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Cancer Genes and Breast Cancers

Written By

Metin Budak and Hatice Segmen

Submitted: 08 March 2022 Reviewed: 04 April 2022 Published: 14 May 2022

DOI: 10.5772/intechopen.104801

Molecular Mechanisms in Cancer IntechOpen
Molecular Mechanisms in Cancer Edited by Metin Budak

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Molecular Mechanisms in Cancer

Edited by Metin Budak and Rajamanickam Rajkumar

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Abstract

Cancer is the name given to all malignant tumors, the main reason for which is uncontrolled growth, and the tumor, which has become a mass as a result of uncontrolled cell proliferation, also attacks the surrounding cells and envelops the whole body (metastasis) in the later stages of the disease. Although cancer is an important health problem, it is not a common disease in childhood. On the other hand, statistics show that cancer affects one in three adults, causes up to 20% of all deaths, and covers about 10% of treatment costs in developed countries. Although it is known that cancer develops under the influence of genetic and environmental factors, environmental factors are more prominent in the formation of some types of cancer. Breast cancer is one of the cancer types known to have tumor suppressor genes in its etiology. These tumor suppressor genes are BRCA1 and BRCA2 genes. Studies have shown that these two genes are particularly effective in the development of familial breast cancers. These types of cancers occur much earlier than non-familial cancers. The research, two genes; It has shown that it is especially effective in the development of familial breast cancers.

Keywords

  • BRCA1
  • BRCA2
  • tumor suppressor
  • oncogenes
  • cancer

1. Introduction

The term cancer is not the name of a single disease, but the name was given to all malignant tumors, the main reason for which is uncontrolled growth. The tumor, which becomes a mass as a result of uncontrolled cell proliferation, also attacks the surrounding cells and tends to spread throughout the body in the later stages of the disease (metastasis). Although cancer is an important health problem, it is not a common disease in childhood. On the other hand, statistics show that cancer affects one in three adults, causes up to 20% of all deaths, and covers about 10% of treatment costs in developed countries [1]. Cancer, which develops as a result of uncontrolled cell growth and development, is a phenomenon that occurs as a result of a complex series of cellular mechanisms working differently from normal. It is known that cancer occurs as a result of mutations in somatic cells and these mutations affect the expression of a series of genes. Cancers can develop in each tissue group depending on age, gender, and environmental factors [2, 3, 4]. Although it is known that cancer develops under the influence of genetic and environmental factors, environmental factors are more prominent in the formation of some types of cancer. It is now known to affect [5, 6]. There are two gene groups known to be involved in cancer formation. These are (1) Tumor suppressor genes and (2) proto-oncogenes [7, 8]. Breast cancers are the leading cancer types known to have tumor suppressor genes in their etiology. BRCA1 and BRCA2 genes are the leading tumor suppressor genes specific to breast cancers [9]. Studies have shown that these two genes are particularly effective in the development of familial breast cancers. While the majority of cancers are sporadic, a small percentage can be hereditary, that is, familial. While the first mutation in the genes involved in hereditary cancers is inherited familial, the fact that the second mutation occurs in a limited number of somatic cells after birth is sufficient for cancerization. These types of cancers occur much earlier than non-familial cancers [9, 10, 11, 12, 13, 14, 15, 16]. According to World Health Organization; When cancer-related deaths in women were investigated between 2019 and 2020 worldwide, the most common type of cancer in all ages and genders is breast cancer, followed by prostate cancer and lung cancer, the least common cancer is thyroid cancer. However, the most common cause of death is lung cancer and breast cancer is the second most common type of cancer. According to International Agency for Research on Cancer of the World Health Organization; new cases and death rates of cancer the worldwide for 2020 are given below (Figure 1) [17, 18, 19, 20], https://gco.iarc.fr/.

Figure 1.

Estimated age-standardized incidence and mortality rates (world) in 2020, worldwide, for both sexes, all ages [17].

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2. Causes of cancer

Although a lot of important information about the etiology of cancer has been obtained in recent years, the molecular mechanisms that cause cancer formation, that is, the excessive proliferation of a normal cell out of control, are still not fully clarified, and a new mechanism may emerge every year and hereditary factors are known to play a role together. Environmental factors include some chemical agents (nicotine), nutrition, radiation, viruses, living environmental conditions, and lifestyle [16, 21, 22].

2.1 Environmental factors

2.1.1 Chemical carcinogens

There is a threshold value for many carcinogens, amounts that do not exceed this threshold value are harmless. One-third of cancers seen in the USA and Europe are cancers that develop due to the use of cigarettes and other tobacco products. Working conditions and some occupational chemicals are among the other environmental factors that cause cancer. It is known that chemical agents such as asbestos and nicotine cause cancer formation [23, 24, 25, 26].

2.1.2 Physical carcinogens

Ionizing Radiation. Skin cancers were common in the hands of radiologists in the periods when primitive devices were used and prevention methods were not well known. In studies conducted in the following years, it has been shown that bone, thyroid, lung, breast cancer, leukemia, and lymphoma develop with the effect of radiation [27, 28, 29]. Ultraviolet Rays (U.V). U.V rays have been shown to be associated with skin cancers. These include basal cell skin cancer, squamous (stratified squamous epithelium) skin cancer, and skin cancers such as melanoma [30, 31, 32, 33, 34].

2.1.3 Hereditary and genetic factors

Although cancer is a genetic disease, very few cancer cases show hereditary characteristics. Among all cancer types, the rate of hereditary cancers is less than 1%. In families with hereditary cancer cases, cancer occurs more frequently than in the normal population. In families where cancer is inherited; The probability of passing the cancer gene from mother or father to child is 50%. Cancer cases in individuals in such families occur at an earlier age than in the general population. The tissues with the most familial cancer cases are colon, endometrium, ovary, and breast [35, 36, 37]. Two groups are very important in the formation of cancer. These; proto-oncogenes are tumor suppressor genes.

2.1.3.1 Proto-oncogenes and oncogenes

It is known that proto-oncogenes that regulate cell growth and differentiation have important roles in normal cell physiology (30). If a proto-oncogene differentiates or starts to be expressed more than normal as a result of mutation or change in external stimulus; These changes cause uncontrolled growth and therefore malignant formations in the cell. With the mutation of proto-oncogenes, they turn into genes called oncogenes that stimulate continuous cell division [38, 39]. Proto-oncogenes can be grouped into 4 groups according to the biochemical properties of protein products [40, 41].

  1. Growth Factors: Growth factors are signal molecules in polypeptide structure that are secreted out of the cell and stimulate differentiation in the target cell. They recognize the target cell with special receptors on the cell surface and stimulate differentiation in the cell. The best-known growth factor is the platelet-derived growth factor (PDGF)(9). Growth factors are proteins that weigh between 4000 and 60,000 daltons and can affect cellular activities even in small amounts. 6 Growth factors are substances that enable growth and proliferation in various cell types. Many growth factors such as epidermal growth factor (EGF), mesodermal growth factor (MGF), platelet-derived growth factor (PDGF), granulocyte colony-stimulating factor (G-KUF), granulocyte macrophage colony-stimulating factor (GM-KUF) are isolated 7. As a result of studies with antioxidants, it has been explained that antioxidants may have a common function with growth factors and also have effects on factors [42, 43].

  2. Epidermal Growth Factor (Epidermal growth factor, EGF): It is a 53 amino acid polypeptide that is identical to Urogastron. It is found in many tissues and is released during platelet degranulation. Most cells have receptors for EGF. The most numerous receptors are found on epithelial cells; however, there are also receptors on endothelial cells, fibroblasts, and smooth muscle cells. It has chemotactic properties for epithelial cells, endothelium, and fibroblasts. It has the feature of stimulating angiogenesis and collagenase activity [44, 45].

    FGF has also been studied in various animal models; After topical application to the wound in the guinea pig ear, basic FGF has been shown to accelerate epithelialization. Cell number and collagen content increased with subcutaneous injection in guinea pigs. Topical basic FGF has a positive effect on wound healing problems that can be caused by infection and diabetes in mice [46, 47, 48, 49].

  3. Growth Factor receptors: Differentiated forms of some viral oncogenes produce normal growth factors with tyrosine kinase activity. Therefore, by binding to normal cells, they stimulate cell division and cause cancer development. The most well-known growth factor receptors are erb B, erb B-2, and fms. GHR, the specific transmembrane receptor of growth hormone (GH), belongs to the class I hematopoietic cytokine receptor superfamily and is widely found in peripheral tissues. This group of receptors is associated with adapter tyrosine kinases such as Janus kinase 2. GHR; consists of three parts: extracellular, transmembrane, and intracellular. The extracellular portion of the GH receptor forms the high-affinity binding protein. GH binds to its receptor by the extracellular binding site of the receptor protein; The receptor is then activated by dimerization. Activation of the receptor is followed by activation of the JAK–STAT pathway, followed by increased expression of IGF-1 and other growth hormone-related genes. After all, GHR; It regulates the effect of GH by removing it from the circulation [50, 51, 52, 53].

  4. Transcription Factors: Core proteins encoded by many genes form transcription factors. Transcriptional control is done by binding these proteins to specific DNA sequences or DNA motifs. Transcription factors provide the expression of the target gene with positive or negative control. Gene activity is mainly regulated at the transcriptional level. As is known, many genes in prokaryotes are clustered in units called operons. Regulation of transcription of genes in operons is provided by activating by activator proteins and inhibiting by repressor proteins. Gene activity in eukaryotes is basically controlled at the transcriptional level. However, eukaryotic chromosomes have both a larger structure and a higher degree of structural organization than prokaryotic chromosomes. Yeast, fruit fly, and human genomes contain 4, 40, and 1000 times more DNA than Escherichia coli genomes, respectively. This redundancy not only gives eukaryotes potentials that are not found in prokaryotes, but also brings new dimensions to the replication and gene activity events in them. The activity of some specific genes in eukaryotic chromosomes depends on transcription factors. For example, transcription of 5S ribosomal RNA genes may depend on the binding of proteins with multiple metal-binding stretches that fit into grooves in DNA to these genes [53, 54, 55, 56].

  5. Programmed Cell Death controls: Normal tissue structure; is achieved by the balance between differentiating cells and dying cells. Programmed cell death is crucial in normal embryogenesis and organ development. It has been shown that the programmed cell death mechanism is lost in cancer cells. This mechanism is specifically controlled by the bcl 2 proto-oncogene. As a result of chromosomal translocations of this gene, it can be activated especially in lymphomas [57, 58, 59].

  6. Oncogene activation mechanisms: Oncogenes can be activated in three ways: 1, Mutations; 2, Gene amplification; 3, Chromosomal rearrangements.

    1. Mutations: Changes occur in the structure of proteins encoded by oncogenes activated as a result of mutations such as point mutations and frameshifts. As a result of these, changes occur in the critical binding sites of the protein, and they lose their protein binding properties and cause cancer development by failing to fulfill their duties.

    2. Gene Amplification: Gene amplification occurs when the number of copies of a gene in the cell genome increases. The increase in gene copy number occurs especially with karyotype duplications. These formations are only seen quite frequently in tumor tissues.

    3. Chromosomal Rearrangements: Chromosomal rearrangements are mostly changes that occur in hematological malignant tumors. Chromosomal translocations, and inversions are the most common rearrangements [60, 61, 62, 63, 64]. The best example of chromosomal rearrangements of human proto-oncogenes is the (9;22) translocation. In approximately 95% of patients with chronic myeloid leukemia (CML), a reciprocal translocation occurs in bone marrow cells between chromosomes 9 and 22. As a result of this translocation, the Philadelphia chromosome, which is smaller than the normal 22 chromosome number, is formed [65, 66, 67]. As a result of this translocation, the abl proto-oncogene is transferred from its normal location 9q34.1 to chromosome 22. The abl gene joins in its new location (“Breakpoint cluster region”) with a special sequence called bcr. The hybrid gene resulting from this fusion causes the synthesis of a new protein believed to be responsible for tumor formation in bone marrow cells. This new protein has tyrosine kinase activity and activates cell division to form tumors [8, 66, 67].

2.1.3.2 Tumor suppressor genes

Tumor suppressor genes were found for the first time as a result of studies on retinoblastoma, one of the very rare hereditary cancer types. Retinoblastoma is the most common type of cancer among childhood eye cancers and occurs bilaterally in 20–30% of cases [68, 69]. All bilateral cases and 15% of unilateral cases show autosomal dominant inheritance. The gene responsible for this disease is the Rb1 gene located proximal to the long arm of chromosome 13 [70, 71]. As a result of chromosomal changes or point mutations, the functional protein related to this gene is either absent or unable to function in cells in tumor tissue. In such cases, hereditary mutation; is found in only one of the gene pairs and is therefore in a heterozygous state. In order for a tumor to develop in a person carrying the mutant gene, a new mutation must also occur in the normal partner of the mutant gene in the retinal cell(9). As a result of a second mutation, a tumor occurs when the other intact allele is changed or lost. This situation is also called loss of heterozygosity [72, 73], (Figure 2).

Figure 2.

Cancer formation model.

In hereditary retinoblastoma cancers, the first mutation occurred in the person either as a result of germline mutations or inherited from one of the parents. In people carrying this gene, retinoblastoma occurs at a very early age [74]. As a result of studies on the localization of many tumor types that show oss of heterozygosity for chromosome 13 and the localization of other tumor suppressor genes, more than 20 tumor suppressor gene regions were identified, the main ones being p53, retinoblastoma, BRCA 1, BRCA 2 (Table 1) [76, 77, 78, 79, 80].

GeneCancerLocalizationFunctionHereditary Syndrome
APCColon cancerCytoplasmCellular adhesionFamilial
DCCColon cancerCell membraneCell adhesion molecule—
NF1NeurofibromasCytoplasmGTPase activatorNeurofibromatosis Type 1
NF2Schwannomas and MeningiomaCell membraneCell membraneNeurofibromatosis Type 2
p53Colon cancer and many other cancersNucleusTranscription factorLi-Fraumeni syndrome
RBRetinoblastomaNucleusTranscription factorRetinoblastoma
RETThyroid cancer pheochromocytomCell membraneTyrosine kinase receptorMultiple endocrine neoplasm Type 2
VHLKidney cancerCell membraneTranscription factorVon Hippel–Lindau disease
WT-1NephroblastomaNucleusTranscription factorWilms tumor
BRCA1Breast cancerBreast tissueDNA repair, mismatch repairFamilial breast cancers
BRCA2Breast cancerBreast tissue epitheliumDNA repair, mismatch repairFamilial breast cancers

Table 1.

Some tumor suppressor genes and the types of cancer they cause [75].

2.1.3.2.1 p53 gene

The p53 gene is located in band 13 of the short arm of human chromosome 17. This gene, which is about 20 kb long; encodes a 2.8 kb mRNA and its product is a core phosphoprotein of 393 amino acids of 53 kD (10). Nucleotide and amino acid sequence analyzes have shown that; The p53 gene contains 5 conserved regions from neopus to human during evolution. This region includes exons 1, 4, 5, 7, and 8. These conserved regions are thought to be essential sites for the p53 wild-type protein. Specifically, the DNA binding region of the p53 gene contains 2 SV40 tumor antigen binding (T-ag), a nuclear localization signal, and multiple phosphorylation sites (Figure 3). The p53 protein controls gene expression positively or negatively by stopping the cell cycle in the G1 phase and binding to specific sequences and transcription factors. Normal p53 protein stops the cell cycle and leads the cell to programmed cell death in the absence of appropriate differentiation or proliferation factors [81, 82, 83, 84, 85].

Figure 3.

Schematic structure of the p53 gene; TAS: Transcription activation region, protein binding region (HSP), SV40 wide T-antigen region, adenovirus E1b and papillomavirus E6 binding region, cellular Mdm2 binding region, nuclear localization signal (NLS), oligomerization region (OLIGO) and phosphorylation region (cdc2 and CDK). The 5 conserved regions in evolution are indicated by the letters I, II, III, IV, and V, and the hot spot regions are indicated by the letters A, B, C, D.

2.1.3.2.2 BRCA1 gene

The chromosomal location of the BRCA 1 gene (Breast cancer susceptibility gene) was first identified in 1990 and cloned in 1994 [86]. The BRCA1 gene has 24 exons (20) with approximately 100,000 base pairs, occupying 4 cM, located in the q12–21 region of chromosome 17; It is a gene that encodes a tumor suppressor protein. The 11th exon of the BRCA1 gene, which is very large, constitutes 61% of the entire gene. The BRCA1 gene encodes a tumor-suppressing protein with DNA binding properties that negatively affect cancer formation [87]. Recent studies have shown that the product of the BRCA1 gene; It has been shown to be a zing-finger protein with a zinc-binding site at the amino end [87, 88, 89].

2.1.3.2.3 Mutation distribution

Breast tumors occur with the loss of both the wild-type allele of the BRCA1 gene at 17q [90]. Since there are 500 different types and the BRCA 1 gene is a large gene, the frequency of mutation is quite high. Several clinically important mutations have been found in this gene. While approximately 90% of these mutations are frameshift or nonsense mutations, the rest are mutations that cause changes in the stop codon and cause the immature protein to be made at the translation stage [35, 91, 92, 93, 94]. Studies have been ongoing since the gene was cloned to develop a test that could detect familial cancer risk by detecting BRCA 1 mutations. The second most common group of mutations in the BRCA1 gene are 185delAG and 5382insG mutations [95, 96]. These constitute 10% of all mutations in the BRCA1 gene. These two mutations are seen with a frequency of approximately 10% in Ashkenazi and non-Ashkenazi Jews. The carrier rate of these mutations in the same group is 1%. Mutations 185delAG and 5382insG have also been shown to be found in Moroccan and non-Jewish families. The high incidence of deletions in the AG sequence at position 185 of BRCA1 has caused this region to be called the ‘Hotspot’ region. In germ-line mutation studies in all women, the incidence of breast cancer before the age of 40 was found to be 20% in 185delAG carriers [95, 97, 98, 99]. While the 5832insC mutation is most common in Russians and Jews of European origin, it is very low in Israeli Jews [100, 101]. The most common mutation in the Russian population is 4153delA4 (Figure 4) [102].

Figure 4.

Mutation distribution in the BRCA1 gene.

2.1.3.2.4 The function of BRCA1

The BRCA 1 protein is a ring-finger protein of 1863′ amino acids (45, 46, 47). BRCA 1 is made in the differentiated epithelial cells of developing organs during embryonic development and puberty development. A significant increase in the mRNA level of BRCA 1 has been observed in breast epithelial cells during pregnancy in women without cancer. BRCA 1 expression in humans is stimulated by estrogen and decreases after birth (38,48). Suppression of BRCA 1 expression increases growth in both normal cells and malignant mammary epithelial cells [86, 90, 93]. Since the BRCA1 gene was isolated, its functions have been thought to play a role in transcription, control the cell cycle, and be associated with DNA repair mechanisms. It is a gene that participates in DNA repair mechanisms by interacting with basic transcriptional mechanisms (with RNA polymerase II, Transcription factors TFIIH, TFIIE, and RNA helicase A). BRCA1 and BRCA2 proteins together provide a repair of DNA double-strand breaks in mitotic cells [103, 104] BRCA1 protein interacts with the gamma-tubulin subunits of the centrosome during mitosis, stopping the cell cycle and providing damage control in DNA [105].

2.1.3.2.5 BRCA2 gene

BRCA2 is another tumor suppressor gene that was mapped to the long arm of the 13th chromosome by Wooster et al. in 1994 (7). The 13q12-13 region containing BRCA2 is also a region close to the retinoblastoma gene (36, 39). The BRCA2 gene is a 70 kb gene with 27 exons, occupies 6 cM, and the product of the gene is a protein consisting of 3418 amino acids(36). The fact that exon 3 is similar to transcription factors indicates that it may have a function in this direction (33,). BRCA2 has a large 11th exon just like BRCA1(50). This exon makes up about 58% of the whole gene [86, 106, 107, 108]. While the risk of breast cancer and ovarian cancer is higher in patients with germline mutations in this gene, 30–40% loss of heterozygosity is observed in patients with sporadic breast and ovarian cancer [109, 110]. Interestingly, almost all BRCA2 mutations are familial [111]. This theorizes that BRCA mutations can theoretically be traced back to an initial sporadic case and may indicate the presence of a ‘founder effect’. The majority of mutations in the BRCA 2 gene cause a frameshift condition. The most common frameshift mutation is the 999del5 mutation, which is also seen in Iceland. Other than that, the mutations seen in other populations are as follows. Ashkenazi Jewish-6174delT, Dutch-5579insA, Finns- 8555 T > G, 999del5, IVS23-2A > G, French Canadians 8765delAG, 3398delAAAAG, Hungarians-9326insA, Pakistanis-3337C > T, Slovenians-IVS16-2A > G [112]. People with certain mutations of the BRCA2 gene increase the risk of breast cancer by causing hereditary breast-ovarian cancer syndrome. As a result of research, hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer, have been identified. BRCA2 mutations are usually the addition or loss of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal and does not work properly. Research emerges as a result of the inability of the dysfunctional BRCA2 protein to repair the damages in the DNA that make up the genome. As a result, there is an increase in mutations due to this faulty synthesis after unrepaired DNA damages, and some of these mutations can lead to uncontrolled division of cells and the formation of a tumor [107, 113, 114].

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3. Conclusion

By revealing the environmental and genetic factors that are effective in the development of breast cancer, which is a very important social problem, studies to prevent breast cancer gain hope. The incidence of breast cancer differs from country to country in the world. While Hawaii, California, and Canada are in the first place with an incidence of 80–90 per hundred thousand per year, the same value is only between 12 and 15 per hundred thousand in Japan. Although the majority of breast cancers are sporadic cases, 5–10% of all cases are hereditary. BRCA1 and BRCA2 genes are known to be effective in the development of breast cancer. The BRCA1 gene is thought to be responsible for 4–5% of all breast cancers and 45% of hereditary breast cancers. The risk of developing breast cancer up to the age of 70 in BRCA1 gene carriers is 94%. The rate of breast cancer cases occurring before the age of 30 is 25%. The BRCA 1 gene is responsible for half of all familial breast cancer cases and 80–90% of multiple breast and ovarian cancer cases. This shows that due to the importance of BRCA1 and BRCA2 genes in the etiology of breast cancer, detecting both BRCA1 and BRCA2 genes, especially in familial breast cancer cases, is important for public health. As a result, routine applications with rapid, reliable, and inexpensive methods to detect BRCA1 and BRCA2 gene mutations are known to be involved in the etiology of breast cancer in patients and families with multiple breast cancer or ovarian cancer or diagnosed with breast cancer at an early age may need to be seen as potential chemotherapy targets.

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Conflict of interest

There is no conflict of interest.

References

  1. 1. Bailar JC, Gornik HL. Cancer undefeated. New England Journal of Medicine. 1997;336(22):1569-1574
  2. 2. Zhang W-j, Wang X-h, Gao S-t, Chen C, Xu X-y, Zhou Z-h, et al. Tumor-associated macrophages correlate with phenomenon of epithelial-mesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients. Journal of Surgical Research. 2018;222:93-101
  3. 3. Conteduca V, Poti G, Caroli P, Russi S, Brighi N, Lolli C, et al. Flare phenomenon in prostate cancer: Recent evidence on new drugs and next generation imaging. Therapeutic Advances in Medical Oncology. 2021;13:1758835920987654
  4. 4. Delgado-López PD, CorralesGarcía EM. Influence of internet and social media in the promotion of alternative oncology, cancer quackery, and the predatory publishing phenomenon. DOI: 10.7759/cureus.2617
  5. 5. Coyle YM. The effect of environment on breast cancer risk. Breast Cancer Research and Treatment. 2004;84(3):273-288
  6. 6. Gray J, Evans N, Taylor B, Rizzo J, Walker M. State of the evidence: The connection between breast cancer and the environment. International Journal of Occupational and Environmental Health. 2009;15(1):43-78
  7. 7. Martínez-Jiménez F, Muiños F, Sentís I, Deu-Pons J, Reyes-Salazar I, Arnedo-Pac C, et al. A compendium of mutational cancer driver genes. Nature Reviews Cancer. 2020;20(10):555-572
  8. 8. Chiu H-S, Somvanshi S, Patel E, Chen T-W, Singh VP, Zorman B, et al. Pan-cancer analysis of lnc RNA regulation supports their targeting of cancer genes in each tumor context. Cell Reports. 2018;23(1):297-312. e12
  9. 9. Waks AG, Winer EP. Breast cancer treatment: A review. JAMA. 2019;321(3):288-300
  10. 10. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy. 2019;11:151
  11. 11. Britt KL, Cuzick J, Phillips K-A. Key steps for effective breast cancer prevention. Nature Reviews Cancer. 2020;20(8):417-436
  12. 12. Tutt AN, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. Adjuvant olaparib for patients with BRCA1-or BRCA2-mutated breast cancer. New England Journal of Medicine. 2021;384(25):2394-2405
  13. 13. Samstein RM, Krishna C, Ma X, Pei X, Lee K-W, Makarov V, et al. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. Nature Cancer. 2020;1(12):1188-1203
  14. 14. Cline MS, Liao RG, Parsons MT, Paten B, Alquaddoomi F, Antoniou A, et al. BRCA challenge: BRCA exchange as a global resouce for variants in BRCA1 and BRCA2. PLoS Genetics. 2018;14(12):e1007752
  15. 15. Choi Y-H, Terry MB, Daly MB, Mac Innis RJ, Hopper JL, Colonna S, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncology. 2021;7(4):585-592
  16. 16. Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, et al. Mutational spectrum in a worldwide study of 29, 700 families with BRCA1 or BRCA2 mutations. Human Mutation. 2018;39(5):593-620
  17. 17. Available from: https://gco.iarc.fr/
  18. 18. Miller KD, Ortiz AP, Pinheiro PS, Bandi P, Minihan A, Fuchs HE, et al. Cancer statistics for the US Hispanic/Latino population, 2021. CA: A Cancer Journal for Clinicians. 2021;71(6):466-487
  19. 19. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year 2020: An overview. International Journal of Cancer. 2021;149(4):778-789
  20. 20. Cao W, Chen H-D, Yu Y-W, Li N, Chen W-Q. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chinese Medical Journal. 2021;134(07):783-791
  21. 21. Tron L, Belot A, Fauvernier M, Remontet L, Bossard N, Launay L, et al. Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French network of cancer registries (FRANCIM) data. International Journal of Cancer. 2019;144(6):1262-1274
  22. 22. da Costa Araújo AP, Mesak C, Montalvão MF, Freitas ÍN, Chagas TQ , Malafaia G. Anti-cancer drugs in aquatic environment can cause cancer: Insight about mutagenicity in tadpoles. Science of the Total Environment. 2019;650:2284-2293
  23. 23. Kobets T, Williams GM. Review of the evidence for thresholds for DNA-reactive and epigenetic experimental chemical carcinogens. Chemico-Biological Interactions. 2019;301:88-111
  24. 24. Grunberger D, Weinstein I. Conformational changes in nucleic acids modified by chemical carcinogens. Chemical Carcinogens and DNA. 2019;62:59-94
  25. 25. Peter Guengerich F, Avadhani NG. Roles of cytochrome P450 in metabolism of ethanol and carcinogens. Alcohol and Cancer. 2018;1032:15-35
  26. 26. Hartwig A, Arand M, Epe B, Guth S, Jahnke G, Lampen A, et al. Mode of action-based risk assessment of genotoxic carcinogens. Archives of Toxicology. 2020;94(6):1787-1877
  27. 27. Hauptmann M, Daniels RD, Cardis E, Cullings HM, Kendall G, Laurier D, et al. Epidemiological studies of low-dose ionizing radiation and cancer: Summary bias assessment and meta-analysis. JNCI Monographs. 2020;2020(56):188-200
  28. 28. Hong J-Y, Han K, Jung J-H, Kim JS. Association of exposure to diagnostic low-dose ionizing radiation with risk of cancer among youths in South Korea. JAMA Network Open. 2019;2(9):e1910584-e1910584
  29. 29. Richardson DB, Cardis E, Daniels RD, Gillies M, Haylock R, Leuraud K, et al. Site-specific solid cancer mortality after exposure to ionizing radiation: a cohort study of workers (INWORKS). Epidemiology (Cambridge, Mass.). 2018;29(1):31
  30. 30. Laikova KV, Oberemok VV, Krasnodubets AM, Gal’chinsky NV, Useinov RZ, Novikov IA, et al. Advances in the understanding of skin cancer: Ultraviolet radiation, mutations, and antisense oligonucleotides as anticancer drugs. Molecules. 2019;24(8):1516
  31. 31. Paulo MS, Adam B, Akagwu C, Akparibo I, Al-Rifai RH, Bazrafshan S, et al. WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to solar ultraviolet radiation and of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer. Environment International. 2019;126:804-815
  32. 32. Grant WB, Moukayed M. Vitamin D3 from ultraviolet-B exposure or oral intake in relation to cancer incidence and mortality. Current Nutrition Reports. 2019;8(3):203-211
  33. 33. Hacker E, Horsham C, Vagenas D, Jones L, Lowe J, Janda M. A mobile technology intervention with ultraviolet radiation dosimeters and smartphone apps for skin cancer prevention in young adults: Randomized controlled trial. JMIR mHealth and uHealth. 2018;6(11):e9854
  34. 34. Solak SS, Yondem H, Urun YG, Cezik M, Can N. High prevalence of high-risk cutaneous squamous cell carcinoma in the thrace region of Turkey. Turk Dermatoloji Dergisi-Turkish Journal of Dermatology. 2020;14(4):83-89
  35. 35. Samadder NJ, Giridhar KV, Baffy N, Riegert-Johnson D, Couch FJ. Hereditary cancer Syndromesd-a primer on diagnosis and management, part 1: Breast-ovarian cancer syndromes. Mayo Clinic Proceedings. 2019;94(6):1084-1098
  36. 36. Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23(38):6445-6470
  37. 37. Frank TS. Hereditary cancer syndromes. Archives of Pathology & Laboratory Medicine. 2001;125(1):85-90
  38. 38. Malebary SJ, Khan R, Khan YD. ProtoPred: Advancing oncological research through identification of proto-oncogene proteins. IEEE Access. 2021;9:68788-68797
  39. 39. Grible JM, Zot P, Olex AL, Hedrick SE, Harrell JC, Woock AE, et al. The human intermediate prolactin receptor is a mammary proto-oncogene. NPJ Breast Cancer. 2021;7(1):1-11
  40. 40. Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, et al. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Molecular and Cellular Biology. 1992;12(11):5152-5158
  41. 41. Velu TJ, Beguinot L, Vass WC, Willingham MC, Merlino GT, Pastan I, et al. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene. Science. 1987;238(4832):1408-1410
  42. 42. Stromberg K, Pigott DA, Ranchalis JE, Twardzik DR. Human term placenta contains transforming growth factors. Biochemical and Biophysical Research Communications. 1982;106(2):354-361
  43. 43. Berg DK. New neuronal growth factors. Annual Review of Neuroscience. 1984;7(1):149-170
  44. 44. Carpenter G, Cohen S. Epidermal growth factor. Journal of Biological Chemistry. 1990;265(14):7709-7712
  45. 45. Boonstra J, Rijken P, Humbel B, Cremers F, Verkleij A, Henegouwen PVB e. The epidermal growth factor. Cell Biology International. 1995;19(5):413-430
  46. 46. LeGrand EK. Preclinical promise of becaplermin (rhPDGF-BB) in wound healing. The American Journal of Surgery. 1998;176(2):48S-54S
  47. 47. Amento EP, Beck LS. TGFb and wound healing. Clinical Applications of TGFb. 2008;157:115-129
  48. 48. Ab Ghani N. The Effect of Insulin and Growth Hormone on Full Thickness Wound of Guinea Pigs. Kuantan, Pahang: Kulliyyah of Medicine, International Islamic University; 2011
  49. 49. Wimmer C, Mees K, Stumpf P, Welsch U, Reichel O, Suckfüll M. Round window application of D-methionine, sodium thiosulfate, brain-derived neurotrophic factor, and fibroblast growth factor-2 in cisplatin-induced ototoxicity. Otology & Neurotology. 2004;25(1):33-40
  50. 50. Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, et al. Role of oncogenes and tumor-suppressor genes in carcinogenesis: A review. Anticancer Research. 2020;40(11):6009-6015
  51. 51. Sainsbury J, Sherbet G, Farndon J, Harris A. Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer. The Lancet. 1985;325(8425):364-366
  52. 52. Singleton KR, Kim J, Hinz TK, Marek LA, Casás-Selves M, Hatheway C, et al. A receptor tyrosine kinase network composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factor receptor drives growth and survival of head and neck squamous carcinoma cell lines. Molecular Pharmacology. 2013;83(4):882-893
  53. 53. Sirkisoon SR, Carpenter RL, Rimkus T, Anderson A, Harrison A, Lange AM, et al. Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene. 2018;37(19):2502-2514
  54. 54. Rajagopal C, Lankadasari MB, Aranjani JM, Harikumar K. Targeting oncogenic transcription factors by polyphenols: A novel approach for cancer therapy. Pharmacological Research. 2018;130:273-291
  55. 55. Hasanpourghadi M, Pandurangan AK, Mustafa MR. Modulation of oncogenic transcription factors by bioactive natural products in breast cancer. Pharmacological Research. 2018;128:376-388
  56. 56. Wu S, Turner KM, Nguyen N, Raviram R, Erb M, Santini J, et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature. 2019;575(7784):699-703
  57. 57. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nature Reviews Clinical Oncology. 2020;17(7):395-417
  58. 58. Matsushima M, Kobayashi K, Eml M, Saito J, Suzumori K, Nakamura Y. Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: Four germline mutations, but no evidence of somatic mutation. Human Molecular Genetics. 1995;4(10):1953-1956
  59. 59. Thomadaki H, Scorilas A. BCL2 family of apoptosis-related genes: Functions and clinical implications in cancer. Critical Reviews in Clinical Laboratory Sciences. 2006;43(1):1-67
  60. 60. Kotsantis P, Petermann E, Boulton SJ. Mechanisms of oncogene-induced replication stress: Jigsaw falling into place. Cancer Discovery. 2018;8(5):537-555
  61. 61. Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, et al. Mechanism of met oncogene activation. Cell. 1986;45(6):895-904
  62. 62. Wilmes S, Hafer M, Vuorio J, Tucker JA, Winkelmann H, Löchte S, et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science. 2020;367(6478):643-652
  63. 63. Tanaka H, Watanabe T. Mechanisms underlying recurrent genomic amplification in human cancers. Trends in Cancer. 2020;6(6):462-477
  64. 64. Jia Q , Chen S, Tan Y, Li Y, Tang F. Oncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms. Experimental & Molecular Medicine. 2020;52(5):713-723
  65. 65. Chereda B, Melo JV. Natural course and biology of CML. Annals of Hematology. 2015;94(2):107-121
  66. 66. Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R, Pies A, et al. A BCR–JAK2 fusion gene as the result of at (9, 22)(p24; q11. 2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes, Chromosomes and Cancer. 2005;44(3):329-333
  67. 67. Singh P, Kumar V, Gupta SK, Kumari G, Verma M. Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: A review. Medical Oncology. 2021;38(1):1-16
  68. 68. Marshall CJ. Tumor suppressor genes. Cell. 1991;64(2):313-326
  69. 69. Knudson AG Jr. Retinoblastoma and, Essentials of Ophthalmic Oncology. Vol. 323. Berlin/Heidelberg, Germany: Springer; 2009. p. 168
  70. 70. Dyson NJ. RB1: A prototype tumor suppressor and an enigma. Genes & Development. 2016;30(13):1492-1502
  71. 71. Berry JL, Polski A, Cavenee WK, Dryja TP, Murphree AL, Gallie BL. The RB1 story: Characterization and cloning of the first tumor suppressor gene. Genes. 2019;10(11):879
  72. 72. Ryland GL, Doyle MA, Goode D, Boyle SE, Choong DY, Rowley SM, et al. Loss of heterozygosity: What is it good for? BMC Medical Genomics. 2015;8(1):1-12
  73. 73. Tomlinson IP, Lambros MB, Roylance RR, Cleton-Jansen AM. Loss of heterozygosity analysis: Practically and conceptually flawed? Genes, Chromosomes and Cancer. 2002;34(4):349-353
  74. 74. Polski A, Xu L, Prabakar RK, Gai X, Kim JW, Shah R, et al. Variability in retinoblastoma genome stability is driven by age and not heritability. Genes, Chromosomes and Cancer. 2020;59(10):584-590
  75. 75. Karp G. Cell and Molecular Biology, Concepts and Experiments 4. Hoboken, New Jersey, United States: John Wiley & Sons; 2005
  76. 76. Dunham A, Matthews L, Burton J, Ashurst J, Howe K, Ashcroft K, et al. The DNA sequence and analysis of human chromosome 13. Nature. 2004;428(6982):522-528
  77. 77. Hu N, Goldstein AM, Albert PS, Giffen C, Tang Z-Z, Ding T, et al. Evidence for a familial esophageal cancer susceptibility gene on chromosome 13. Cancer Epidemiology and Prevention Biomarkers. 2003;12(10):1112-1115
  78. 78. Dahlén A, Debiec-Rychter M, Pedeutour F, Domanski HA, Höglund M, Bauer HC, et al. Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors. International Journal of Cancer. 2003;103(5):616-623
  79. 79. Hosoki S, Ota S, Ichikawa Y, Suzuki H, Ueda T, Naya Y, et al. Suppression of metastasis of rat prostate cancer by introduction of human chromosome 13. Asian Journal of Andrology. 2002;4(2):131-136
  80. 80. Topyalin N, Budak M, Ozbay N, Yildiz M, Kaner T, Aydin A, et al. A comparative histopathological and immunohistochemical study of Survivin and Ki-67 proteins in glial tumours. Biotechnology & Biotechnological Equipment. 2019;33(1):504-509
  81. 81. Bourdon J-C. p53 and its isoforms in cancer. British Journal of Cancer. 2007;97(3):277-282
  82. 82. Xu Y. Regulation of p53 responses by post-translational modifications. Cell Death & Differentiation. 2003;10(4)
  83. 83. Oren M. Relationship of p53 to the control of apoptotic cell death. Seminars in Cancer Biology. 1994;5:221-227
  84. 84. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome. Cancer Research. 2000;60(24):6788-6793
  85. 85. Sayhan N, Yazici H, Budak M, Bitisik O, Dalay N. P53 codon 72 genotypes in colon cancer. Association with Human Papillomavirus Infection, Research Communications in Molecular Pathology and Pharmacology. 2001;109(1-2):25-34
  86. 86. Blackwood MA, Weber BL. BRCA1 and BRCA2: From molecular genetics to clinical medicine. Journal of Clinical Oncology. 1998;16(5):1969-1977
  87. 87. Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M. Direct DNA binding by Brca1. Proceedings of the National Academy of Sciences. 2001;98(11):6086-6091
  88. 88. Parvin JD. Overview of history and progress in BRCA1 research: The first BRCA1 decade. Cancer Biology & Therapy. 2004;3(6):505-508
  89. 89. Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2. The Journal of Pathology. 2013;230(4):347-349
  90. 90. Neuhausen SL, Marshall CJ. Loss of heterozygosity in familial tumors from three BRCA1-linked kindreds. Cancer Research. 1994;54(23):6069-6072
  91. 91. Futreal PA, Liu Q , Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266(5182):120-122
  92. 92. Stratton JF, Gayther SA, Russell P, Dearden J, Gore M, Blake P, et al. Contribution of BRCA1 mutations to ovarian cancer. New England Journal of Medicine. 1997;336(16):1125-1130
  93. 93. Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. New England Journal of Medicine. 1997;336(20):1409-1415
  94. 94. Rajendran P, Alzahrani AM, Rengarajan T, Veeraraghavan VP, Krishna Mohan S. Consumption of reused vegetable oil intensifies BRCA1 mutations. Critical Reviews in Food Science and Nutrition. 2021;62:1-8
  95. 95. Durr-e-Samin MS-U, Rehman MS-U-R. Association of BRCA1 185 del AG with early age onset of breast cancer patients in selected cohort from Pakistani population. Pakistan Journal of Medical Sciences. 2018;34(5):1158
  96. 96. Schlosser S, Rabinovitch R, Shatz Z, Galper S, Shahadi-Dromi I, Finkel S, et al. Radiation-associated secondary malignancies in BRCA mutation carriers treated for breast cancer. International Journal of Radiation Oncology* Biology* Physics. 2020;107(2):353-359
  97. 97. Salmi F, Maachi F, Tazzite A, Aboutaib R, Fekkak J, Azeddoug H, et al. Next-generation sequencing of BRCA1 and BRCA2 genes in Moroccan prostate cancer patients with positive family history. PLoS One. 2021;16(7):e0254101
  98. 98. Laraqui A, Cavaillé M, Uhrhammer N, ElBiad O, Bidet Y, El Rhaffouli H, et al. Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco. Journal of Genomics. 2021;9:43
  99. 99. Algebaly A, Suliman R, Al-Qahtani W. Comprehensive study for BRCA1 and BRCA2 entire coding regions in breast cancer. Clinical and Translational Oncology. 2021;23(1):74-81
  100. 100. Rizk MM, El-etreby NM, El-Attar LM, Elzyat EA, Saied MH. A case–control study of BRCA1 founder mutations 185delAG and 5382insC in a cohort of Egyptian ovarian cancer patients using pyrosequencing technique. Egyptian Journal of Medical Human Genetics. 2022;23(1):1-9
  101. 101. Anisimenko M, Paul G, Kozyakov A, Gutkina N, Berdyugina D, Garanin AY, et al. The spectrum of BRCA1 gene mutations in early onset breast cancer patients from Russia. Сибирский онкологический журнал. 2018;17(4):53-58
  102. 102. Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva R, Ponder B. Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. UKCCCR Familial Ovarian Cancer Study Group. American Journal of Human Genetics. 1996;58(3):451
  103. 103. Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: Past and present. Experimental Cell Research. 2013;319(5):575-587
  104. 104. Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proceedings of the National Academy of Sciences. 1997;94(11):5605-5610
  105. 105. Weber A, Chung H-J, Springer E, Heitzmann D, Warth R. The TFIIH subunit p89 (XPB) localizes to the centrosome during mitosis. Analytical Cellular Pathology. 2010;32(1-2):121-130
  106. 106. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nature Reviews Cancer. 2004;4(9):665-676
  107. 107. Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science. 2002;297(5588):1837-1848
  108. 108. Patel KJ, Veronica P, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, et al. Involvement of Brca2 in DNA repair. Molecular Cell. 1998;1(3):347-357
  109. 109. Consortium BCL. Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute. 1999;91(15):1310-1316
  110. 110. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789-792
  111. 111. Sarantaus L, Huusko P, Eerola H, Launonen V, Vehmanen P, Rapakko K, et al. Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. European Journal of Human Genetics. 2000;8(10):757-763
  112. 112. Karami F, Mehdipour P. A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. BioMed Research International. 2013;2013:928562
  113. 113. Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: a systematic review and meta-analysis. Journal of the National Cancer Institute. 2014;106(6):dju091
  114. 114. Holloman WK. Unraveling the mechanism of BRCA2 in homologous recombination. Nature Structural & Molecular Biology. 2011;18(7):748-754

Written By

Metin Budak and Hatice Segmen

Submitted: 08 March 2022 Reviewed: 04 April 2022 Published: 14 May 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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