Hereditary Breast and Ovarian Cancer Assignment Help

Question : Pick a topic that is directly related to proteomics, genomics or genetics. You must describe and review the methods and results from 2-3 papers that are related (based on the same specific topic that you picked). Even though you are describing someone else’s work, your mini review paper must be 100% in your own words.

Answer :

Introduction

It has been determined that the global burden of breast cancer would increase to more than 2 million new cases every year by the year 2030. It has also been estimated that about 10% of these cases are likely to be from hereditary breast and ovarian cancer syndrome. The identification of the individuals with these syndromes with the help of pedigree as well as BRCA 1 and BRCA 2 mutation analyses (Darooei, et al., 2017). The germ line mutations in the BRCA 1 and BRCA 2, along with certain other genes have been determined to be the genetic cause of hereditary breast and ovarian cancer (Silva, et al., 2014). It has also been determined that the germline PALB2 inactivating mutations are also affiliated with a heightened risk of hereditary breast and ovarian cancer. This is primarily due to its role in the process of DNA repair through collaboration with the BRCA proteins. The penetrance and prevalence of PALB2 mutations amongst many populations remains unknown which demands for further study in this region (Velázquez, et al., 2019). In the following discussions, four different articles that have presented detailed study regarding the causes and prevalence of hereditary breast and ovarian cancer, have been reviewed, especially with respect to their methodology that was used and the results that have been obtained in each of the studies.

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Articles to be Reviewed

The articles that shall be reviewed in the following discussion include as listed below:

Article 1: “A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer” by Velázquez, C., Esteban-Cardeñosa, E.M., Lastra, E., Abella, L.E., de la Cruz, V., Lobatón, C.D., Durán, M. and Infante, M., published in 2019.

Article 2: “Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients” by Silva, F.C., Lisboa, B.C., Figueiredo, M.C., Torrezan, G.T., Santos, É.M., Krepischi, A.C., Rossi, B.M., Achatz, M.I. and Carraro, D.M., published in 2014.

Article 3: “Pedigree and BRCA gene analysis in breast cancer patients to identify hereditary breast and ovarian cancer syndrome to prevent morbidity and mortality of disease in Indian population” by Darooei, M., Poornima, S., Salma, B.U., Iyer, G.R., Pujar, A.N., Annapurna, S., Shah, A., Maddali, S. and Hasan, Q., published in 2017.

Article 4: “Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain)” by Sánchez-Bermúdez, A.I., Sarabia-Meseguer, M.D., García-Aliaga, Á., Marín-Vera, M., Macías-Cerrolaza, J.A., Henaréjos, P.S., Guardiola-Castillo, V., Ayala-de la Peña, F., Alonso-Romero, J.L., Noguera- Velasco, J.A. and Ruiz-Espejo, F., published in 2018.

Review of Methods

In the study by Velázquez, et al. (2019), the researchers had employed the patient selection method, whereby individuals of the study patients of breast cancer and ovarian cancer, who also had first degree relatives in the same familial side with ovarian cancer. Furthermore, control population of 320 DNA samples as representatives were obtained that did not have any kind of history of familial cancer. With respect to the genetic analysis basis associated with the study, the researchers had conducted coding sequence and splicing site of the entire PALB2 was screened and heteroduplex analysis was used through the capillary array electrophoresis (HA-CAE) and this method was actually developed by Velázquez, et al. (2019) in their own laboratory. The fragments that demonstrated altered pattern for HA-CAE were sequenced using the Applied Biosystems kit (ABI), BigDye Terminator Sequencing Kit v3.1, along with unmarked reverse and forward primers on the ABI 3100 DNA Sequencer.

The nomenclature of the mutation was on the basis of GenBank reference sequence, NM_024675.3. Standard RNA isolation, along with RT-PCR analysis was conducted for the patient lymphocyte pellets that were stored at -80°C prior to the use. Furthermore, Velázquez, et al. (2019) had used P260-B1 Kit for performing the Multiplex ligation dependent probe amplification (MLPA).in silico analysis was also conducted to identify the pathogenicity of the variants and statistical analysis of the 160 cases along with the 320 population controls were compared with the help of the Fisher Exact test or Pearson Chi-square test, as was appropriate for the situation.

In the study that was conducted by Silva, et al. (2014), the researchers had employed the patient selection method, whereby one hundred and twenty un-associated patients of breast cancer that fulfilled the criteria for the hereditary breast and ovarian cancer were selected from the period of 2007 and 2010. The criteria for making the inclusion included that the diagnosis for the breast cancer have been made amongst people less than the age of 45 years with no family history of these cancers and the diagnosis for the breast cancer have been made amongst people less than the age of 45 years with at least one or more close blood relatives have been diagnosed with breast / fallopian tube / ovarian / primary peritoneal cancer during any age of life.

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The third criteria for selection was that the diagnosis for the breast cancer have been made amongst people between the age of 45 to 50 years with at least one or more close blood relatives have been diagnosed with breast / fallopian tube / ovarian / primary peritoneal cancer within the age of 50 years. The fourth criteria for the selection was that the diagnosis for the breast cancer have been made amongst people more than the age of 50 years with at least one or more close blood relatives have been diagnosed with breast / fallopian tube / ovarian / primary peritoneal cancer during any age of life. The fifth criteria were that two primary BC with the first occurrence being before the age of 50 years. Point mutation screening were made from the DNA that were extracted from the blood and was purified using the DNA isolation kit. Evaluation was conducted for the entire coding sequence as well as the exon-intron boundaries of the genes BRCA1 and BRCA2. Like Velázquez, et al. (2019), Silva, et al. (2014) had also used the MLPA, along with capillary sequencing for the detection of the copy number variations as well as the point mutation.

In the study that has been conducted by Darooei, et al., (2017) the researchers had employed the patient selection method, whereby patients with breast cancer and undergoing oncology treatments were selected during the period of 2014 and 2015. The same was screened by a genetic counsellor. The criteria for the selection screening included individuals with the characteristics of hereditary breast and ovarian cancer and these attributes included the age of the onset of cancer being less than 40 years, women who had self proclaimed positive own family history, the male patients of breast cancer, and the triple negative breast cancer. The individuals fulfilling the criteria were provided with required counselling of genetic pretesting and 3mL of blood sample of the peripheral ethylenediaminetetraacetic acid (EDTA) were obtained or collected from the patients and the complete gene sequence was acquired for BRCA1 and BRCA2. These were exposed on the Ion Proton Platform. Amplicon
library was constructed using the highly multiplexed primer pools. Sanger sequencing was also conducted with the help of cycle sequencing kit.

In the study that has been conducted by Sánchez-Bermúdez, et al. (2018) the researchers had employed the patient selection method, whereby 643 families with hereditary breast and ovarian cancers were selected through genetic counselling and DNA were isolated from their peripheral blood for conducting the screening process to determine the mutations in the BRCA1 and BRCA2 using the next generation sequencing and Sanger sequencing. Furthermore, fore the BRCA1 and BRCA2, the large genomics rearrangements were performed with the help of MLPA, which was similar to that of Velázquez, et al. (2019) and Silva, et al. (2014).

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Review of Results

It was determined by Velázquez, et al. (2019) that there exists a frameshift mutation that segregates within family of early onset cancer. Furthermore, four missense variants were also identified through the research that was conducted. Furthermore, it was also determined through the research that none of the identified variants that were tested for a predicted splicing disruption, demonstrated an aberrant pattern in transcription. In the results of the research conducted by Velázquez, et al. (2019), detections for large genomic rearrangements were not made. Although identification for the PALB2 truncating mutations are made very rarely, however, through the segregation analysis as well as the early onset cancer, it can be determined that a significant contribution towards the hereditary breast and ovarian cancer in the Spanish population is due to the mutations of PALB2. Furthermore, it has also been determined that through the PALB2 screening, the genetic counselling can be improved
through pedigree management, prevention measures as well as therapy selection through PARP inhibitor. In addition, it has been determined by Velázquez, et al. (2019) that the mutations that are present in the PALB2 result in defective DNA repair that can be explored as treatment opportunities.

The research that was conducted by Silva, et al. (2014) exhibited positive detection of 26% in the series. The BRCA1 pathogenic mutations have been determined in 20 cases that were addressed in the research and two cases of copy number variations, along with 7 cases of BRCA2 mutations were also detected. Amongst the entire population of samples, three patients exhibited mutations of TP53 R337H, while another case was about mutation of CHEK2 1100delC. About 25% that is, seven, of the mutations in BRCA1 and BRCA2 have been described that also encompasses splice-site BRCA1 mutation and the pathogenicity for the same was detected immediately due to the presence of an anomalous translation that demonstrated the loss of the final 62 base pairs of the exon number 7. Furthermore, it was also observed that amongst the BRCA 2 mutated patients, microdeletions were present in the exon 4 of ATM. In addition, amongst the patients with BRCA 1 or BRCA 2 negative, exons in PTEN were also identified.

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Through the study that has been conducted by Darooei, et al., (2017) demonstrated that of the entire sample population of 127 individuals, only 24 have been successful in fulfilling the criteria associated with hereditary breast and ovarian cancer syndrome, while through detailed pedigree analysis and verbal autopsy, it has been determined that the sequencing done for BRCA1 as well as the next 2 generations that were conducted revealed that in 13 cases, that is amongst 54% of participants, mutation was revealed and these encompassed of 4 BRCA2 mutation amongst 31% of total population and 9 BRCA1 mutations amongst 69% of total population. Furthermore, it has also been determined through the post test counselling that targeted mutation analysis of 64 individuals belonged to the high risks due to the pathogenic mutation of the 13 families.

The results from the study conducted by Sánchez-Bermúdez, et al. (2018) revealed that amongst 0.7% of the families with breast and ovarian cancers, the presence of RAD51C pathogenic variant c.404G > A were determined, while amongst 1.3% of the families with just ovarian cancers RAD51D pathogenic variant c.694C > T were identified. In addition, three unknown clinical significance variants, namely, c.307T > G in RAD51C, c.715C > T in RAD51D and c.413A > G in RAD51D, were also detected. It was also determined that individuals suffering from premenopausal ovarian tumours were carriers for RAD51D.

Conclusion

From the discussion that has been presented above, it can be determined that there exists certain common steps in the evaluation of the genes and its extraction and application, which play crucial role in the further research processes and the same has been observed in the case of the four research studies that have been reviewed. Furthermore, it is associated with the genetic understanding of the factors that are to be evaluated so as to develop the kind of process that would simplify the detection process as well as enable in providing better suggestions to the patients of the breast cancer.

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