Question

Answer in detail please, high percentage of my grade

1) Discuss how fusion genes can originate from chromosomal breaks, and how these fusion genes can lead to cancer

b) Within your answer, please discuss in detail the genotype, and how this leads to the phenotype of at least one type of cancer

c) discuss the genetic screening techniques that can be used to assess this disorder, and any recent developments in this area

d) discuss how a detailed understanding of the genotype could lead to novel therapeutics for cancers originating from fusion genes

Answer 1

a) Spontaneous breakage of chromosomes increases with exposure to mutagenic chemicals and ionizing radiation. The resulting broken ends of DNA are recombinogenic, and this can lead to chromosome fusions, aneuploidy, or rearrangements such as inversions, translocations, and deletions. The rearrangement of the genome inside of a cell causes genomis instability and mutation in genes which can result in cancer as well as other diseases. Due to gene fusion many genes in the body, called proto-oncogenes, are mutated in  becoming oncogenes and thus leads to cancer.

b)The first fusion gene, known as the Philadelphia chromosome, was discovered in 1973 in chronic myelogenous leukemia. The Philadelphia chromosome forms when chromosome 9 and chromosome 22 break and exchange portions. This creates an abnormally small chromosome 22 and a new combination of instructions for your cells that can lead to the development of chronic myelogenous leukemia. The central portion of the breakpoint cluster region (BCR) gene ( chromosome 22 )fused to the second exon of the Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene (chromosome 9 ). BCR-ABL1 has been found to occur in more than 95% of chronic myeloid leukemia patients and to exert its oncogenic phenotype by encoding a constitutively active ABL1 kinase (thyrosine kinase). Tyrosine kinase promotes cancer by allowing certain blood cells to grow out of control.

c) Blood test: A complete blood count may reveal abnormalities in your blood cells, such as a very high number of white blood cells.

Bone marrow test : Bone marrow biopsy and bone marrow aspiration are used to collect bone marrow samples for laboratory testing. These tests involve collecting bone marrow from the hipbone.

Specialized tests : such as fluorescence in situ hybridization (FISH) analysis and the polymerase chain reaction (PCR) test,and next-generation sequencing (NGS), analyze blood or bone marrow samples for the presence of the Philadelphia chromosome or the BCR-ABL gene.

d) There are currently several clinical trials aimed at treating fusion-positive patients with a range of targeted therapies, which will hopefully lead to better treatment options for patients in the future.Different fusion genes add key features required for risk stratification and increasing numbers of chimeric proteins encoded by the gene fusions serve as specific targets for treatment, resulting in the development of many therapies against fusion genes. For example in chronic myelogenous leukemia, the target of these drugs is the protein produced by the BCR-ABL gene, tyrosine kinase.The first fusion-targeted drug was Imatinib, a tyrosine kinase inhibitor approved by the Food and Drug Administration in 2001 for the treatment of Philadelphia chromosome positive chronic myeloid leukemia. This drug's vast therapeutic benefit led them to be known as the “magic bullet” to cure cancer.

There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA.  The effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, can be studied for developing therapeutics.