancer Susceptibility ◽  
Common Genetic Variants

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.

Variations of C14ORF39 and SYCE1 identified in idiopathic premature ovarian insufficiency and nonobstructive azoospermia

2021 ◽  
Author(s):  
Dong Hou ◽  
Chencheng Yao ◽  
Bingying Xu ◽  
Wei Luo ◽  
Hanni Ke ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Premature Ovarian Insufficiency ◽  
Functional Study ◽  
Nonobstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Functional Studies ◽  
Whole Exome ◽  
Inheritance Mode ◽  
Genetics And Genomics

Abstract Context Premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) are the most sever disease causing irreversible infertility in female and male respectively. The contribution of synaptonemal complex (SC) genes variations in the pathogenesis of sporadic patients with POI and NOA has not been systematically illustrated. Objective To investigate the role of SC genes in the pathogenesis of sporadic POI and NOA. Design Genetic and functional study. Setting University-based reproductive medicine center. Patient(s) A total of 1,030 patients with sporadic POI and 400 patients with sporadic NOA. Intervention(s) The variations of SC genes were filtered in the in-house database of whole exome sequencing performed in 1,030 patients with sporadic POI and 400 patients with sporadic NOA. The pathogenic or likely pathogenic variations following recessive inheritance mode were selected according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed by Sanger sequencing. The pathogenic effects of the variations were verified by functional studies. Main Outcome Measure(s) ACMG classification and functional characteristics. Result(s) Two homozygous variations of C14ORF39 and two recessive variations of SYCE1 were firstly identified in sporadic patients with POI and NOA respectively. Functional studies showed the C14ORF39 variations significantly accelerated the protein degradation, and the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis. Conclusion(s) Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function.

scholarly journals Role of ACTN4 in Tumorigenesis, Metastasis, and EMT

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1427 ◽  
Author(s):  
Dmitri Tentler ◽  
Ekaterina Lomert ◽  
Ksenia Novitskaya ◽  
Nikolai A. Barlev
Keyword(s):  
Chromosomal Region ◽  
Epithelial Mesenchymal Transition ◽  
Research Progress ◽  
Actin Binding ◽  
Mesenchymal Transition ◽  
Functional Studies ◽  
Cytoskeleton Reorganization ◽  
Different Types ◽  
Nuclear Processes

The actin-binding protein ACTN4 belongs to a family of actin-binding proteins and is a non-muscle alpha-actinin that has long been associated with cancer development. Numerous clinical studies showed that changes in ACTN4 gene expression are correlated with aggressiveness, invasion, and metastasis in certain tumors. Amplification of the 19q chromosomal region where the gene is located has also been reported. Experimental manipulations with ACTN4 expression further confirmed its involvement in cell proliferation, motility, and epithelial-mesenchymal transition (EMT). However, both clinical and experimental data suggest that the effects of ACTN4 up- or down-regulation may vary a lot between different types of tumors. Functional studies demonstrated its engagement in a number of cytoplasmic and nuclear processes, ranging from cytoskeleton reorganization to regulation of different signaling pathways. Such a variety of functions may be the reason behind cell type and cell line specific responses. Herein, we will review research progress and controversies regarding the prognostic and functional significance of ACTN4 for tumorigenesis.

scholarly journals The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment

2014 ◽  
Vol 8 ◽  
pp. CMO.S15239 ◽  
Author(s):  
Angelo Battaglia
Keyword(s):  
Gene Expression ◽  
Multidisciplinary Approach ◽  
Cancer Susceptibility ◽  
Published Data ◽  
Cancer Syndrome ◽  
Functional Studies ◽  
Interaction Partners ◽  
Definition Of ◽  
Tumor Types

Germline BAP1 (BRCA1-associated protein-1) mutations are involved into a novel specific cancer syndrome and strictly associated with a high cancer susceptibility. Recent data suggest that BAP1 has activity toward target substrates explaining why loss of BAP1 causes a pro-tumorigenic deregulation of gene expression. The recently published data reviewed raise the hypothesis that BAP1 regulates a common subset of substrates, which in turn causes a pro-tumorigenic deregulation of gene expression, and alternatively suggest the role of BAP1 as tumorigenesis suppressor/promoter also by independent mechanisms. The clinical phenotype of BAP1 alterations includes MBAITs (melanocytic BAP1-mutated atypical intradermal tumors), uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), mesothelioma (MM), and possibly several other tumors. In clinical practice, early diagnosis is crucial for curative resection of all these tumor types. The uniformed and unambiguous definition of MBAITs as clinical/pathological predictive markers could provide physicians means to identify patients who may carry germline BAP1 mutations and thus could be at high risk of developing CM, UM, MM, RCC, and possibly other tumors. As part of a novel multidisciplinary approach, physicians, pathologists, and clinicians involved into diagnostics should be aware of the histological features and the spectrum of tumors associated with BAP1 loss. Further clinical, epidemiological, and functional studies are required to fully explain the roles of BAP1 and its interaction partners in neoplasia, to define mechanisms behind shared and non-shared clinical and pathological criteria.

scholarly journals Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene

Neurogenetics ◽  
2021 ◽  
Author(s):  
Berardo Rinaldi ◽  
Yu-Han Ge ◽  
Elena Freri ◽  
Arianna Tucci ◽  
Tiziana Granata ◽  
...  
Keyword(s):  
Causative Role ◽  
Cerebellar Syndrome ◽  
Pathogenic Variants ◽  
Healthy Mother ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant ◽  
Gene Maps ◽  
Index Subject

AbstractAMPA-type glutamate receptors (AMPARs) are postsynaptic ionotropic receptors which mediate fast excitatory currents. AMPARs have a heterotetrameric structure, variably composed by the four subunits GluA1-4 which are encoded by genes GRIA1-4. Increasing evidence support the role of pathogenic variants in GRIA1-4 genes as causative for syndromic intellectual disability (ID). We report an Italian pedigree where some male individuals share ID, seizures and facial dysmorphisms. The index subject was referred for severe ID, myoclonic seizures, cerebellar signs and short stature. Whole exome sequencing identified a novel variant in GRIA3, c.2360A > G, p.(Glu787Gly). The GRIA3 gene maps to chromosome Xq25 and the c.2360A > G variant was transmitted by his healthy mother. Subsequent analysis in the family showed a segregation pattern compatible with the causative role of this variant, further supported by preliminary functional insights. We provide a detailed description of the clinical evolution of the index subjects and stress the relevance of myoclonic seizures and cerebellar syndrome as cardinal features of his presentation.

scholarly journals Whole-exome sequencing in a patient with synchronous triple primary malignancies involving lung cancer: a case report

2020 ◽  
Vol 3 (4) ◽  
pp. 306-310
Author(s):  
Dan Li ◽  
Min Yu ◽  
Ping Zhou ◽  
Jie Yang ◽  
Yongsheng Wang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cancer Susceptibility ◽  
Gene Mutations ◽  
Cancer Recurrence ◽  
Multiple Primary Cancers ◽  
Driver Gene ◽  
Cancer Susceptibility Genes ◽  
Whole Exome ◽  
Multiple Primary

Abstract The incidence of multiple primary malignancies (MPMs) has been increasing rapidly in recent years, however, the genetic pathogenesis is largely unknown on account of rare cases, especially for those patients who are diagnosed with three or more tumors. Under these circumstances, whole-exome sequencing (WES) may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies. Here, we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies: esophageal squamous cell carcinoma (ESCC), lung adenocarcinoma (LA), and hepatocellular carcinoma (HCC). Tumors were surgically removed within 3 months. WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted. Each tumor displayed a distinct somatic mutation profile, providing direct evidence of independent origins. No shared driver gene mutation or neoantigen was detected among the three tumors. Two germline alterations of cancer susceptibility genes—SPINK1 c.194 + 2T>C and JAK3 c.425G>A were identified. This case is the first report of synchronous primary triple cancers covering the esophagus, lung, and liver. Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds, the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations. Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets, and it can be difficult to find a treatment to cover all the tumors.

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