scholarly journals Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients’ Management and Therapy Outcomes

2019 ◽  
Vol 20 (21) ◽  
pp. 5498 ◽  
Author(s):  
Silvia Mezzalira ◽  
Elena De Mattia ◽  
Michela Guardascione ◽  
Chiara Dalle Fratte ◽  
Erika Cecchin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Somatic Mutations ◽  
Dna Analysis ◽  
Resistance Mechanism ◽  
Treatment Decision ◽  
Genetic Alterations ◽  
Dynamic Monitoring ◽  
Tumor Biopsy ◽  
Free Dna ◽  
Promising Strategy

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC.

scholarly journals Detection of a novel panel of somatic mutations in plasma cell-free DNA and its diagnostic value in hepatocellular carcinoma

2019 ◽  
Vol Volume 11 ◽  
pp. 5745-5756 ◽  
Author(s):  
Yu Xiong ◽  
Cheng-Rong Xie ◽  
Sheng Zhang ◽  
Jin Chen ◽  
Zhen-Yu Yin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Plasma Cell ◽  
Somatic Mutations ◽  
Diagnostic Value ◽  
Cell Free Dna ◽  
Free Dna

Landscape of somatic mutations in different subtypes: Advanced breast cancer with circulating tumour DNA analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23039-e23039
Author(s):  
Zongbi Yi ◽  
Fei Ma ◽  
Yanfang Guan ◽  
Fang Li Yuan ◽  
Xiaoying Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regression Analysis ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Somatic Mutations ◽  
Dna Analysis ◽  
Tumour Size ◽  
Multiple Logistic Regression Analysis ◽  
Genetic Alterations ◽  
Advanced Breast

e23039 Background: It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of gene expression. Yet the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely undetermined. Methods: Overall, 100 blood samples were obtained from 100 advanced female breast cancer patients who underwent therapy at Cancer Hospital, Chinese Academy of Medical Sciences from March 2015 to September 2016. Mutations in 1021 tumor-related genes in ctDNA was assayed by gene-panel target-capture next-generation sequencing. Results: Somatic genomic alterations in ctDNA including copy number variants and point mutations were identified in 96 of 100 patients (96.0%). The number of somatic mutations varied markedly between individual patients (mean 2.9, range1-31). No difference was found between four subtypes for the number of somatic mutations. However, the mean number of somatic mutations was higher in age at 40-50 year than patients over age 60 ( p= 8.46 vs 3.88; p= 0.01). Results from multivariate analyses showed that the number of somatic mutations was increased with the number of endocrine therapy line ( p= 0.007). TP53 and PIK3CA were two most frequently mutated genes detected in ctDNA of 100 patients which were recurrently detected in 43 (43.0%) and 32 (32.0%) patients, respectively. ESR1/PIK3CA were more prevalent in HR+ cancers ( p= 0.007, 0.025 respectively). NOTCH1 are more frequently detected in HER2- group than in HER2+ patients (15.63% vs 2.94%; p= 0.033). In multiple logistic regression analysis indicated that pathological grade, tumour size at diagnosis and PR statue were positive associated with PIK3CA mutations. Multiple regression analysis also revealed that ki-67, metastatic at diagnosis, number of metastatic sites, number of endocrine line were associated with ESR1 mutations. Conclusions: The results revealed that different subtypes ABC have their own genetic alterations features. Certain gene mutations may be related to clinical treatment especially endocrine therapy.

scholarly journals Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics

2021 ◽  
Vol 22 (14) ◽  
pp. 7411
Author(s):  
Jingjing Jiao ◽  
Jessica I. Sanchez ◽  
Erika J. Thompson ◽  
Xizeng Mao ◽  
Joseph B. McCormick ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Liver Fibrosis ◽  
Somatic Mutations ◽  
Advanced Fibrosis ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna ◽  
Significant Difference ◽  
Advanced Liver Fibrosis

Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival.

Genomic comparison of matched primary and metastatic germ cell tumors (GCT).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4556-4556 ◽  
Author(s):  
Francois Audenet ◽  
Mark Donoghue ◽  
Eugene J. Pietzak ◽  
Sumit Isharwal ◽  
Michael L. Cheng ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Germ Cell Tumors ◽  
Genomic Analysis ◽  
Metastatic Tumor ◽  
Genetic Alterations ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Primary Tumors ◽  
Free Dna ◽  
Significant Difference

4556 Background: Tumor genomic analysis may be useful in patients with GCT as a means of identifying potentially actionable genomic alterations or mutations such as TP53 that confer resistance to chemotherapy. As GCTs often exhibit significant morphologic heterogeneity, we evaluated the level of concordance between genomic alterations in matched primary and metastatic GCT samples. Methods: GCT patients enrolled on an institutional prospective sequencing protocol with available primary and metastatic tumor tissue were eligible. Each tumor was subjected to MSK-IMPACT, an exon capture sequencing assay, which detects copy number alterations (CNAs) and mutations in 410 cancer-related genes. For each primary-metastasis pair, concordance and clonality was assessed using the FACETS algorithm. Results: Matched primary-metastasis tumor pairs were available for 36 patients (78% nonseminoma, 22% seminoma, median age 33.5 years). All patients received chemotherapy, with 25 (69%) receiving treatment prior to analysis of the metastatic samples. The frequency of genetic alterations was low with a median of 3 mutations (1-7), 7 amplifications (1-26) and 1 deletion (1-9) detected per sample, with no significant difference in mutational/CNA burden between primaries and metastases. Of 109 unique mutations across patients, only 44 (40%) were concordant between the primary and matched metastasis, including 5 of 9 hotspot mutations. For CNAs, 184 (81%) of 226 were concordant. Only 24 of 109 (22%) mutations were clonal (defined as predicted to be present in all cancer cells) in either the primary or metastatic matched samples; of these, only 4 were clonal in both the primary and metastatic samples, including 2 hotspots. However, 4 of 5 alterations in TP53/MDM2 were shared by both the primary and metastasis pairs. In a separate exploratory cohort, 4 TP53 mutations were identified in 3 primary tumors and 1 metastasis, and all 4 mutations were also detected by cell-free DNA profiling. Conclusions: Genomic concordance, particularly for mutations, is poor between primary and metastatic GCT samples. Cell-free DNA analysis may help overcome this limitation by identifying alterations in progressive tumors without need for a new biopsy.

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

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.

scholarly journals Identification of Somatic Mutations in Thirty-year-old Serum Cell-free DNA From Patients With Breast Cancer: A Feasibility Study

2020 ◽  
Vol 20 (5) ◽  
pp. 413-421.e1
Author(s):  
Mathilde Ritter ◽  
Viola Paradiso ◽  
Patrik Widmer ◽  
Andrea Garofoli ◽  
Luca Quagliata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Feasibility Study ◽  
Somatic Mutations ◽  
Cell Free Dna ◽  
Free Dna
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