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How might the Sequencing of Cancer Cell Genomic DNA influence treatment ?
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Summary Learning Objectives Molecular Biology and Oncology (MBO)
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How might the sequencing of Cancer Cell Genomic DNA influence decisions on treatment?Where traditional chemotherapy has proved to ineffective, sequencing of Cancer Cell Genomic DNA
allows for more effective targeted therapies. This paper aims to demonstrate how sequencing of
Cancer Cell Genomic DNA can lead to increasingly personalized treatment plans for patients both in
clinical practice and in research.
Sequencing of Cancer Cell Genomic DNA has contributed to the development of large Genomic
databases such as The Cancer Genome Atlas which can better inform physicians on the molecular
profile of their patients and can also be used by scientists to further understanding of cancer cell
mutational profiles.
How is Cancer Cell DNA sequenced? The most common form of Cancer Cell DNA sequencing is Next
Generation Sequencing. Sequencing involves taking DNA and breaking into up into fragments. These
fragments are then amplified through Polymerase Chain Reaction and then attached to a bead.
These beads are then put into a microarray. A solution of free nucleotides is added. When a
complementary nucleotide is added to the template DNA, the phosphate group released triggers a
detectable light signal. Thus, by having the complementary sequence of the given DNA, we can work
out the original sequence through Chargaff’s rules of base- pairing. Whole genome sequencing is too
costly to be done on a readily basis so whole exon sequencing is most used to sequence Cancer Cell
DNA. Exons are the protein coding segments of a cancer cell genome.
Sequencing is critical in pinpointing which mutations in a tumour cell caused it to become oncogenic.
How do we differentiate between passenger mutations and oncodriver mutations? By sequencing
normal tissue and comparing it to tumor tissue, mutations that are common between them can be
visualized as well as those that are not. Thus, these can be identified as onco-driver mutations.
The sequencing of Cancer Cell Genomic DNA allows for the identification of tumor-specific onco
driver genes or so-called actionable mutations. Tumours tend to be heterogenous and vary inside
patients and between patients. In a single patient, a malignant cell can divide into multiple cell
lineages. This can result in subclones which may not respond to the same drug. Inter-patient tumour
heterogeneity describes how different genes can be mutated in different patients with the same
form of Cancer. For example, Breast Cancer can be subdivided into ER positive, HER2 positive, PR
positive and triple Negative. Thus, treating patients with an all size fits one approach is ineffective for
Cancer as a whole.
Around 5% to 10% of Cancers are hereditary. Sequencing has been used to detect presence of
oncogenes linked to hereditary cancers. This technique is employed by Genetic Screening. For
example, inherited BRACA 1 and BRACA 2 mutations indicate a significant chance of developing
breast cancer in later life. This could help with earlier diagnosis and mean more treatments could
proceed before tumors metastasize or even present themselves in the patient. Patients can then
take preventative measures to reduce their risk of developing cancer.
The heterogenic property of tumors means that a selective proportion of cells in a tumor will be
resistant to a particular drug at any point in time. Clones that survive treatment are evidenced to
play a large role in initiating remission of tumors. Perhaps the heterogeneity of tumors can be solved
by delivering more than one drug systematically ; Sequencing cells of different sub – clones and
characterizing each of their individual mutations could provide insight into how to synthesize drugs
which are targeted for each cell lineage. Sequencing could help us identify Truncal Mutations and
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