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Cancer predisposition by BRCA1 and BRCA2 gene mutation
BRCA1 (breast cancer 1 gene-related cancers) and BRCA2 (breast cancer 2 gene-related cancers) are two human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer. Some ethnic groups are at particular risk for carriage of these mutations (estimated 2% of US Ashkenazi Jews). Women who inherit a mutated copy of either gene have an elevated lifetime risk of breast and ovarian cancer. Men with these mutations also have an increased risk of breast and other cancers.
In their normal state, BRCA1 and BRCA2 genes prevent breast cancer by producing a protein that stops breast cancer cells from multiplying out of control. As the function of these genes is to keep breast cells growing normally and to prevent any growth of breast cancer cells, these genes are considered to be tumor suppressor genes. Every person (women and men) has two copies of each of these genes in their breast cells. As long as at least one of the copies of each gene in every breast cell is working properly, breast cells function normally. However, if both copies of the gene have mutations, abnormal cell growth can no longer be prevented. When abnormal growth occurs, breast cells begin to multiply at very rapid rates. Some of the extra cells can invade healthy breast tissue, causing invasive breast cancer. In non-invasive breast cancer, abnormal cell growth occurs, but the surrounding breast tissue is not invaded. All breast cancers are caused by abnormal genes. The abnormalities, or mutations, in the genes can be either inherited or acquired:-
- Inherited genetic abnormality. Some people are born with one abnormal gene from one parent and one normal gene from the other parent.
- Acquired (or non-hereditary) genetic abnormality. A gene can became abnormal as a result of "wear and tear", through an error in how the gene reproduces, or from a variety of other factors, such as exposure to toxins, environmental effects, diet, hormonal influences, or unknown causes. Acquired genetic abnormalities account for 85% to 90% of breast cancers.
Whether you inherited an abnormal breast cancer gene or acquired it, if you have one normal gene, that normal gene will still work to control cell growth and prevent cancer. But, if circumstances cause that normal gene to malfunction or break down, cancer may result. A woman with an abnormality (mutation) in a BRCA1 or BRCA2 gene has a higher risk of developing breast cancer or ovarian cancer than do other women. For example, women with a mutation in BRCA1 or BRCA2 have a 3 to 7 time higher risk of developing breast cancer than do women lacking the genetic mutations (1).
However, that not all women with an abnormal BRCA1 or BRCA2 gene do not develop breast cancer. Women with a mutation in BRCA1 have a 50% lifetime risk of developing breast cancer. Women with a mutation in BRCA2 have a 50%-60% lifetime risk of developing breast cancer. Women with an abnormal BRCA1 or BRCA2 gene can consider medical options for reducing their risk. Of course, we cannot control our genetic make-up. Women with an abnormal BRCA1 or BRCA2 gene can consider medical options for reducing their risk. In addition, there are many risk factors for breast cancer and ovarian cancer that are controllable. A healthy lifestyle and a positive attitude help to maintain wellness (1).
Germ line mutations in either of these genes account for 20-60% of breast cancer cases in families where multiple individuals are affected. Mutations in a small number of other genes, some identified and some unknown are predicted to account for the remainder of familial risk. Epidemiological studies sparked by the discovery of BRCA1 and BRCA2 have made clear several features of inherited mutations in the genes. The mutations are highly penetrated, carrying a lifetime risk of 30-70% for cancer incidence, with variation related to genetic background (2).
Ovarian cancer risk assessment
Increased risk factors for ovarian cancer are infertility, late menopause and family history. Family history is especially important if there are greater than two first-degree relatives with ovarian carcinoma. Familial predisposition is also seen in families with mutations of the BRCA1 gene and the BRCA2 gene. These families have a greater risk of both ovarian and breast cancer (3).
Woman has two affected close relative, the risk is increased to about 1 in 10. If there are more cases of ovarian malignancy, especially with an early age of diagnosis, then the risks are those of an autosomal dominant family. Any breast cancers within the family need to be taken into account when assessing risk. The clearly autosomal dominant predisposition to ovarian cancer is seen in epithelial cancers. Mutations in BRCA1/2 account for the majority of families with inherited ovarian cancers, even those families without cases of breast cancer. However, there may be a further breast/ovarian cancer predisposition gene that have not been mapped or cloned. Non-epithelial ovarian tumors are seen in Peutz-Jeghers and Gorlin syndromes (4).
Prophylactic oophorectomy has been suggested to prevent ovarian cancer although there may still be a risk of peritoneal cancer. Primary peritoneal cancer does occur with an increased incidence in BRCA1 families and therefore CA125 levels should still be measured even after prophylactic oophorectomy in high-risk families. It has been shown in known BRCA1 mutation carriers that the combined oral contraceptive decreases the risk of ovarian cancer by up to 60%. However, it must be balanced with the increased risk of breast cancer. The age of onset varies from early as fourth decade in some families (4).
Breast cancer risk assessment
Breast cancer is common, with women developing the disease. The population risk in men is 1 in 1200. A family history of breast cancer is a major risk factor in women. The risk is proportional to the number of relatives affected and is inversely related to the age at diagnosis of breast cancer within the family. Hormonal factors are also known to influence the risk of breast cancer, with prolonged exposure to either endogenous or exogenous estrogen increasing the risk. About 5-10% of breast is inherited. Assessing a woman's risk of breast cancer is straightforward in a family with an autosomal dominant pattern of cancers. First degree relatives of affected women in these families have a 50% risk of inheriting a mutation and the associated risk of developing malignancy. However, most of the families that attend counseling will not have such a strong history. A large epidemiological study (cancer and steroid hormone study) in the US has provided useful information that allows the estimation of lifetime risk depending on the number of affected cases and the age of diagnosis. For example, a woman with a first degree relative diagnosed with breast cancer under the age of 40 years has lifetime risk of breast cancer of 1 in 6 (double the population risk), whilst a woman whose mother and a maternal aunt were both diagnosed with breast cancer at the age of 50 years, has a lifetime risk of 1 in 3-4. The age of onset of familial breast cancers tend to occur before the menopause. The pattern of malignancies within a family may be an indication of the gene involved. BRCA1 and BRCA2 account for the majority of familial high penetrance breast cancers, but research is currently aimed at localizing BRCA3 (4).
Not all gene changes, or mutations, are deleterious (harmful). Some mutations may be beneficial, whereas others may have no obvious effect (neutral). Harmful mutations can increase a person's risk of developing disease, such as cancer. A women's lifetime risk of developing breast/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2. Harmful BRCA1 mutations may also increase a woman's risk of developing cervical, uterine, pancreatic cancer and colon cancer. Harmful BRCA2 mutations may additionally increase the risk of pancreatic, stomach, gallbladder, bile duct cancer and melanoma. Men with harmful BRCA1 mutations also have an increased risk of breast cancer and, possibly, of pancreatic, testicular and early onset prostate cancer. However, male breast cancer, pancreatic and prostate cancer appears to be more strongly associated with BRCA2 gene mutations (5). According to estimates of life time risk, about 12.0% of women (120 out of 1,000) in the general population will develop breast cancer sometime during their lives compared with about 60% of women (600 out of 1,000) who have inherited a harmful BRCA1 or BRCA2. In other words, a woman who has inherited a harmful mutation in BRCA1 or BRCA2 is about five times more likely to develop breast cancer than a woman who does not have such a mutation. Lifetime risk estimates for ovarian cancer among women in the general population indicate that 1.4% (14 out of 1,000) will be diagnosed with ovarian cancer compared with 15 to 40% of women (150-400 out of 1,000) who have a harmful BRCA1 or BRCA2 mutation (5).
The majority of mutations are small insertions or deletions distributed throughout the genes, which are predicted to result in truncation of the encoded protein. Many mis-sense and nonsense alterations have also been described. Mutations in BRCA1 or BRCA2 are not simply associated with increased breast cancer risk. Mutation carriers are also susceptible to cancers of the ovary, prostate, pancreas and male breast. Other associations may be revealed when more epidemiological information becomes available. Inheritance of one defective BRCA1 or BRCA2 allele suffices to confer cancer predisposition. Breast and ovarian tumors from, predisposed individuals almost invariably exhibit loss of heterozygosity while retaining the mutant allele indicating that the protein products of the genes may behave in some respects as tumor suppressors. It is puzzling, therefore, that somatic mutations in BRCA1 or BRCA2 do not frequently occur in sporadic (non-familial) breast cancers. This weakens, but does not disprove, the notion that the gene products operate in a cellular pathway that is defective in the majority of breast cancers. One possible explanation for the discrepancy is that the genetic alterations in sporadic cancers target other molecules whose functions are linked to those of BRCA1 or BRCA2. Thus, hopes that delineation of the functions of BRCA1 and BRCA2 might reveal common mechanisms underlying pathogenesis have stimulated much interest in the cell biology of these proteins (2).
BRCA1
Given the high risk of contra lateral breast cancer in BRCA1 mutation carriers, there is a good argument for altering management of initial early breast cancers. In the general population, breast-conserving surgery may be offered to young women. However, it is felt by some that a BRCA1mutation carrier should immediately be offered bilateral mastectomy. Oophorectomy is a further treatment option that should be considered. Age of onset of breast cancer is 35 onwards and age of onset of ovarian cancer is 50 years onwards. Inheritance of BRCA1 gene is autosomal dominant. The chromosomal location of this gene is 17q21 (4).
BRCA1: 24 exons (22 coding) encoding a 1863 amino acid protein. Mutations are found throughout the gene but some founder mutations exist. Two mutations account for the majority of inherited breast cancer within the Ashkenazi Jewish population: 185delAG (1%) and 5382insC (0.2%), along with a founder mutation in BRCA2. There is strong genotype-phenotype correlation. Mutations in BRCA1 have not been found in sporadic breast cancers (4).
The BRCA1 protein has a ring finger domain that is involved in mediating protein-protein or protein-DNA interactions. It is a nuclear protein and is preferentially expressed during late G-S-phase transition to arrest cell cycle progression. BRCA1 appears to be involved in the control of mitotic spindles and segregation of daughter chromosomes. It is also involved in DNA repair in conjunction with BRCA2.
Mutation testing is available but time consuming. Some laboratories offer a ‘quick screen' looking for mutations in exons 11, 2 and 20 only. Once a mutation is identified within a family, predictive testing becomes an option (4).
Given the high risk of contra lateral breast cancer in BRCA1 mutation carriers, there is a good argument for altering management of initial early breast cancers. In the general population, breast-conserving surgery may be offered to young women. However, it is felt by some that a BRCA1mutation carrier should immediately be offered bilateral mastectomy. Oophorectomy is a further treatment option that should be considered (4).
BRCA2
There is controversy over the value of prostate-specific antigen (PSA) estimation in men with a BRCA2 mutation. It is recommended that men with BRCA2 mutations should undergo regular breast examination. The age of onset of breast cancer is 35 onwards and that is 50 onwards in case of ovarian cancer. Inheritance of this gene is autosomal dominant type. Its chromosomal location is 13q12 (4).
BRCA2: 27 exons encoding a 3418 amino acid protein. Mutations are found throughout the gene but some founder mutations exist. A single mutation, 6174delT, accounts for the majority of inherited breast cancer within the Ashkenzi Jewish population along with the founder mutations in BRCA1. There is a weak genotype-phenotype correlation, with mutations in exon 11 between nucleotides 3035 and 6629 (the ovarian cluster region) conferring a risk of ovarian cancer of 20% as compared to mutations outside this region conferring a risk of 10%. Mutations have not been found in sporadic breast cancers (4).
BRCA2 is a histone acetyl transferase that may be involved with regulation of transcription and tumor suppressor function. It also interacts with Rad51, a protein involved in DNA repair. Along with BRCA1 it is preferentially expressed during late G-phase and early S-phase of the cell cycle. Both BRCA1 and BRCA2 are involved in pathways that may trigger p53 activity. Mutation testing is available but time consuming. Some laboratories offer a ‘quick screen' looking for mutations in exons 10 and 11 only. Once a mutation is identified within a family, predictive testing becomes an option (4).
BRCA1 and BRCA2 have very different primary sequences. BRCA1 is a 1,863-residue protein of unknown structure and has a few identifiable features. An N-terminal RING domain has been implicated in several protein-protein interactions (for instance, with BARD1). The C-terminus of BRCA1 contains two 95-residue BRCT (for BRCA1 C terminal) domains, which are also found in many other proteins involved in DNA repair and cell cycle regulation. Tumor-associated mutations in BRCA1 are predicted to disrupt the folding or stability of the BRCT domain or to alter the putative interface for dimerization – this would be consistent with effects upon protein function (2).
The 3,418 residue BRCA2 gene product does not exhibit significant similarity to any known protein. Eight 30-40 residue motifs– the so-called BRC repeats – are encoded in exon 11 and conserved between several mammalian species, which suggests they have an essential function. In fact, the BRC repeats have been shown to mediate the binding of BRCA2 to RAD51, a mammalian protein essential for DNA repair and genetic recombination. Despite the apparent dissimilarity in protein sequence and structure, there is considerable evidence that BRCA1 and BRCA2 have common biological functions. BRCA1 and BRCA2 exhibit similar patterns of expression and sub cellular localization. They are both expressed in many tissues in a cell-cycle dependent manner; their levels are highest during S phase, which is suggestive of functions during DNA replication. Both are localized to the nucleus in somatic cells, where they coexist in characteristic sub-nuclear foci that redistribute following DNA damage. In meiotic cells, both proteins co-localize to the synaptonemal complexes of developing axial filaments. This pattern of expression and localization is shared with RAD51, a mammalian homologue of the bacterial protein RecA, which is essential in Escherichia coli for the repair of DNA double-strand breaks (DSBs) by genetic recombination. Indeed, both BRCA1 and BRCA2 have been reported to bind to RAD51 (2).
BRCA1 and BRCA2 co-localize in mitotic and meiotic cells and physically associate with one another through a region in BRCA1 (residues 1314-1863) distinct from that reported to bind to RAD51. Again, the interaction may not be direct, and it appears to involve a small fraction (perhaps 2-5%) of the total cellular pool of each protein. It remains to be firmly demonstrated that BRCA1 functions together with BRCA2 and RAD51 in a multi-molecular complex, and the functional significance of their reported interactions is yet to be rigorously defined (2).
BRCA1 and BRCA2 co-localize with RAD51 provoked speculation that they participate in some aspect of the cellular response to DNA damage. Direct evidence for such a function has come from studies on cells that harbor mutations in the breast-cancer-susceptibility genes. The cellular response to DNA damage involves the activation of cell cycle checkpoints and the recruitment of the machinery for DNA repair, processes that are intimately linked to one another. Failure to activate these checkpoints or DNA repair following DNA damage manifests as increased sensitivity to genotoxic agent (2).
The X-ray sensitivity of cells lacking BRCA1 or BRCA2 suggests they have a defect in the repair of DNA double-strand breaks (DSBs), the major lesion inflicted by ionizing radiation. Mammalian cells use several mechanisms to repair DSBs, in particular non-homologous end joining (NHEJ) and homologous recombination. NHEJ, which culminates in the ligation of broken DNA fragments without regard to the homology of sequences at their ends, is critically dependent on the DNAdependent protein kinase (DNA-PK) and its accessory molecules Ku70 and Ku80. By contrast, DSB repair by homologous recombination is achieved through the exchange of genetic information between the damaged template and a homologous DNA sequence, such as that found on a sister chromatid. Its mechanism in mammalian cells is poorly understood (2).
There is now good evidence that BRCA2 is essential for DSB repair by homologous recombination. Cells that contain truncated BRCA2 progressively accumulate aberrations in chromosome structure during passage in culture; these typically include tri-radial and quadri-radial chromosomes as well as chromosome breaks. Chromosomal aberrations similar to those reported in BRCA2-deficient cells are also induced by loss of BRCA1. BRCA2 controls the intracellular transport and function of RAD51. In BRCA2-deficient cells, RAD51 (which does not contain a consensus nuclear localization signal) is inefficiently transported into the nucleus, which suggests that one function of BRCA2 is to move RAD51 from its site of synthesis to its site of activity. In addition, BRCA2 also appears to control the enzymatic activity of RAD51 (2).
There is accumulating evidence that BRCA1 performs multiple functions in the cellular response to DNA damage through its interactions with different protein partners. BRCA1 also physically associates, directly or indirectly, with proteins other than RAD51 whose yeast homologues are known to participate in recombination (2).
Recent data indicate that BRCA1 contributes to DNA damage responses through its interaction with enzymes that alter chromatin and DNA structure. Biochemical characterization of BRCA1-containing protein complexes reveals an association with SWI/SNF proteins that remodel chromatin, with regulators of histone acetylation/deacetylation and with two DNA helicases – BLM (the product of the gene mutated in the disease Bloom's syndrome, which predisposes to cancer and the novel helicase BACH. There are intriguing but preliminary hints that these interactions are relevant to cancer predisposition. Bloom's syndrome is associated with cancer predisposition in multiple tissues, and heterozygous mutations in BACH1 occur in a small number of breast cancers (2).
BRCA1 has been implicated in the transcriptional regulation of several genes activated in response to DNA damage. These include those encoding the p21 CIP1 cyclin-dependent kinase inhibitor and the GADD45 tumor suppressor, both of which are downstream targets of the p53 pathway. BRCA1 might also be connected to the basal transcriptional machinery. It co- purifies with the RNA polymerase II holoenzyme through an interaction with a helicase component. The biological relevance of this interaction is uncertain (2).
There is no unified theory for BRCA protein function. Clearly, although compelling evidence implicates both BRCA1 and BRCA2 in the response of mammalian cells to DNA damage, there is little sign that a single property or protein-protein interaction underpins the essential function of either protein in this response. This is particularly so for BRCA1, for which there is evidence of involvement at multiple levels in the DNA damage response. It might, by contrast, be reasonable to posit that the role of BRCA2 in control of the RAD51 recombinase, and through it in DNA repair by homologous recombination constitute a key function. This view will also probably prove simplistic if current circumstantial evidence that the roles of BRCA2 in normal mitotic progression and transcriptional regulation are relevant to DNA repair and chromosomal stability becomes more definitive. At least in the case of BRCA1, cancer-associated mutations affecting a number of different regions spanning the length of the protein have the common property of being unable to reconstitute DSB repair when expressed in BRCA1-deficient cells. This finding indicates that many of the protein-protein interactions of BRCA1 promote a common function. Equivalent data are not yet available for the BRCA2 protein. However, over 90% of cancer-associated mutations in BRCA2 result in truncation of the protein. The identification of two conserved nuclear localization signals in the extreme C-terminal 156 residues of BRCA2 suggests that most of these disease-causing mutants will be non-functional owing to cytoplasmic mis-localization. Other important issues connected with cancer predisposition by BRCA mutations are equally enigmatic. In humans, inheritance of one defective BRCA allele is enough to increase cancer predisposition. No defects have yet been identified in heterozygous cells that could explain their susceptibility to transformation. Perhaps the least understood feature of disease connected with BRCA mutations is its tissue specificity. Although it has been suggested that DSB repair by HR is particularly important in such tissues to remove DNA adducts known to be induced by hormones such as estrogen, it is equally possible that the BRCA proteins have alternative functions unconnected to DNA repair whose loss fosters transformation. There are already some intriguing but highly speculative hints that BRCA1 is essential for ductal morphogenesis in the developing breast and that BRCA1 or BRCA2 regulates the growth response to estrogen receptor signaling. Further studies to address these issues will be essential to reveal how the BRCA proteins can function as tissue-specific tumor suppressors (2).
It is important to note, however, that most research related to BRCA1 and BRCA2 has been done on large families with many individuals affected by cancer. Estimates of breast and ovarian cancer risk associated with BRCA1and BRCA2 mutations have been calculated from studies of these families. Because family members share a proportion of their genes and, often, their environment, it is possible that large number of cancer cases seen in these families may be due in part to other genetic or environmental factors. Therefore, risk estimates that are based on families with many affected members may not accurately reflect the levels of risk for BRCA1 and BRCA2 mutation carriers in the general population. Recent studies reveal that the BRCA proteins are required for maintenance of chromosomal stability in mammalian cells and function in the biological response to DNA damage. The new work suggests that, although the phenotypic consequences of their disruption are similar, BRCA1 and BRCA2 play distinct roles in the mechanisms that lead to the repair of DNA double-strand break. Many research studies are being conducted to find newer and better ways of detecting, treating and preventing cancer in BRCA1 and BRCA2 mutation carriers. Additional studies are focused on improving genetic counseling methods and outcomes.
References:
- http://www.healthsearches.org/Categories_of_Q&A/Genetics_&_Breast_Cancer/1064.php
- http://jcs.biologists.org/content/114/20/3591.full
- Hall. G. D, Patel. P. M &Prtheroe. A. S, In: Key topics in Oncology, ed. Bios Scientific Publisher, UK, pp 181-185 (1998).
- Lalloo. F & Well. E.H, In: Genetics for Oncologists, Remedica Publishing Limited, London, UK, pp 92-93 (2002).
- http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA
About the Author
I was born in Kolkata, Qualified Ph.D on 1989 from Calcutta University (Spl. Endocrinology), acquired research experience of more than 22 years with publications of around 29 papers in various national / international journals , acquired teaching experience of more than 15 years, acquired experience of writing biology text book under ISC course which is currently under Cambridge press (Kolkata) for publication. Awarded Sangit Prabhakar and Prayag Sangit Samiti in Indian Classical music. Awarded certificate of appreciation – Celebrations of the centenary of Ramkrishna Mission & of Swamy Vivekananda's historic return from west in 1897 as well as of 66th foundation day of the pratisthan. Ramakrishna Mission Seva Pratisthan (Kol-India), expressed its participation of my contribution to the success of the seminar in 1997.
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