Kras-Diagnosing the Little-Known Cancers Oncogene through Liquid Biopsy: Review

2020 ◽  
Author(s):  
Hafiz Syed Mohammad Osama Jafri
Keyword(s):  
Liquid Biopsy ◽  
Prognostic Significance ◽  
Cost Effective ◽  
Circulating Tumor Dna ◽  
Cancer Therapies ◽  
Oncogenic Signaling ◽  
Quick Method ◽  
Downstream Signaling ◽  
Mutational Status ◽  
Initial Stage

Tissue biopsy, until date, is a gold standard for tumor diagnosis, grading, treatment, and detecting genetic evidences for identifying appropriate personalized treatments. However, it is painful, invasive, expensive, and risky making sequential biopsies basically impractical. Detection of Kras genes through liquid biopsy is the growing theragnostic technique, which is more sensitive, specific, much cost-effective and quick method for detecting the mutational status of cancers. Liquid biopsy detects biomarkers present in various body fluids, such as plasma, urine, saliva and cerebrospinal fluid, harboring cancer degraded fragments and cells shed by carcinoma such as circulating tumor cells, microRNA and circulating tumor DNA. It can be utilized as a pre-screening test for initial stage cancers also where multiple sampling is required for monitoring cancer therapies. Kras is the most extensively mutated cancer oncogene involve in altering the downstream signaling pathways, increasing oncogenic signaling, which is typically associated with poor prognosis and resistance to therapy. This review was conducted to clarify its prognostic significance as well as its mutational role in different carcinomas. To identify studies related to Kras mutation Medline, PubMed, Google Scholar and Web of Science search engines were explored and forty two relevant researches were finalized from year 2005 to 2019.

scholarly journals Translational Application of Circulating DNA in Oncology: Review of the Last Decades Achievements

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1251 ◽  
Author(s):  
Tuaeva ◽  
Falzone ◽  
Porozov ◽  
Nosyrev ◽  
Trukhan ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Liquid Biopsy ◽  
Prognostic Significance ◽  
Circulating Tumor Dna ◽  
Molecular Techniques ◽  
Unknown Primary ◽  
Diagnostic Strategies ◽  
Early Diagnosis Of Cancer ◽  
Mutational Status ◽  
Ctdna Analysis

In recent years, the introduction of new molecular techniques in experimental and clinical settings has allowed researchers and clinicians to propose circulating-tumor DNA (ctDNA) analysis and liquid biopsy as novel promising strategies for the early diagnosis of cancer and for the definition of patients’ prognosis. It was widely demonstrated that through the non-invasive analysis of ctDNA, it is possible to identify and characterize the mutational status of tumors while avoiding invasive diagnostic strategies. Although a number of studies on ctDNA in patients’ samples significantly contributed to the improvement of oncology practice, some investigations generated conflicting data about the diagnostic and prognostic significance of ctDNA. Hence, to highlight the relevant achievements obtained so far in this field, a clearer description of the current methodologies used, as well as the obtained results, are strongly needed. On these bases, this review discusses the most relevant studies on ctDNA analysis in cancer, as well as the future directions and applications of liquid biopsy. In particular, special attention was paid to the early diagnosis of primary cancer, to the diagnosis of tumors with an unknown primary location, and finally to the prognosis of cancer patients. Furthermore, the current limitations of ctDNA-based approaches and possible strategies to overcome these limitations are presented.

scholarly journals Circulating Tumor DNA as a Liquid Biopsy for Cancer

2015 ◽  
Vol 61 (1) ◽  
pp. 112-123 ◽  
Author(s):  
Ellen Heitzer ◽  
Peter Ulz ◽  
Jochen B Geigl
Keyword(s):  
Liquid Biopsy ◽  
Dna Analysis ◽  
Clonal Evolution ◽  
Cost Effective ◽  
Circulating Tumor Dna ◽  
Analytical Sensitivity ◽  
Plasma Dna ◽  
Multicenter Studies ◽  
Almost All ◽  
Tumor Dna

Abstract BACKGROUND Targeted therapies have markedly changed the treatment of cancer over the past 10 years. However, almost all tumors acquire resistance to systemic treatment as a result of tumor heterogeneity, clonal evolution, and selection. Although genotyping is the most currently used method for categorizing tumors for clinical decisions, tumor tissues provide only a snapshot, or are often difficult to obtain. To overcome these issues, methods are needed for a rapid, cost-effective, and noninvasive identification of biomarkers at various time points during the course of disease. Because cell-free circulating tumor DNA (ctDNA) is a potential surrogate for the entire tumor genome, the use of ctDNA as a liquid biopsy may help to obtain the genetic follow-up data that are urgently needed. CONTENT This review includes recent studies exploring the diagnostic, prognostic, and predictive potential of ctDNA as a liquid biopsy in cancer. In addition, it covers biological and technical aspects, including recent advances in the analytical sensitivity and accuracy of DNA analysis as well as hurdles that have to be overcome before implementation into clinical routine. SUMMARY Although the analysis of ctDNA is a promising area, and despite all efforts to develop suitable tools for a comprehensive analysis of tumor genomes from plasma DNA, the liquid biopsy is not yet routinely used as a clinical application. Harmonization of preanalytical and analytical procedures is needed to provide clinical standards to validate the liquid biopsy as a clinical biomarker in well-designed and sufficiently powered multicenter studies.

Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11015-11015 ◽  
Author(s):  
Jeanne Tie ◽  
Isaac Kinde ◽  
Hui-Li Wong ◽  
Joseph James McKendrick ◽  
Peter Gibbs ◽  
...  
Keyword(s):  
Massively Parallel Sequencing ◽  
Prognostic Significance ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Rank Test ◽  
Cancer Center ◽  
Circulating Dna ◽  
Plasma Samples ◽  
Mutational Status

11015 Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with < 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.

scholarly journals Liquid Biopsy to Identify Actionable Genomic Alterations

2018 ◽  
pp. 978-997 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Misako Nagasaka ◽  
Viola W. Zhu
Keyword(s):  
Liquid Biopsy ◽  
Residual Disease ◽  
Single Gene ◽  
Prognostic Significance ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Braf Mutations ◽  
Clinicopathologic Characteristics ◽  
Pik3ca Mutations

Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify “shedders” and “nonshedders” of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.

scholarly journals Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Patients With Meningiomas

2020 ◽  
Vol 10 ◽  
Author(s):  
Yuki Kuranari ◽  
Ryota Tamura ◽  
Noboru Tsuda ◽  
Kenzo Kosugi ◽  
Yukina Morimoto ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Laboratory Data ◽  
Progression Free Survival ◽  
Cost Effective ◽  
Tumor Location ◽  
Neutrophil To Lymphocyte Ratio ◽  
Ki 67 ◽  
Who Grade ◽  
Lymphocyte Ratio ◽  
Subtotal Removal

BackgroundMeningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies.Materials and MethodsThis retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS).ResultsForty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P &lt; 0.001, &lt; 0.001, 0.002, &lt; 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014).ConclusionsNLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.

scholarly journals Predictive Evaluation on Cytological Sample of Metastatic Melanoma: The Role of BRAF Immunocytochemistry in the Molecular Era

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1110
Author(s):  
Andrea Ronchi ◽  
Marco Montella ◽  
Federica Zito Marino ◽  
Michele Caraglia ◽  
Anna Grimaldi ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Molecular Analysis ◽  
Predictive Value ◽  
Diagnostic Performance ◽  
Cost Effective ◽  
Needle Aspiration ◽  
Braf V600e ◽  
Mutational Status ◽  
Needle Aspiration Cytology ◽  
Sensitivity Specificity

Background: Cutaneous malignant melanoma is an aggressive neoplasm. In advanced cases, the therapeutic choice depends on the mutational status of BRAF. Fine needle aspiration cytology (FNA) is often applied to the management of patients affected by melanoma, mainly for the diagnosis of metastases. The evaluation of BRAF mutational status by sequencing technique on cytological samples may be inconvenient, as it is a time and biomaterial-consuming technique. Recently, BRAF immunocytochemistry (ICC) was applied for the evaluation of BRAF V600E mutational status. Although it may be useful mainly in cytological samples, data about BRAF ICC on cytological samples are missing. Methods: We performed BRAF ICC on a series of 50 FNA samples of metastatic melanoma. BRAF molecular analysis was performed on the same cytological samples or on the corresponding histological samples. Molecular analysis was considered the gold standard. Results: BRAF ICC results were adequate in 49 out of 50 (98%) cases, positive in 15 out of 50 (30%) cases and negative in 34 out of 50 (68%) of cases. Overall, BRAF ICC sensitivity, specificity, positive predictive value and negative predictive value results were 88.2%, 100%, 100% and 94.1%, respectively. The diagnostic performance of BRAF ICC results was perfect when molecular evaluation was performed on the same cytological samples. Hyperpigmentation represents the main limitation of the technique. Conclusions: BRAF ICC is a rapid, cost-effective method for detecting BRAF V600E mutation in melanoma metastases, applicable with high diagnostic performance to cytological samples. It could represent the first step to evaluate BRAF mutational status in cytological samples, mainly in poorly cellular cases.

scholarly journals Prostate Cancer Liquid Biopsy Biomarkers’ Clinical Utility in Diagnosis and Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3373
Author(s):  
Milena Matuszczak ◽  
Jack A. Schalken ◽  
Maciej Salagierski
Keyword(s):  
Prostate Cancer ◽  
Liquid Biopsy ◽  
Current Knowledge ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Digital Rectal Examination ◽  
Cost Effective ◽  
Non Invasive ◽  
Diagnosis And Prognosis

Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level in the blood serum. PSA is a marker produced by prostate cells, not just cancer cells. Therefore, an elevated PSA level may be associated with other symptoms such as benign prostatic hyperplasia or inflammation of the prostate gland. Due to this marker’s low specificity, a common problem is overdiagnosis, which leads to unnecessary biopsies and overtreatment. This is associated with various treatment complications (such as bleeding or infection) and generates unnecessary costs. Therefore, there is no doubt that the improvement of the current procedure by applying effective, sensitive and specific markers is an urgent need. Several non-invasive, cost-effective, high-accuracy liquid biopsy diagnostic biomarkers such as Progensa PCA3, MyProstateScore ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed in recent years. This article compares current knowledge about them and their potential application in clinical practice.

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