The Concept of BRCA1 Gene - Term Paper Example

BRCA1 gene Introduction BRCA1 gene is found at 17q21. It has 24 exons which code for 1863 amino acids. It is a tumor suppressor gene which is important in DNA repair. It repairs DNA by maintenance of chromosomal stability, homologous recombination, cell cycle regulation, activation of DNA damage checkpoints, ubiquitylation and transcription-coupled DNA repair. Mutations in the BRCA1 gene are very penetrant and present a lifetime risk of 46-87% of breast cancer development in mutation carriers by the age of 70 years. Mutations in the gene are also associated with ovarian cancer development. An increased risk of prostate cancer has also been suggested male carriers of deleterious BRCA1 gene mutations. Currently, over 1600 sequence variants of BRCA1 gene have been described. Some of these sequence variations are only present in specific ethnic groups and as such are known as founder mutations. As consequence of founder effects coupled with geographical and environmental factors, BRCA1 gene mutation prevalence varies among various populations. Studies have indicated that variation in mutation prevalence range from 1.8 to 13.1% in developed countries. Description of BRCA1 gene BRCA1 gene is a tumor suppressor gene. It is a large gene that is spread over about 100 kb of the genome. It has 24 exons and it encodes a nuclear phosphoprotein that has 1863 amino acids. The molecular weight of the protein encoded by BRCA1 gene is approximately 220 kD. BRCA1 protein has an amino terminal ring finger motif that is similar to those in proteins which interact with nucleic acids such as RNA and DNA in addition to those that interact with proteins. The human BRCA1 gene shares 58% amino acid identity with the mouse protein. Moreover, the mRNA expression patterns of BRCA1 gene in both human and mice are quite similar. BRCA1 gene plays a regulatory role in the tissue differentiation and proliferation. The human BRCA1 gene co-localises and co-immuno-precipitate with RAD 51 and as such is involved in DNA damage repair. Treatment with reagents that damage DNA results in BRCA1 gene protein phosphorylation and relocation to intranuclear structures where DNA replication takes place. This indicates that BRCA1 gene is involved in DNA damage repair. A study involving mice showed that murine BRCA1 gene is responsible for genomic integrity. In this study it was demonstrated that BRCA1-/- embryos exhibited hypersensitivity to ɣ-irradiation and chromosomal abnormalities. This shows that BRCA1 gene is involved in mediating genomic stability. Germ line mutation of BRCA1 gene has been implicated in familial ovarian and breast cancer in addition to other cancers such as prostate cancer. BRCA1 gene has 1a and 1b as alternatives for the first exon. Each of these exons has its own promoter region. Exon 1a containing transcripts are the predominant transcripts expressed in mammary epithelium. The BRCA1 gene is found within 50kb of the IAI.3B gene. The promoter region of IAI.3B gene and the BRCA1 gene have a complex organization. The BRCA1 exon 1a is found 295 bp from exon 1a of the IAI.3B duplication. An analysis of 5’ region of BRCA1 gene has shown that there is a CpG island that extends over more than 1200 nucleotides that starts at exon 1a of the IAI.3B duplication and involves exons 1a and 1b of BRCA1 gene and its associated promoter regions. Studies have shown that hypermethylation of the promoter region is one of the mechanisms involved in mutation for the inactivation of tumor suppressor genes. BRCA1 gene and tumorigenesis There is evidence that suggest BRCA1 gene to have a tumor suppressor activity in sporadic tumors. Once sporadic tumors become invasive, the activities of BRCA1 gene become markedly lower. Studies have indicated that antisense oligonucleotides to BRCA1 gene results in an increased proliferation of mammary epithelium and the MCF-7 cell line. Moreover, when a normal copy of BRCA1 gene is introduced into cell lines which are derived from sporadic tumors results in reduction of tumorigenecity. Various explanations have been put forward for the decreased activity of BRCA1 gene in invasive breast tumor cells. One of the explanations is that an upstream regulator of activity might be involved. Another explanation is that the BRCA1 gene is inactivated when the tumor is dedifferentiated or enters abnormal and different development program. These explanations may occur inclusively or exclusively of each other since BRCA1 gene control alteration by upstream genes may be a result of an altered developmental program. Another possible explanation for decreased BRCA1 gene activity in tumorigenesis is that an epigenetic change may inactivate the locus. Such epigenetic inactivation may involve hypermethylation of the gene. Although hypermethylation of the promoter region of other genes is associated with loss of activity in breast cancer, hypermethylation of the BRCA1 gene promoter region is not the only explanation for decrease in BRCA1 gene activity. However, there exists a possibility that methylation of BRCA1 gene promoter region could be a reflection of a widespread hypermethylation of CpG islands in patients who have hypermethylation. It is also likely that hypermethylation might inactivate the normal allele in persons who carry a germ-line mutation in which tumor do not show loss of heterozygosity. Effects of BRCA1 gene mutations Different mutations have been reported on the BRCA1 gene. Most of these mutations are characterized by insertions, deletions, splice variants and non-sense mutations that result in a truncated protein. Detection of BRCA1 gene mutations are based on PCR techniques which enable detection of sequence alterations such as small deletions, insertions, and point mutations. This has resulted in identification of very many mutations. Other studies have also reported large genomic rearrangements (LGRs) that are not detectable by PCR based techniques. The studies have employed multiplex-ligation-dependent probe amplification (MLPA) procedure that enables the screening of LGRs. Other techniques such as southern blotting, long range PCR, real time PCR and fluorescence in situ hybridization based methods can also be utilized in detection of LGRs. Studies have shown that LGRs account for between 0 and 27% of all diseases resulting from BRCA1 gene mutations. Currently, over 18 different LGRs have been characterized. These LGRs include both deletions and duplications of one or more exons in BRCA1 gene. Detection of BRCA1 gene mutations in carriers allows non-directive clinical decision to be made to manage high lifetime risk of ovarian and breast cancer. Such managements may include follow up prophylactic mastectomy, and salpingo-oophorectomy. Many studies have reported an increased risk of developing breast and ovarian cancer among women with germ line mutations in the BRCA1 gene. It has been suggested that mutations in BRCA1 gene presents 80 to 90% lifeline risk of developing breast cancer and 40 to 65% lifeline risk of developing ovarian cancer. In spite these reports; the magnitude of risk to BRCA1 gene mutation carriers is still a controversial issue. The controversy is partly due to variation in populations and study designs utilized. Lack of specific mutation stratification could also explain the controversy surrounding the magnitude of risk to carrier of mutations to BRCA1 gene. According to Breast Cancer Information Core Database over 1560 mutations and polymorphisms exists in the BRCA1 gene. However, the impact of each of these mutations on cancer type, expressivity and age dependent penetrance is either unexploited or controversial. Various studies conducted in the past decade have supported the hypothesis that various mutations in the BRCA1 gene results in different cancer related risks. One such study indicated that there is an increased risk of developing ovarian cancer than breast cancer among carriers of BRCA1 gene mutations at 5’ to exon 13 of the BRCA1 gene as opposed to mutations at 3’ to exon 13. However, later studies did not confirm these findings. Another study demonstrated that different BRCA1 gene mutations have specific effects that affect the age of onset of ovarian or breast cancer. This study reported that mutations of BRCA1 gene at exon 2 has a lower penetrance than mutations at exons 11, 13 and 20 of BRCA1 gene for both ovarian and breast cancers. The study reported that the 185delAG mutation of the BRCA1 gene is a low penetrance mutation that is age dependent as compared to exon 13 duplication mutations. Other studies implicating BRCA1 gene mutations in prostate cancer have also been conducted. One such studies reported that common variations in the BRCA1 gene makes carriers to be more susceptible to prostate cancer than non carriers of such mutations. The study reported that mutation of BRCA1 gene at Gln356Arg presents an increased risk of prostate cancer development in carriers of this mutation. Even though most BRCA1 germline mutations are common in patients with early onset breast cancer who have strong family history of a disease, various reports exist of such mutations in patients without a strong family history of the disease. Thus it is important to screen people in instances where tumors are high grade and bilateral. Lack of family history could be as a result of either de novo germ line mutation initiation in some ancestor or non-informative families. However, it is worthy noting that the incidence of detected de novo BRCA1 gene mutations is very low. Although BRCA1 gene mutations have been implicated in the onset of various cancers especially breast and ovarian cancer, some studies have indicated that mutations in the BRCA1 gene are predictive of a good response to certain treatments. One such study reported an 83% pathologic complete response rate in BRCA1 breast cancer carriers in a neoadjuvant setting with cisplatin. Moreover, another study reported promising results in targeting the BRCA1 gene related homologous recombination pathway with the new poly(ADP)-Ribose Polymerase inhibitors. Conclusion BRCA1 gene is a tumor suppressor gene. It is a large gene that is spread over about 100 kb of the genome. BRCA1 gene is found at 17q21. It has 24 exons and it encodes a nuclear phosphoprotein that has 1863 amino acids. It repairs DNA by maintenance of chromosomal stability, homologous recombination, cell cycle regulation, activation of DNA damage checkpoints, ubiquitylation and transcription-coupled DNA repair. BRCA1 gene has 1a and 1b as alternatives for the first exon. Each of these exons has its own promoter region. There is evidence that suggest BRCA1 gene to have a tumor suppressor activity in sporadic tumors. Different mutations have been reported on the BRCA1 gene. Detection of BRCA1 gene mutation employ techniques such as multiplex-ligation-dependent probe amplification (MLPA) procedure, southern blotting, long range PCR, real time PCR and fluorescence in situ hybridization based methods for LGRs and other PCR based techniques for detection of sequence alterations such as small deletions, insertions, and point mutations. Many studies have reported an increased risk of developing breast and ovarian cancer among women with germ line mutations in the BRCA1 gene. Other studies have implicated BRCA1 gene mutations in prostate cancer. References Parthasarathy, S. (2007). Building Genetic Medicine: Breast Cancer, Technology, and the Comparative Politics of Health Care. London: MIT Press Palombi, L. (2009). Gene Cartels: Biotech Patents in the Age of Free Trade. London: Edward Elgar Publishing Hayat, M. (2006). Handbook of Immunohistochemistry And in Situ Hybridization of Human Carcinomas: Molecular Genetics, Gastrointestinal Carcinoma, And Ovarian Carcinoma, Volume 4. London: Academic Press Lee, J., McMahon, P., Kong, C., Kopans, D., Ryan, P., Ozanne, E., Halpern, E., & Gazelle, S. (2010). Cost-effectiveness of Breast MR Imaging and Screen-Film Mammography for Screening BRCA1 Gene Mutation Carriers. Radiology, 254, 793-800 Tan-Wong, S., French, J., Proudfoot, N., & Brown, M. (2008). Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene. Proceedings of the National Academy of Sciences of the United States of America, 105(13), 5160-5165 Konishi, H., et al. (2011). Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proceedings of the National Academy of Sciences of the United States of America, 108(43), 17773-17778 Genetics Home Reference. (2007). BRCA1. 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