Cancer Cancer genetics and genomics Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body. 05.12.24 Cancerous tumors spread into, or invade, nearby tissues and can travel to distant places in the body to form new tumors (a process called metastasis). Cancer can start almost anywhere in the human body. Abnormal or damaged cells grow and multiply when they shouldn’t. These cells may form tumors, which are lumps of tissue. Tumors can be cancerous or not cancerous (benign). Benign tumors do not spread into, or invade, nearby tissues. When removed, benign tumors usually don’t grow back, whereas cancerous tumors sometimes do. Benign tumors can sometimes be quite large, however. Some can cause serious symptoms or be life threatening, such as benign tumors in the brain. Tumors can be solid, cancers of blood (leukemias) do not form solid tumors. 1 Cancer 2 General scheme for development of a carcinoma Cancer is not a single disease. Rather, it comes in many forms and degrees of malignancy and varying biologic processes. There are three main classes of cancer: in an epithelial tissue • Sarcomas, in which the tumor has arisen in mesenchymal tissue, such as bone, muscle, or connective tissue, or in nervous system tissue. • Carcinomas, which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts • Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma, which arise in cells of hematopoietic lineage, including bone marrow and the lymphatic system Progression from normal epithelium to local proliferation, invasion across the lamina propria, spread to local lymph nodes, and final distant metastases to liver and lung. Within each of the major groups, tumors are classified by site, tissue type, histologic appearance, degree of malignancy, chromosomal aneuploidy and, increasingly, by which gene variants, fusions, and abnormalities in gene expression. Data repositories for tumours: cBioPortal, COSMIC, PECAN, and Genomic Data Commons (GDC). 3 4 Cancer Cancer and Genetics All cancer is a genetic disease of somatic cells because of aberrant cell division or loss of normal programmed cell death. The link between cigarette smoking and lung cancer (among others) has been recognized for half a century, but not all smokers develop a tobacco-related malignancy. For many cancers, environmental factors are etiologically important, whereas heredity plays a lesser role. Studies have shown that smokers with short chromosome telomeres appear to be at substantially greater risk for tobacco-related cancers than people with short telomeres who have never smoked, or smokers who have long telomeres. Some cancers are called “industrial cancers,” which result from prolonged exposure to carcinogenic chemicals, for example, cancer of the skin in tar workers, cancer of the bladder in aniline dye workers, angiosarcoma of the liver in process workers making polyvinyl chloride and cancer of the lung (mesothelioma) in asbestos workers. Lung cancer can also cluster in families, and a range of germline pathogenic variants, polymorphisms, and susceptibility loci have been identified as risk factors. It is possible, if not likely, that a proportion may have a genetic predisposition to the action of the carcinogen. 5 Genetic architecture of cancer risk 6 Differentiation Between Genetic and Environmental Factors in Cancer The relationship between cancer risk and the presence of variants with variable penetrance can be expressed graphically. For many cancers, distinguishing between genetic and environmental causative factors is not obvious. There is usually neither a clear-cut mode of inheritance nor a clearly identified environmental cause. In the majority of cancers there is a low risk to relatives because genetic associations tend to be with common, low-penetrance alleles identified in genome-wide association studies. The risk to relatives increases markedly when the cancer is associated with rare, high-penetrant genetic variants, such as variants in the BRCA1 / BRCA2 genes, e.g., hereditary breast and ovarian cancer. Cancer 7 8 Epidemiology Epidemiology The incidence of breast cancer varies greatly between different populations. Breast cancer is the most common cancer in women and the second most common cancer overall, accounting for 11.6% of new cancer diagnoses worldwide in 2018. - It has long been established that reproductive and menstrual histories are risk factors. Age-standardized incidence rates highest in women in Australia and New Zealand (94.2 per 100,000) and Western Europe (92.6 per 100,000). Incidence rates up to 3.6 times lower are seen in women from the Middle Africa (27.9 per 100,000) and South-Central Asia (25.9 per 100,000). Parous women, especially multiparous, are at lower risk of developing breast cancer than nulliparous women. Furthermore, the younger the age at first pregnancy and the later the age at menarche, the lower the risk of breast cancer. Although these differences could be attributed to genetic differences between these population groups, study of immigrant populations moving from an area with a low incidence to one with a high incidence has shown that the risk of developing breast cancer rises with time to that of the native population, supporting the view that non-genetic factors are highly significant. Breastfeeding, regular exercise, and reduced alcohol intake also appear to have a role in decreasing breast cancer risk. Some of this changing risk may be accounted for by epigenetic factors. 9 10 Epidemiology Family and Twin Studies It has long been recognized that people from lower socioeconomic groups have an increased risk of developing gastric cancer. The clustering of cancer cases within families can provide significant evidence supporting a genetic contribution. Carcinogens: - The lifetime risk of developing breast cancer Specific dietary irritants: salts and preservatives. Potential environmental agents: nitrates A woman who lives until 80 in Western Europe is now approximately 1 in 8. Gastric cancer also shows variations in incidence in different populations, with age-standardized incidence rates almost four times higher in Eastern Asia compared with Western Europe. Migration studies have shown that the risk of gastric cancer for immigrants from high-risk populations does not fall to that of the native low-risk population until two to three generations later. A woman who has a first-degree relative with breast cancer, the risk to develop breast cancer is between 1.5 and 3 times the risk for the general population. It has been suggested that this could be attributed to exposure to environmental factors at an early critical age. For example, early infection with Helicobacter pylori, can cause chronic gastric inflammation and is associated with a fivefold to sixfold increased gastric cancer risk. 11 The risk varies according to the age of onset in the affected family member: the earlier the age at 12 diagnosis, the greater the risk to close relatives Family and Twin Studies Disease Associations Concordance rates for breast cancer in both monozygotic (MZ) and dizygotic (DZ) twins are low. Blood groups are genetically determined, and therefore the association of a particular blood group with a disease suggests a possible genetic contribution to the etiology. They are only slightly greater in MZ female twins, at 17% compared with 13% in DZ female twins. This suggests that, overall, environmental factors are more important than genetic factors. Twin studies in gastric cancer have not shown an increased concordance rate in either MZ or DZ twins. *concordance is the probability that a pair of individuals will both have a certain characteristic (phenotypic trait) given that one of the pair has the characteristic. 13 14 Disease Associations Viral Factors A large number of studies have shown an association between blood group A and gastric cancer. Some viruses are associated with certain types of human tumor. It is estimated that those with blood group A have a 20% increased risk of developing gastric cancer. Virus Family Virus Type Tumor Papova Papilloma Warts (plantar and genital), urogenital cancers (cervical, vulval, vaginal and penile), skin cancer, oral (mouth/tongue/oropharynx) Herpes Epstein-Barr Burkitt lymphoma a , nasopharyngeal carcinoma, lymphomas in immunocompromised hosts Hepadna Hepatitis B Hepatocellular carcinoma Hepacivirus Hepatitis C Hepatocellular carcinoma, non-Hodgkin lymphoma Human gamma herpesvirus 8 (HHV-8) KSHV Kaposi sarcoma, lymphoma (particularly in the context of HIV infection) Blood group A is associated with an increased risk of developing pernicious anemia, which is also closely associated with chronic gastritis. Pernicious anemia, one of the causes of vitamin B12 deficiency, is an autoimmune condition that prevents the body from absorbing vitamin B12. Without adequate vitamin B12, there is a reduction in the number of red blood cells carrying oxygen throughout the body. 15 16 Viral Factors The genetic information of retroviruses is encoded in RNA and they replicate through DNA by coding for an enzyme known as reverse transcriptase, which makes a double-stranded DNA copy of the viral RNA. Cancer and Genetics This DNA intermediate integrates into the host cell genome, facilitating appropriate protein manufacture, which results in the repackaging of new progeny virions. Naturally occurring retroviruses have only three genes necessary to ensure replication and recently it has been identified a fourth gene that transforms host cells both in vitro and in vivo , causing malignancy. This viral gene is known as an oncogene . 17 Cancer and Genetics Oncogenes Oncogenes are the altered forms of normal genes. These normal genes are known as protooncogenes and they usually have key roles in cell growth and differentiation pathways. Genes that are usually altered in cancers: - 18 Proto-oncogenes Tumor suppressor genes DNA mismatch repair genes - contribute to the genesis of variants in other genes directly affecting DNA repair, cell-cycle control, and cell-death pathways. Cellular oncogene, refers to a mutated protooncogene, which has oncogenic properties. Approximately 100 oncogenes have been identified. Cellular oncogenes are highly conserved in evolution, suggesting that they have important roles as regulators of cell growth, maintaining the ordered progression through the cell cycle, cell division and differentiation. Pathogenic germline variants in at least 100 genes and somatic variants in hundreds of others are known to contribute to the total burden of human cancer. 19 20 Types of Oncogenes Identification of Oncogenes ● Three ways of activation of Oncogenes: Growth Factors: stimulate cells to grow stimulating the transition of a cell from G 0 to the start of the cell cycle. ● Growth Factor Receptors: many oncogenes encode proteins that form growth factor receptors, possessing tyrosine kinase domains that allow cells to bypass normal control mechanisms. ● Intracellular Signal Transduction Factors ● DNA-Binding Nuclear Proteins: specific transcription factors that activate or suppress neighboring - Oncogenes at Chromosomal Translocation Breakpoints - Oncogene Amplification - DNA Transfection Studies DNA sequences. ● Cell-Cycle Factors and Apoptosis: related to cell cycle progression and apoptosis. Abnormal regulation of the cell cycle, for example, at G 1 when a cell becomes committed to DNA synthesis in the S phase, or G 2 for cell division in the mitosis (M) phase, can result in uncontrolled cell growth. Loss of factors that lead to normal programmed cell death, apoptosis 21 Oncogenes at Chromosomal Translocation Breakpoints 22 Chronic Myeloid Leukemia Presence of an abnormal chromosome in white blood cells from patients with CML: the Philadelphia, or Ph 1, chromosome. Chromosome aberrations are common in malignant cells, which often show marked variation in chromosome number and structure. Philadelphia chromosome: In malignant cells chromosomal structural changes take place, often translocations. - This can result in rearrangements within or adjacent to proto-oncogenes or it can lead to novel chimeric genes with altered biochemical function or altered proto-oncogene activity level. - 23 A chromosome 22 from which long arm material has been reciprocally translocated with the long arm of chromosome 9 Is found in blood or bone marrow cells but not in other tissues from these patients. This chromosomal rearrangement is seen in 90% of those with CML. 24 Chronic Myeloid Leukemia Burkitt Lymphoma This translocation transfers the cellular Abelson (ABL) oncogene from chromosome 9 into a region of chromosome 22 known as the breakpoint cluster region (BCR), resulting in a chimeric transcript derived from both the c- ABL and the BCR genes. An unusual form of neoplasia seen in children in Africa. The majority (90%) of affected children have a translocation of the c -MYC oncogene from the long arm of chromosome 8 onto heavy (H) chain immunoglobulin locus on chromosome 14. This results in a chimeric gene expressing a fusion protein consisting of the BCR protein at the amino end and the ABL protein at the carboxy end, which transforms activity, leading to the out of control growth of certain blood cells. As a consequence of this translocation, MYC comes under the influence of the regulatory sequences of the respective immunoglobulin gene and is overexpressed tenfold or more. The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC overexpression can cause tumorigenesis. 25 26 Oncogene Amplification Oncogene Amplification Proto-oncogenes can also be activated by the production of multiple copies of the gene, known as gene amplification. Breast Carcinomas: it 20% of them it is seen amplification of ERBB2 ( HER2 ), MYC, and cyclin D1. This is correlated with a number of well-established prognostic factors such as The number of copies of the oncogene per cell can increase several hundred times, with greater amounts of oncoprotein as a consequence. - The amplified sequence of DNA in tumor cells gives rise to small extra chromosomes (double-minute chromosomes) seen in approximately 10% of tumors, especially in the later stages of the malignant process. lymph node status estrogen and progestogen receptor status tumor size histological grade. Currently available tests of oncogene activity in breast cancer cover more than 20 genes and assign a recurrence score which, in combination with the patient’s age and tumor type, can be used to prognosticate in terms of recurrence risk, but can also be used to predict the benefit of chemotherapy in early breast cancer, or radiotherapy in ductal carcinoma in situ . Amplification of specific proto-oncogenes is a feature of certain tumors and is frequently seen with the MYC family of genes. 27 28 Detection of Oncogenes by DNA Transfection Studies Tumor Suppressor Genes Human DNA can be transferred to cell lines in culture (transfection) and study if this transfection leads to cancerous cells. Constitute the largest group of hereditary cancer genes. Studies in the 1960s showed that fusion of malignant cells with normal cells in culture resulted in the suppression of the malignant phenotype in the hybrids. Malignancy recurred with the loss of certain chromosomes from the hybrids, suggesting that normal cells contain one or more genes with tumor suppressor activity which, if lost or inactive, resulted in malignancy. RAS gene family When DNA from a human bladder carcinoma cell line was trasnfected to mouse fibroblasts, they observed loss of contact inhibition of the cells in culture. This is how they discovered the human RAS gene family. The human RAS gene family consists of three closely related members: ● ● ● Tumor suppressor genes suppress inappropriate cell proliferation. HRAS (Harvey rat sarcoma virus) KRAS (Kristen rat sarcoma virus) NRAS (neuroblastoma ras viral oncogene) More than 20 tumor suppressor genes have been identified. The RAS genes code for four isoproteins whose role is to mediate signals related to cell survival and senescence. RAS gene variants are identified in 25% of all cancers, with KRAS being the most commonly mutated. 29 30 Tumor Suppressor Genes DNA repair genes A tumor suppressor gene encodes a protein that acts to regulate cell division, keeping it in check. When a tumor suppressor gene is inactivated by a mutation, the protein it encodes is not produced or does not function properly, and as a result, uncontrolled cell division may occur. Such mutations may contribute to the development of a cancer. DNA repair genes are the intracellular ‘repair workers’. They support and maintain genetic stability and are specifically involved in the repair of damaged DNA, these genes help correct mistakes in DNA replication. They perform an indirect effect on cell proliferation or survival by influencing the ability of the organism to repair any non-lethal damage in other genes, including proto-oncogenes, oncogenes, genes that regulate and control apoptosis and tumour suppressor genes. Compromise in the function of the DNA repair genes can predispose to mutations and so predispose the development of multi-mutational damage and the neoplastic transformations that are recognized as cancer. 31 32 DNA Methylation The methylation of DNA is an epigenetic phenomenon. Epigenetics and Cancer Methylation of DNA has the effect of silencing gene expression and maintaining stability of the genome. It is important to keep areas with repetitive DNA (heterochromatin) methylated which might otherwise become erroneously involved in recombination events leading to altered regulation of adjacent genes. Epigenetics refers to heritable changes to gene expression that are not owing to differences in the genetic code. Such gene expression can be transmitted stably through cell divisions, both mitosis and meiosis. Cancer cells can suffer from hypomethylation or hypermethylation events. Genomes of cancer cells can be hypomethylated compared with those of normal cells, primarily within repetitive DNA. This may lead to activation of an allele that is normally silent, and hence the high expression of a product that confers advantageous cellular growth. This appears to be an early event in many cancers and may correlate with disease severity. DNA hypomethylation and removal of normal gene silencing may lead to oncogene activation, and hence cancer risk. 33 34 DNA Methylation Hypermethylation may also give rise to an increased cancer risk, in this case through silencing of tumor suppressor genes. This results in changes in chromatin structure (hypoacetylation of histone) that effectively silence transcription. When genes involved in cell regulatory activity are silenced, cells have a growth advantage. 35 Emery's Elements of Medical Genetics and Genomics Turnpenny, Peter D., BSc MB ChB FRCP FRCPCH FRCPath FHEA; Ellard, Sian, OBE BSc PhD FRCPath; Cleaver, Ruth, 36 BSc MB ChB PGCert MRCP © 2022. Telomere Length and Cancer Telomere Length and Cancer Telomeres are specialized chromatin structures at the tips of chromosomes and have a protective function. Short telomeres are a feature of the premature aging syndromes, such as some chromosome breakage disorders associated with early-onset cancer. The rate of telomere shortening is markedly increased in these conditions, so that cells and tissues literally “age” more quickly. They consist of multiple double-stranded tandem repeats of the TTAGGG DNA sequence, with a length of approximately 10 to 15 kb in human cells. Some cancer cells express high levels of telomerase, thus maintaining cell viability. Most metastatic tissue contains telomerase-positive cells, suggesting that telomerase is required to sustain such growth, but cancer cells generally have relatively short telomeres. Thus, telomerase activation in cancer rescues short telomeres and perpetuates genomically unstable cells. Telomerase is an enzyme that can lengthen the telomeres in those cells in which it is expressed. Every cell division appears to result in the loss of some TTAGGG repeats. This progressive loss of telomere length is a form of cellular clock believed to be linked to both aging and human disease. When telomeres reach a critically short length, there is loss of protection, and a consequence is chromosomal, and therefore genomic, instability, which reduces cell viability. 37 38 DNA Tumor Profiling, Mutational Signatures, and Tumor DNA Tumor Profiling, Mutational Signatures, and Tumor Mutational Burden Mutational Burden The development of next-generation sequencing (NGS) has revolutionized cancer research as it allows to examine cancer at the genetic level in detail. Each cancer tumor has a unique set of mutations (often thousands) compared to a person’s normal, inherited DNA. Tumors from two different people with the same cancer type may look similar under a microscope (histologically), their DNA profiles often show both shared and unique mutations. NGS can quickly read and analyze the DNA in cancer cells, helping scientists understand which genetic changes drive cancer. It shows individual gene mutations within cancer cells. Mutational Signatures are specific patterns of DNA mutations that arise due to distinct mutational processes during the development of cancer. These signatures provide insights into the underlying causes of mutations, such as environmental exposures, cellular dysfunctions, or defective DNA repair mechanisms. Large databases like COSMIC (Catalogue of Somatic Mutations in Cancer) gather and organize these genetic changes from various cancers around the world, creating the biggest collection of known cancer mutations. Some mutations don’t drive cancer growth directly; they’re simply “passenger” mutations, tagging along without significantly impacting the cancer. Studying these can provide insights into how tumors develop over time. Learning more about these signatures is already shaping cancer diagnosis and treatment. 39 40 DNA Tumor Profiling, Mutational Signatures, and Tumor Circulating Tumor DNA Mutational Burden Next-generation sequencing allows the detection of circulating tumor DNA (ctDNA) in patients with cancer. Tumor DNA may be present in the plasma of a cancer patient as either circulating tumor cells (CTCs) or cell-free DNA. The “tumor mutational burden” (TMB) is the total number of mutations in a cancer, and helps predict responses to certain cancer therapies. It has been shown that the frequency of CTCs and ctDNA in plasma correlates with the stage of cancer in the patient. The more advanced the cancer, the higher the frequency of CTC and ctDNA; this also correlates with survival. In cancers like metastatic colorectal cancer (CRC) with high TMB,some treatments are showing promising results, marking a step towards integrating genomics into routine cancer care. These genomic insights could eventually expand personalized treatment options for more types of cancer. Characterizing and monitoring cancer has the potential advantage of providing a more comprehensive profile because individual tumors may harbor different clonal expansions of abnormal tissue which are not always captured in a biopsy. 41 Detection of circulating tumor DNA could also be used as screening method, especially in high-risk individuals. 42 Genetics of Common Cancers Many cancers are attributed to inherited predisposing genetic factors. Inherited Cancer Syndromes Approximately 5% to 10% of colorectal and breast cancers arise as a result of an inherited cancer susceptibility gene. 43 44 Familial Adenomatous Polyposis Approximately 1% of persons who develop CRC do so through inheriting the altered gene for Fibroblast Activation Protein Alpha (FAP). Affected individuals develop numerous polyps of the large bowel. By the age of 35 years, the vast majority of affected individuals will have many polyps in which there is a high risk of carcinomatous change, with 93% of untreated patients developing bowel cancer by the age of 50 years. 45 46 Colorectal Cancer Breast Cancer The development of colorectal cancer is a multistage process of accumulating genetic errors in cells. This is the most common cancer in women. Some 15% to 20% of women with breast cancer have a positive family history of the disorder. The risk to a female relative is greater when one or more of the following factors is present: The majority of CRCs are thought to develop from “benign” adenomas, although only a small proportion of adenomas proceed to invasive cancer. 1. 2. 3. 4. 5. a clustering of cases in close female relatives early age (<50 years) at presentation the occurrence of bilateral disease (both breasts affected) the occurrence of ovarian cancer a paternal (or close male relative) history of breast cancer. The adenomas that proceed to invasive cancer have sown to have RAS gene variants in the majority of the cases. In the transition from a small “benign” adenoma to carcinoma, it is more important the accumulation of alterations, rather than the sequence. 47 48 Breast cancer Features Suggestive of an Inherited Cancer Susceptibility Syndrome in a Family BRCA1 and BRCA2 Genes: BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are damage DNA repair genes. These are the most well-known genes linked to hereditary breast cancer. Mutations in either gene significantly increase the risk of breast cancer, as well as ovarian cancer. Inheriting a harmful mutation in BRCA1 or BRCA2 can lead to a 45-65% chance of developing breast cancer by age 70. ➔ ➔ ➔ ➔ ➔ ➔ ➔ Other High-Risk Genes: - Tumor suppressor gene TP53 mutations are linked to Li-Fraumeni syndrome, which raises the risk of several cancers, including breast cancer. Tumor suppressor gene PTEN mutations cause Cowden syndrome, associated with a higher risk for breast and other cancers. PALB2 mutations are linked to an increased breast cancer risk similar to BRCA2. Moderate-Risk and Low-Risk Genes: Genes like ATM, CHEK2, and RAD51 contribute to a moderate increase in breast cancer risk. These mutations alone may not strongly predispose an individual to breast cancer, but they can have a cumulative effect when combined with lifestyle or environmental factors. Several close (first- or second-degree) relatives with a common cancer Several close relatives with related cancers (e.g., breast and ovary or bowel and endometrial) Two family members with the same rare cancer An unusually early age of onset Bilateral tumors in paired organs (breasts, kidneys, ovaries…) Synchronous or successive tumors Tumors in two different organ systems in one individual 49 50 Inherited Cancer-Predisposing Syndromes Familial cancer-predisposing syndrome, in families where cancer occurs: - Lifetime risk of breast cancer in females according to the family history of breast cancer at more than one site in an individual at different sites in various members of the family more commonly than would be expected The majority of the rare inherited familial cancer-predisposing syndromes currently recognized are dominantly inherited, with offspring of affected individuals having a 50% chance of inheriting the gene and therefore of being at increased risk of developing cancer. Cancer-predisposing syndromes carry a risk of a second primary tumor (multifocal or bilateral in the case of breast cancer) and generally present at a relatively young age compared with sporadic forms, and tumors may occur at different sites in the body, although one type of cancer usually predominates. 51 Population risk 1 in 8 Sister diagnosed at 65–70 years of age 1 in 8 Sister diagnosed at younger than 40 years of age 1 in 4 Two first-degree relatives affected at younger than 40 years of age 1 in 3 52 Screening for Familial Cancer Lifetime risk of colorectal cancer for an individual according to the family history of colorectal cancer Population risk 1 in 50 One first-degree relative affected 1 in 17 One first-degree relative and one second-degree relative affected 1 in 12 One relative younger than 45 years of age affected 1 in 10 Two first-degree relatives affected 1 in 6 Three or more first-degree relatives affected 1 in 2 Prevention or early detection of cancer is the ultimate goal of screening individuals at risk of familial cancer. Prevention for certain cancers can include a change in lifestyle or diet, drug therapy, prophylactic surgery or screening. Although the potential for prevention of cancer through screening those at high risk is considerable, it is important to remember that this does little to impact the overall rate of cancer in the population because these syndromes are relatively rare. 53 Requirements of a Screening Test for Persons at Risk for a Familial Cancer-Predisposing Syndrome or at Increased Risk for the Common Cancers - The test should detect a malignant or premalignant condition at a stage before it is producing symptoms, with high sensitivity and specificity. - The treatment of persons detected by screening should improve the prognosis. - The benefit of early detection should outweigh potential harm from the screening test - The test should preferably be non-invasive, as most at-risk individuals require long-term surveillance - Adequate provision for prescreening counseling and follow-up should be available 54 Screening for Familial Cancer Screening for Familial Cancer In the case of the rare familial cancer-predisposing syndromes, those who should be screened can be identified on a simple mendelian basis. Screening intervals are determined from the natural history of the particular cancer. Early diagnosis is critical in breast cancer care, so for those at high risk, for example BRCA1 gene carriers, screening begins with annual breast MRI from 30 years of age, with the addition of mammograms from 40 years of age. For women with more moderately increased risk, annual mammography is recommended from 40 years of age. For those with a family history of the common cancers, such as bowel or breast, the risk levels at which screening is recommended, and below which screening is not likely to be of benefit, will vary. At each extreme of risk, the decision is usually straightforward, but with intermediate-level risks there may be doubt as to relative benefits and risks of screening. Screening programs must target those at highest risk, as well as cover those at moderate risk. The majority of cancer screening programs do not start until adulthood. In some families the age of onset of cancer can be especially early, and there may be scope to deviate from national guidelines in such cases. 55 56 Cancer therapy Cancer treatment option is determined according to cancer type, grade, prognosis and the individual. Cancer Therapy Treatment options are chemotherapy, surgery, radiotherapy, hormone treatment, photodynamic therapy, hyperthermia, immunotherapy, stem cell transplantation and targeted therapy. Gene therapy is different from traditional therapy methods since it can be applied without leading to many side effects. 57 Gene therapy in 58 Gene therapy in Cancer Cancer Suicide gene therapy: prodrugs which turn into an active form and show cytotoxic effects in the cells are transferred into cancer cells. This treatment involves delivering genes to cancer cells, which encode enzymes capable of converting non-toxic prodrugs into toxic agents,selectively killing the cancer cells. Cesur-Ergün B, Demir-Dora D. Gene therapy in cancer. J Gene Med. 2023; 25(11):e3550. doi:10.1002/jgm.3550 59 Tumor suppressor gene activation: The cell cycle is inhibited or apoptosis is promoted by transferring tumor supressor genes into cancer cells. p53 gene is extensively studied due to its crucial function in detecting DNA damage and activating pathways leading to cell cycle arrest or apoptosis. Research has demonstrated that introducing p53 in cancer cells can inhibit tumor growth and promote regression in animal models. 60 Gene therapy in Cancer Cancer therapy Inhibition of oncogene activation: Oncogenes are the main genes contributing to the conversion of normal cells to cancer cells. Therapeutic nucleic acids like antisense oligonucleotides, siRNA and miRNA molecules are used to inhibit the expression of oncogenes, inhibiting protein synthesis. Immunotherapy: Cancer immunotherapies are designed to induce or enhance T cell reactivity against tumor antigens. T cells help protect the body from infection and may help fight cancer. Cancer cells have the ability to evade immune detection, gene therapy approaches have evolved to enhance the immune response. This includes introducing genes that encode immunostimulatory factors and co-stimulatory molecules to strengthen T-cell activity. .CAR T-cell therapy, or chimeric antigen receptor T-cell therapy, is an advanced form of immunotherapy used to treat certain cancers, primarily blood cancers like leukemia and lymphoma. In this therapy, a patient's own T-cells (a type of immune cell) are collected and genetically modified in a laboratory to produce chimeric antigen receptors (CARs) on their surface. These receptors are designed to recognize specific antigens on the cancer cells. Antiangiogenic gene therapy: Angiogenesis (blood vessel formation) provides the necessary nutrients for the proliferation of cancer cells and thus among the main targets of antiangiogenic cancer treatment is inhibition of angiogenic inducers or the use of angiogenic inhibitors. 61 62 63 64 Globally approved gene therapy medicinal products used for cancer treatment Virus therapy that uses a modified adenovirus to target and kill cancer cells Virus therapy CAR-T CAR-T
