scholarly journals Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
David S. Goerlitz ◽  
Jan Blancato ◽  
Archana Ramesh ◽  
Md. Islam ◽  
Garrett T. Graham ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Ionizing Radiation ◽  
Chromatin Remodeling ◽  
Liver Tumors ◽  
Strand Break ◽  
Mtor Signaling ◽  
Driver Mutations ◽  
Driver Genes ◽  
Primary Liver Tumors ◽  
Mutational Landscape

AbstractLiver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/β-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

Sicily Network for Liver Cancer: A Multidisciplinary Network Model for the Management of Primary Liver Tumors

2020 ◽  
Vol 30 (10) ◽  
pp. 1048-1053 ◽  
Author(s):  
Ciro Celsa ◽  
Giuseppe Cabibbo ◽  
Duilio Pagano ◽  
Vito di Marco ◽  
Calogero Cammà ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Network Model ◽  
Liver Tumors ◽  
Primary Liver Tumors

Eight years after introducing liver resection at the Oncology Institute of Vojvodina

2013 ◽  
Vol 21 (3-4) ◽  
pp. 101-104
Author(s):  
Ivan Majdevac ◽  
Nikola Budisin ◽  
Milan Ranisavljevic ◽  
Dejan Lukic ◽  
Imre Lovas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Resection ◽  
Liver Tumors ◽  
Liver Parenchyma ◽  
Malignant Neoplasms ◽  
Chemotherapy Treatment ◽  
Primary Liver Tumors ◽  
Cancer Metastases ◽  
Colorectal Cancer Metastases ◽  
Medical Histories

Background: Hepatectomies are mostly performed for the treatment of hepatic benign or malignant neoplasms, intrahepatic gallstones, or parasitic cysts of the liver. The most common malignant neoplasms of the liver are metastases from colorectal cancer. Anatomic liver resection involves two or more hepatic segments, while non-anatomic liver resection involves resection of the metastases with a margin of uninvolved tissue. The aim of this manuscript was to show results of hepatectomies performed at the Oncology Institute of Vojvodina. Methods: We performed 133 liver resections from January 1997 to December 2013. Clinical and histopathological data were obtained from operative protocols, histopathological reports, and patients? medical histories. Results: We did 80 metastasectomies, 51 segmentectomies, and 18 radiofrequent ablations (RFA). Average number of colorectal cancer metastases was 1.67 per patient. We also made 10 left hepatectomies. In all cases, we made non-anatomic resections. Conclusion: Decision about anatomic versus non-anatomic resections for colorectal metastasis and primary liver tumors should be made before surgical exploration. Preservation of liver parenchyma is important with respect to liver failure and postoperative chemotherapy treatment.

Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors.

1988 ◽  
Vol 62 (2) ◽  
pp. 629-632 ◽  
Author(s):  
C Pasquinelli ◽  
F Garreau ◽  
L Bougueleret ◽  
E Cariani ◽  
K H Grzeschik ◽  
...  
Keyword(s):  
Liver Tumors ◽  
Chromosome 4 ◽  
Primary Liver Tumors ◽  
Cellular Dna

scholarly journals Evaluation of non-targeting, C- or N-pH (low) insertion peptide modified superparamagnetic iron oxide nanoclusters for selective MRI of liver tumors and their potential toxicity in cirrhosis

RSC Advances ◽  
2019 ◽  
Vol 9 (25) ◽  
pp. 14051-14059
Author(s):  
Abdulrahman Ahmed Mahmood ◽  
Jianqi Zhang ◽  
Rufang Liao ◽  
Xiwei Pan ◽  
Dan Xu ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Liver Cancer ◽  
Contrast Agent ◽  
Cancer Diagnosis ◽  
Liver Tumors ◽  
Superparamagnetic Iron Oxide ◽  
Mri Contrast Agent ◽  
Potential Toxicity ◽  
Mri Contrast ◽  
Specific Enhancement

The acid-responsive pHLIP modified SPION as an MRI contrast agent for liver cancer diagnosis requires the validation of both the tumor-specific enhancement and a safe profile in cirrhosis.

scholarly journals Actin-Related Protein 6 (Arp6) Influences Double-Strand Break Repair in Yeast

2021 ◽  
Vol 1 (2) ◽  
pp. 225-238
Author(s):  
Mohsen Hooshyar ◽  
Daniel Burnside ◽  
Maryam Hajikarimlou ◽  
Katayoun Omidi ◽  
Alexander Jesso ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Genetic Interaction ◽  
Interaction Analysis ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Dna Damaging Agents ◽  
Repair Efficiency ◽  
Chromosomal Breaks

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

Multigene Combined Detection by RT-qPCR Using Cytological Specimens

2021 ◽  
pp. 1-10
Author(s):  
Yang Ma ◽  
Jingxia Zhao ◽  
Yun Du ◽  
Rui Wang ◽  
Xiaokun Ji ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking Status ◽  
Single Gene ◽  
Rna Extraction ◽  
Pcr Amplification ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Driver Genes ◽  
Mutation Status ◽  
Pik3ca Mutations

<b><i>Objective:</i></b> The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. <b><i>Materials and Methods:</i></b> 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. <b><i>Results:</i></b> The purity of RNA (<i>p</i> = 0.005) and DNA (<i>p</i> = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (<i>p</i> = 0.047), but not correlated with age (<i>p</i> = 0.141) and smoking status (<i>p</i> = 0.083). We found that the EGFR mutation status was correlated with gender (<i>p</i> = 0.003), age (<i>p</i> = 0.015) and smoking habits (<i>p</i> = 0.007), and ALK mutation status was correlated with age (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.

scholarly journals MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii389-iii389
Author(s):  
Rahul Kumar ◽  
Maximilian Deng ◽  
Kyle Smith ◽  
Anthony Liu ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Copy Number ◽  
Driver Mutations ◽  
P Value ◽  
Next Generation ◽  
Driver Genes ◽  
Methylation Array ◽  
Primary Tumors ◽  
Group 4 ◽  
Group 3

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value &lt; 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.

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