Essay 1. Describe what are the genetic mechanisms of oncogene
activation. How can those be detected? Give three examples of
Oncogenes and possible therapeutic intervention.
https://lifesciences-campus.lifestrategies.dyndns.ws/health/proto-oncogene
A proto-oncogene is a healthy gene found in the cell. There are many protooncogenes. Each one is responsible for making a protein involved in cell growth,
division, and other processes.
if a mutation occurs in a proto-oncogene, the gene can become turned on when
isn’t supposed to be. If this happens, the proto-oncogene can turn into a
malfunctioning gene called an oncogene. Cells will start to grow out of control,
which leads to cancer.
These mutations are considered “dominant” mutations. This means that only one copy of
the gene needs to be mutated in order to cause a proto-oncogene to become an oncogene
and cause cancer.
There are at least 3 different types of mutations that can cause a proto-oncogene to
become an oncogene:

Point mutation. This mutation alters, inserts, or deletes one or more nucleotides
(building blocks of DNA and RNA) in a gene sequence. This activates the protooncogene.

Gene amplification. This mutation leads to extra copies of the gene.

Chromosomal translocation (rearrangement). This is when the gene is
relocated to a new chromosomal site that leads to higher expression.
According to the American Cancer Society, most of the mutations that cause cancer are
acquired, not inherited
https://www.ncbi.nlm.nih.gov/books/NBK12538/
Mutation
Mutations activate protooncogenes through structural alterations in their encoded proteins. Various
types of mutations, such as base substitutions, deletions, and insertions, are capable of activating
protooncogenes.76 Retroviral oncogenes, for example, often have deletions that contribute to their
activation. Point mutations are frequently detected in the ras family of protooncogenes (K-ras, Hras, and N-ras).77 It has been estimated that as many as 15% to 20% of unselected human tumors
may contain a ras mutation. Mutations in K-raspredominate in carcinomas. Studies have found Kras mutations in about 30% of lung adenocarcinomas, 50% of colon carcinomas, and 90% of
carcinomas of the pancreas.78 N-ras mutations are preferentially found in hematologic malignancies,
with up to a 25% incidence in acute myeloid leukemias and myelodysplastic syndromes.79,80 The
majority of thyroid carcinomas have been found to have ras mutations distributed among K-ras, Hras, and N-ras, without preference for a single ras family member but showing an association with
the follicular type of differentiated thyroid carcinomas.81,82 The majority of ras mutations involve
codon 12 of the gene, with a smaller number involving other regions such as codons 13 or
61.83 Ras mutations in human tumors have been linked to carcinogen exposure. The consequence
of ras mutations is the constitutive activation of the signal-transducing function of the rasprotein.
Gene Amplification
Gene amplification refers to the expansion in copy number of a gene within the genome of a
cell. The process of gene amplification occurs through redundant replication of genomic DNA,
often giving rise to karyotypic abnormalities called double-minute chromosomes (DMs) and
homogeneous staining regions (HSRs).87DMs are characteristic minichromosome structures without
centromeres. HSRs are segments of chromosomes that lack the normal alternating pattern of lightand dark-staining bands. Both DMs and HSRs represent large regions of amplified genomic DNA
containing up to several hundred copies of a gene. Amplification leads to the increased expression
of genes, which in turn can confer a selective advantage for cell growth.
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Chromosomal Rearrangements
These rearrangements consist mainly of chromosomal translocations and, less frequently,
chromosomal inversions. Chromosomal rearrangements can lead to hematologic malignancy via
two different mechanisms: (1) the transcriptional activation of protooncogenes or (2) the creation of
fusion genes. Transcriptional activation, sometimes referred to as gene activation, results from
chromosomal rearrangements that move a proto-oncogene close to an immunoglobulin or T-cell
receptor gene (see Figure 6-5). Transcription of the protooncogene then falls under control of
regulatory elements from the immunoglobulin or T-cell receptor locus. This circumstance causes
deregulation of protooncogene expression, which can then lead to neoplastic transformation of the
cell.
Fusion genes can be created by chromosomal rearrangements when the chromosomal breakpoints
fall within the loci of two different genes. The resultant juxtaposition of segments from two
different genes gives rise to a composite structure consisting of the head of one gene and the tail of
another. Fusion genes encode chimeric proteins with transforming activity. In general, both genes
involved in the fusion contribute to the transforming potential of the chimeric oncoprotein.
Mistakes in the physiologic rearrangement of immunoglobulin or T-cell receptor genes are thought
to give rise to many of the recurring chromosomal rearrangements found in hematologic
malignancy
https://www.intechopen.com/chapters/49173
BRAF mutations are the most common somatic mutations in cutaneous melanoma and
are extremely rare in mucosal melanoma. There are found in 48% of metastatic biopsy
specimens and can precede neoplastic transformation. Over 90% of the identified
mutations in BRAF are in codon 600. The most common is BRAFV600E, resulting in
substitution of glutamic acid for valine.
There were identified mutations in hotspot codons (12, 13, and 61) of
different RAS genes (HRAS, NRAS, or KRAS), but the most prevalent
were HRAS substitutions that occurred preponderent at codon 61 (HRAS
Q61L mutation), with fewer mutations at codon 12 and codon 13 [13]. Mutations in NRAS appear to be significant in melanoma even earlier than the discovery of BRAF
C-KIT gene encodes a receptor tyrosine kinase (KIT). All the mutations were founded
in exon 11, 13, and 17. The most common is V559A mutation that results in an amino
acid substitution at position 559 in KIT, from a valine (V) to an alanine (A) [16]. While
BRAF and NRAS mutations are common and significant in cutaneous melanomas, CKIT mutations were detected in acral melanomas, mucosal melanomas, conjunctival
melanomas, and cutaneous melanomas.
https://www.nature.com/articles/onc2016351
An in vivo screening system to identify tumorigenic genes
Abstract
Screening for oncogenes has mostly been performed by in vitro transformation assays. However,
some oncogenes might not exhibit their transforming activities in vitro unless putative essential
factors from in vivo microenvironments are adequately supplied. Here, we have developed an in
vivo screening system that evaluates the tumorigenicity of target genes. This system uses a
retroviral high-efficiency gene transfer technique, a large collection of human cDNA clones
corresponding to ~70% of human genes and a luciferase-expressing immortalized mouse mammary
epithelial cell line (NMuMG-luc). From 845 genes that were highly expressed in human breast
cancer cell lines, we focused on 205 genes encoding membrane proteins and/or kinases as that had
the greater possibility of being oncogenes or drug targets. The 205 genes were divided into five
subgroups, each containing 34–43 genes, and then introduced them into NMuMG-luc cells. These
cells were subcutaneously injected into nude mice and monitored for tumor development by in
vivoimaging. Tumors were observed in three subgroups. Using DNA microarray analyses and
individual tumorigenic assays, we found that three genes, ADORA2B, PRKACB and LPAR3, were
tumorigenic. ADORA2B and LPAR3 encode G-protein-coupled receptors and PRKACBencodes a
protein kinase A catalytic subunit. Cells overexpressing ADORA2B, LPAR3 or PRKACB did not
show transforming phenotypes in vitro, suggesting that transformation by these genes requires in
vivo microenvironments. In addition, several clinical data sets, including one for breast cancer,
showed that the expression of these genes correlated with lower overall survival rate.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894612/
Any therapy with the stated goal to treat and possibly cure cancer must
show differential toxicity toward tumor cells relative to normal cells
In principle, cancer can be treated by inducing cancer cells to undergo
apoptosis, necrosis, senescence, or differentiation. These changes can be
brought about by disrupting cancer cell-autonomous processes, by
interfering with autocrine/paracrine signaling within tumors, or by
blocking heterotypic signaling between tumor cells and the surrounding
tissues or blood vessels. Enhancing immune surveillance against cancer
cells expressing novel antigens is also an attractive approach that has
shown efficacy in specifically killing cancer cells (Muller and Scherle, 2006
What type of mutations drive oesophageal adenocarcinoma? Comment
on three different genomic catastrophes that can occur in oesophageal
adenocarcinoma.
Botezatu, Anca et al. "Mechanisms of Oncogene Activation" In New Aspects in Molecular and
Cellular Mechanisms of Human Carcinogenesis, edited by Dmitry Bulgin. London: IntechOpen,
2016. 10.5772/61249
Ihara, T., Y. Hosokawa, K. Kumazawa, K. Ishikawa, J. Fujimoto, M. Yamamoto, T.
Muramkami, et al. 2017. “An in Vivo Screening System to Identify Tumorigenic
Genes.” Oncogene 36 (14): 2023–29. https://doi.org/10.1038/onc.2016.351.
Luo, Ji, Nicole L. Solimini, and Stephen J. Elledge. 2009. “Principles of Cancer Therapy:
Oncogene and Non-Oncogene Addiction.” Cell 136 (5): 823–37.
https://doi.org/10.1016/j.cell.2009.02.024.
371 words, plagiarism:16%