So I got a 100% on this paper; Here are my Professors own word. This is really an excellent paper. You have terrific writting skills. The level at which it is written is beyond the level of an undergraduate genetics course. It is superbly written, presented, and organized. The thorough investigative research you put into this paper is evident. I dont think Ive ever had a student write on this cancer type. I learned a lot from reading it. Great job! Douglas S. Spurdens BIO-355A-ON-SU14 Human Genetics & Genomics Professor Damon Perez June 15, 2014 Mesenchymal chondrosarcomas Mesenchymal chondrosarcomas is a very rare form of malignant cancer found in cartilage and extra-skeletal locations oftentimes mimicking the structures of the tissues that the cancer embodies. Like other cancers two of the key attributes of this cancer is that it proliferates, and it ignores signals giving it to stop growing. This particular form of cancer has a predilection for the craniofacial bones; however, the vertebrae, ribs, pelvis, and humerus are also frequent sites of involvement. As with this form of cancer, mutated somatic cells lay dormant for many years until metastasizing rapidly into the lungs. Mesenchymal chondrosarcoma typically affects women in their youth and is a type of genetic mutation in which translocations, deletions, and rearrangements of unspecified chromosomes occur. Prognosis is poor; patients who receive treatment most likely will not live after diagnosis. Continuing on, this paper will address the epidemiology, statistics, and histology and then move forward to the genetics and genomics of the cancer Mesenchymal chondrosarcomas. The Indian Journal of Urology states that mesenchymal chondrosarcomas comprises of only 2% of all sarcomas first observed by Lichtenstein and Bernstein in 1959. From 1959- 1985 only 111 cases have been observed, making this cancer extremely rare (Tyagi, Kakkar, Vasishta, & Aggarwal, 2014). Prevalent slightly more so in women than men, those who had underwent this form of cancer were between the ages of 13-35. (Goldberg & Grier, 2014). It is not clear as to what causes this cancer but certain people are more susceptible such as those with Olliers Disease, Maffucci Syndrome, Multiple Hereditary Exostoses, Wilms’ Tumor, Paget’s disease, and diseases in children that required previous treatment with chemotherapy or radiation therapy (Bovee, 2002). Prospects are poor for those with mesenchymal chondrosarcomas, from 23 patients observed at the Mayo clinic, 73.9% died of the disease around 6 months to 23 years after diagnosis. The 5- and 10-year survival rates for the tumor were 54.6 and 27.3 percent respectively (Goldberg & Grier, 2014). Therefor death is the most likely outcome for this form of cancer. Mesenchymal chondrosarcomas is a point mutation with changes of the DNA base, as was stated earlier; the mutation can have several consequences or no obvious effects on the phenotype. In Mesenchymal chondrosarcomas we can see that a missense mutation has occurred where changes in the codon replaces one amino acid for another. As a result, dysregulation of genes takes place and the mutated cartilage cells grow out of control. In an article published by Hindawi Corporation, when analyzed under HES staining (Hematoxylin and eosin stain), “…mesenchymal chondrosarcomas cancer cells have a biomorphic histological appearance, and are identified as having small round blue cell and sheets of spindle cells, which are markedly, uniform in size” (David, et al., 2011). Undifferentiated cells predominate the cartilage areas and may make up 10 to 50% of the tumors material and the rest is chondroid matrix (2011). These high cellular areas are composed mostly of cancer cells and other areas are composed of well-differentiated cartilage. Some tumors become vascular, angiogenesis occurs, and vascular endothelial growth proceeds. Some areas may have anastomosing vessels and resemble hemangiopericytoma; however, hemangiopericytoma does not produce cartilage (Bone Tumor. org, 2014). Mesenchymal chondrosarcomas has a predisposition, invasive to particular areas of the body such as the diaphysis of the jaw, pelvis, femur, ribs, and spine; often involves extraosseous structures such as orbit, paraspinal region, meninges, extremity soft tissue and within and around the brain (Goldberg & Grier, 2014). Mesenchymal chondrosarcomas develops as a ‘de novo’ metastatic tumor in bone formation from a deregulated osteoblast-osteoclast coupling which induces the release of factors initially trapped in the bone matrix, which in turn promote tumor cell proliferation (David, et al., 2011). Using nearby stem cells in the bone ‘niche’ that this cancer inhabits provides a microenvironment that is rich in sources this cancer needs to survive and grow. The physiology of Mesenchymal chondrosarcomas is complex however as we continue on the genetic abnormalities associated with this cancer have researchers even more confounded. A case report published by Modern Pathology, Translocation der(13;21)(q10;q10) in Skeletal and Extra skeletal Mesenchymal Chondrosarcoma conducting a study on three specimens, “Deletions of exons on 8q13;8q21, a Robertsonian translocation, loss of chromosomes 8 and 20 material, and gain of chromosome 12 material in all three specimens were the same” (Nahmann, et al., 2002). A Robertsonian translocation can occur on chromosomes 8, 13,14,15,21, and 22, in this particular cancer the translocation and deletions of exons happens on chromosome del(8)(q13.3q21.1). Human Genetics, Concepts and Applications, (p.252) “Robertsonian translocations are when the short arms of two different acrocentric chromosomes break…forming a single large chromosome with two long arms and the tiny arms are lost” (Lewis, 2012). When this occurs, it causes deletions in some cases with unnoticeable phenotypes. Although tumor suppressor p53 overexpression in 61% of the tumors, there were no mutations found (Hans Gelderbloma, 2008). A journal published on the NCBI website entitled, Identification of a Novel, Recurrent HEY1-NCOA2 Fusion in Mesenchymal Chondrosarcoma based on a Genome-wide Screen of Exon-level Expression Data, “Genome-wide screen for gene fusions using Affymetrix Exon array expression data to study a variety of mesenchymal tumors identified a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma” (Lu Wang, 2013). The study analyzed cancer gene fusion patterns and exon expression from 5’ to 3’ end of both translocation genes screening for HEY1-NCOA2 fusion transcripts in a set of 14 cases diagnosed histologically as mesenchymal chondrosarcoma. The exon expression plot of NCOA2 showed dramatic intragenic discontinuity with the change point fusion transcript mapped between NCOA2 exon 12 and exon 13, HEY1 exon 4 fused in-frame to NCOA2 exon13 (Lu Wang, 2013). Out of the 14 cases, HEY1-NCOA2 fusion transcript identified in 5/7 and the remaining 7 cases was unhelpful due to stark RNA degradation (Lu Wang, 2013). NCOA2 interacts with ligand-bound nuclear receptors, a super family of protein hormones that serve as transcription factors that facilitates chromatin remodeling and transcription of nuclear receptor target genes (N/A, 2014). Proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death; Ligand- bound receptors are the opposite of this, called oncogenes. (Heidi Chial, 2008). Ligand- bound receptors are regulators that are responsible for development such as cellular division, differentiation, homeostasis and stress response containing 400-900 amino acids (Goldberg & Grier, 2014). When mutation occurs these ligand receptors fail to facilitate there normal function and transcription fails and disease takes place, in this case researchers believe mesenchymal chondrosarcomas develops. On the website Annals of Clinical and Laboratory Science, another factor involved with this cancer is “the malignant mesenchymal chondroblasts expression of CD99, IL-1α, cPKC-α, p-PKC-α/βII, PDGFR-α, p-JNK, Ki-67, and bc1-2 antigens suggest mechanisms that explain tumor growth while protecting against apoptosis” (Brown & Boyle, 2003). Lastly, this disorder initiated by a mutation in any one of the three genes EXT1, EXT2, or EXT3. Expression of miRNA’s in mesenchymal chondrosarcomas is deregulated causing a tumor signature, which could be helpful for identifying tissue origin and molecular variation and could constitute potent biomarkers for cancer diagnosis. Because the tumor of this type of cancer can remain dormant for many years, often times the tumor is found when a minor incident such as a broken bone and a visit to the doctors takes place, and an x-ray, MRI, CT scan, or blood test discovers the tumor. In order for researchers to make a clear diagnostic of this cancer, pathologists look for a combination of two specific translocation appearances on the biopsy specimen. To do this they are using RT-PCR or FISH for evidence of the HEY1-NCOA2 fusion for the presence in all suspected mesenchymal chondrosarcomas patients. Pathologists are also taking antibodies, which is a specific molecule that can bind directly against the Sox 9 gene (specific to this tumor) and found that the test was a reliable indicator of the diagnosis of mesenchymal chondrosarcoma. The HEY1-NCOA2 fusion needs further evaluation in a larger cohort of tumors to establish more precisely the specificity and sensitivity of this fusion for the diagnosis of mesenchymal chondrosarcomas and the spectrum of possible fusion variants. (Goldberg & Grier, 2014). Treatment, as mentioned, for patients who develop metastatic disease during or after therapy, the prognosis is poor. No specific mesenchymal chondrosarcoma research protocols are available at this time for a cure. The most common treatments are adjuvant chemotherapy, surgery, and radiation. However, researchers are hoping to use the Sox 9 gene in future endeavors to trigger other changes in the cancer cell that would leave the tumor vulnerable to certain medications. Unfortunately, this form of cancer has been giving geneticist problems, for example. In chondrosarcoma, the use of celecoxib, a COX-2 inhibitor, first results in a decrease in tumor volume followed unfortunately by a relapsed tumor growth after 6 weeks (David, et al., 2011). Options that are hopeful in the near future lie in kinase molecule research and proton therapy for a cure. Proton therapy is able to ‘target’ only cancer cells and not the healthy cells that surround the tumor. In the future geneticist could possibly find a gene ‘solution’ instead of surgery they may insert a gene into your body’s cells specific to your cancer that will serve as a cure. Unfortunately, there are no viable gene (based) therapies in the near future for this particular cancer at this time. This malignant type of cancer found in cartilage and extra-skeletal locations is taxing researcher’s ability to pin point a specific chromosome mutation, not only because of its translocation frequency, but also because of its rarity. This particular cancer oftentimes lays dormant for many years until metastasizing quickly, spreading rapidly into the lungs, and leading to a swift death for whom are afflicted. Prediction are poor; patients who receive treatment most likely will not live after diagnosis. However, researchers are hoping that the Sox 9 gene could trigger other changes in the cancer cell that would leave the tumor vulnerable to certain medications. The HEY1-NCOA2 fusion will need to be evaluated in a larger cohort of tumors to establish more precisely the specificity and sensitivity of this fusion variant, also Identification of the der(13;21)(q10;q10) translocation may be useful diagnostically for mesenchymal chondrosarcoma. Reflection on this topic with a Biblical perspective, curing cancer, and other disease is a good thing. God told us to master our environment, and believe that finding a way to defeat horrible disease is one-step closer to God’s kingdom on earth. I have said this before; I believe God will reveal all of His creation to us in time, even down to the smallest of things, such as our genes. References Bovee. (2002). What is chondrosarcoma? Retrieved from The Liddy Shriver Sarcoma Initiative: sarcomahelp.org/chondrosarcoma.html Brown, R. E., & Boyle, J. L. (2003). Mesenchymal Chondrosarcoma: Molecular Characterization by a Proteomic Approach, with Morphogenic and Therapeutic Implications. Retrieved from Annals of Clinical & Laboratory Science: annclinlabsci.org/content/33/2/131.full David, E., Blanchard, F., Heymann, M., De Pinieux, G., Gouin, F., Redini, F., & Heymann, D. (2011). The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets. Retrieved from Hidawi: hindawi/journals/sarcoma/2011/932451/ Goldberg, J., & Grier, H. (2014). Mesenchymal Chondrosarcoma. Retrieved from The Liddy Shriver Sarcoma Initiative: sarcomahelp.org/mesenchymal-chondrosarcoma.html Hans Gelderbloma, P. C. (2008). The Clinical Approach Towards Chondrosarcoma. Retrieved from The Oncologist: theoncologist.alphamedpress.org/content/13/3/320.long Heidi Chial, P. (2008). Proto-oncogenes to Oncogenes to Cancer. Scitable by Nature Education. Retrieved from nature/scitable/topicpage/Proto-Oncongenes-to-Oncogenes-to-Cancer-883 Lewis, R. (2012). Human Genetics Concepts and Applications. New York,NY: Mcgraw-Hill. Lu Wang, T. M. (2013). Identification of a Novel, Recurrent HEY1-NCOA2 Fusion in Mesenchymal Chondrosarcoma based on a Genome-wide Screen of Exon-level Expression Data. NCBI. doi:10.1002/gcc.20937 N/A. (2014). The Ligand Binding Domain of Nuclear Receptors. Retrieved from www-personal.umich.edu/~lpt/domain.htm Nahmann, S., Krallman, P., Unni, K., Fidler, E., Neff, J., & Bridge, J. (2002). Translocation der(13;21)(q10;q10) in Skeletal and Extraskeletal Mesenchymal Chondrosarcoma. Modern Pathology. Retrieved from nature/modpathol/journal/v15/n5/full/3880565a.html Tyagi, R., Kakkar, N., Vasishta, R., & Aggarwal, M. (2014). Mesenchymal chondrosarcoma of kidney. Indian Journal of Urology, 225-227.
Posted on: Wed, 18 Jun 2014 22:15:59 +0000
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