scholarly journals Gene Therapy Targeting p53 and KRAS for Colorectal Cancer Treatment: A Myth or The Way Forward?

2021 ◽  
Vol 22 (21) ◽  
pp. 11941
Author(s):  
Hidayati Husainy Hasbullah ◽  
Marahaini Musa
Keyword(s):  
Colorectal Cancer ◽  
Gene Therapy ◽  
Cancer Treatment ◽  
Ethical Issues ◽  
Public Awareness ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Early Screening ◽  
Genetic Changes

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and is responsible as one of the main causes of mortality in both men and women. Despite massive efforts to raise public awareness on early screening and significant advancements in the treatment for CRC, the majority of cases are still being diagnosed at the advanced stage. This contributes to low survivability due to this cancer. CRC patients present various genetic changes and epigenetic modifications. The most common genetic alterations associated with CRC are p53 and KRAS gene mutations. Gene therapy targeting defect genes such as TP53 (tumor suppressor gene encodes for p53) and KRAS (oncogene) in CRC potentially serves as an alternative treatment avenue for the disease in addition to the standard therapy. For the last decade, significant developments have been seen in gene therapy for translational purposes in treating various cancers. This includes the development of vectors as delivery vehicles. Despite the optimism revolving around targeted gene therapy for cancer treatment, it also has various limitations, such as a lack of availability of related technology, high cost of the involved procedures, and ethical issues. This article will provide a review on the potentials and challenges of gene therapy targeting p53 and KRAS for the treatment of CRC.

scholarly journals A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 147 ◽  
Author(s):  
Carlo Capalbo ◽  
Francesca Belardinilli ◽  
Domenico Raimondo ◽  
Edoardo Milanetti ◽  
Umberto Malapelle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Metastatic Colorectal Cancer ◽  
Gene Mutations ◽  
Bioinformatic Analysis ◽  
Genetic Alterations ◽  
Molecular Heterogeneity ◽  
Clinical Approach ◽  
First Line ◽  
Ras Genes

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

scholarly journals Genomic characterization of meningiomas.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2020-2020
Author(s):  
Priscilla Kaliopi Brastianos ◽  
Peleg Horowitz ◽  
Sandro Santagata ◽  
Robert T. Jones ◽  
Aaron McKenna ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Point Mutations ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Chromosome 1 ◽  
Tumor Type ◽  
Driver Genes ◽  
Genetic Changes ◽  
Fresh Frozen ◽  
Copy Number Changes

2020 Background: Understanding the genetic alterations in cancer has lead to groundbreaking discoveries in targeted therapies. Meningiomas are among the most common primary brain tumors, with approximately 18,000 new cases diagnosed annually. Though certain genes have been associated with the development of meningiomas, most notably the tumor suppressor gene neurofibromatosis 2 (NF2), the genetic changes that drive meningiomas remain poorly understood. Our objective was to comprehensively characterize the somatic genetic alterations of meningiomas to gain insight into the molecular pathways that drive this disease. Methods: Fresh frozen specimens and paired blood were collected from 16 consented patients. DNA was extracted from regions of high tumor purity determined by evaluation of H&E slides. Whole-genome sequencing from 10 tumor-normal pairs and whole-exome sequencing from 6 tumor-normal pairs was carried out. We performed an unbiased screen for point mutations, insertions-deletions, rearrangements and copy-number changes across the exomes and genomes. Recurrent (potential driver) events were then analyzed with additional algorithms for statistical significance. Results: Alterations in the NF2 gene were present in 9 of 16 patients. Multiple novel rearrangements and recurrent non-NF2 mutations were also identified in the cohort. Massive genomic rearrangement termed chromothripsis was observed in chromosome 1 in one sample, which has never previously been described in meningiomas, and represents a potentially new mechanism of malignant transformation in this tumor type. Conclusions: While NF2 mutations appear to drive a majority of these tumors, our analysis has uncovered additional potential driver genes in meningiomas, particularly in those tumors negative for NF2 alterations. To our knowledge, this is the first study to comprehensively characterize the totality of somatic genetic alterations in meningiomas, and brings us closer to the development of new therapeutic targets for this disease.

Associations Between Loss of ARID1A Expression and Clinicopathologic and Genetic Variables in T1 Early Colorectal Cancer

2019 ◽  
Vol 152 (4) ◽  
pp. 463-470 ◽  
Author(s):  
Yoshihiro Kishida ◽  
Takuma Oishi ◽  
Takashi Sugino ◽  
Akio Shiomi ◽  
Kenichi Urakami ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutations ◽  
Lymphatic Invasion ◽  
Early Colorectal Cancer ◽  
Clinicopathologic Features ◽  
Kras Mutations ◽  
Genetic Changes ◽  
Cancer Related Gene ◽  
T1 Colorectal Cancer ◽  
Next Generation Sequencing Ngs

Abstract Objectives To evaluate the relationships between adenine-thymine-rich interactive domain 1A (ARID1A) expression and the clinicopathologic features in T1 colorectal cancer (CRC) and to investigate whether the presence of ARID1A protein is related to genetic changes. Methods We retrospectively studied 219 surgically resected T1 CRCs. ARID1A expression was assessed by immunohistochemical methods, and the correlation between ARID1A expression and clinicopathologic features was evaluated. The relationship between ARID1A expression and 409 cancer-related gene mutations was also evaluated using next-generation sequencing (NGS). Results Immunohistochemical staining indicated negative ARID1A expression in 4.6%. Loss of ARID1A expression was significantly associated with younger age, lymphatic invasion, and lymph node metastasis (LNM). NGS showed that PKHD1, RNF213, and MSH6 mutations were more frequent in ARID1A-negative tumors, whereas KRAS mutations were more common in ARID1A-positive tumors. Conclusions In T1 CRC, negative ARID1A expression was correlated with early onset, lymphatic invasion, and LNM. Mutations in some cancer-related genes were possibly related with ARID1A expression.

PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma

2004 ◽  
Author(s):  
Tsuyoshi Saito ◽  
Yoshinao Oda ◽  
Ken-Ichi Kawaguchi ◽  
Tomonari Takahira ◽  
Hidetaka Yamamoto ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Synovial Sarcoma ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Genetic Alterations

scholarly journals MLH1 and MSH2 Gene Mutations and Polymorphisms in Six Malay Families with Hereditary Nonpolyposis Colorectal Cancer

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wan Khairunnisa Wan Juhari ◽  
Khairul Bariah Ahmad Amin Noordin ◽  
Wan Faiziah Wan Abdul Rahman ◽  
Andee Dzulkarnaen Zakaria ◽  
Ahmad Shanwani Mohd Sidek ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Nucleotide Polymorphisms ◽  
Msh2 Gene ◽  
Hereditary Nonpolyposis ◽  
The Impact

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.

Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2138-2143 ◽  
Author(s):  
Patricia D. Castro ◽  
Jan C. Liang ◽  
Lalitha Nagarajan
Keyword(s):  
Tumor Suppressor ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Putative Tumor Suppressor Gene ◽  
Single Clone ◽  
Acute Myelogenous ◽  
Aggressive Clinical Course

Abstract Nonrandom interstitial deletions and monosomy of chromosomes 5, 7, and 17 in refractory myelodysplasia (MDS) and acute myelogenous leukemia (AML) suggest a multistep pathway that culminates in aggressive clinical course. Because cytogenetic studies frequently identify chromosome 5 and 17 deletions within a single clone, we searched for allele loss for 5q loci and TP53 gene mutations in the same leukemic samples. Cosegregating deletions of chromosomes 5 and 17 were found to specifically include the 5q13.3 interval between the lociD5S672 and D5S620/D5S626, a locus hypothesized to harbor a tumor suppressor gene1 and the TP53 gene on 17p. A rare patient with secondary refractory MDS and an unbalanced translocation [der(5;17)], which resulted in deletions of the 5q13.3-qter and 17p loci, provided clues on the sequence of genetic alterations. Serial molecular analysis of this patient revealed a dysplastic clone with der(5;17), which gave rise to a leukemic clone on acquiring an inactivating mutation of TP53. Our findings are consistent with functional cooperation between a putative tumor suppressor gene at 5q13.3 that contributes toward the progression of early stages of MDS, and the TP53 gene when mutated, causes transformation to AML.

scholarly journals Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Soulafa Mamlouk ◽  
Tincy Simon ◽  
Laura Tomás ◽  
David C. Wedge ◽  
Alexander Arnold ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Early Colorectal Cancer ◽  
High Grade ◽  
Neoplastic Progression ◽  
Genetic Changes ◽  
Chromosome 20 ◽  
Genetic Profiles

Abstract Background Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Results Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Conclusion Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.

scholarly journals Clinical significance of FBXW7 tumor suppressor gene mutations and expression in human colorectal cancer: a systemic review and meta-analysis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Shang ◽  
Chuanwang Yan ◽  
Ran Liu ◽  
Lili Chen ◽  
Dongdong Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Significance ◽  
Web Of Science ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Expression Level ◽  
Systemic Review ◽  
China National Knowledge Infrastructure ◽  
Low Expression

Abstract Background Various studies investigating the clinical significance of FBXW7 mutation and/or expression have yielded inconclusive results in colorectal cancer (CRC) patients. Therefore, the present meta-analysis summarizes previous evidence and evaluates the clinical significance, including the prognostic role, of FBXW7 status in CRCs. Methods The meta-analysis was conducted by searching the databases of PubMed, China National Knowledge Infrastructure (CNKI), WANFANG data, Web of Science, Embase, and Web of Science. Pooled odds ratios (ORs) and hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to assess the relationships between FBXW7 status and clinicopathological features and survival in CRC, respectively. Results Ten studies involving 4199 patients met the inclusion criteria and included in our meta-analysis. FBXW7 mutation/low expression was obviously correlated with advanced T stage (OR = 0.44, 95% CI: 0.27–0.74, P <  0.01) and lymph node metastasis (OR = 1.88, 95% CI: 1.40–2.53, P <  0.01), but was not associated with other parameters. Further investigation found that FBXW7 mutation/low expression predicted poor OS (HR = 1.25, 95% CI: 1.06–1.47, P <  0.01), but not DFS in CRC (HR = 1.04, 95% CI: 0.60–1.82, P = 0.88). Subgroup analysis found that FBXW7 status was obviously correlated with OS in cohorts recruited after 2009 (HR = 1.32, 95% CI: 1.17–1.50, P <  0.01), from eastern Asia (HR = 1.27, 95% CI: 1.04–1.55, P = 0.02), detected by immunohistochemistry/qRT-PCR (HR = 1.39, 95% CI: 1.22–1.59, P <  0.01), and analysed with multivariate method (HR = 1.47, 95% CI: 1.25–1.74, P <  0.01). Conclusions This study indicates that FBXW7 status, expression level especially, is associated with OS but not DFS in CRC. FBXW7 expression level may function as a prognostic biomarker in CRC.

p53 and K-ras Gene Mutations Correlate With Tumor Aggressiveness But Are Not of Routine Prognostic Value in Colorectal Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1375-1375 ◽  
Author(s):  
Silvia Tortola ◽  
Eugenio Marcuello ◽  
Isabel González ◽  
Germán Reyes ◽  
Rosa Arribas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
P53 Gene ◽  
Radical Resection ◽  
Genetic Alterations ◽  
Rank Test ◽  
P53 Mutations ◽  
Ras Gene ◽  
Ras Mutations

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

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