Chapter 09 Cancer Genetics PDF

Chapter 09 Cancer Genetics Dra Verónica Veses Jiménez Chapter overview Basic concepts in cancer. Molecular basis of cancer: – Oncogenes – Tumor suppressor genes – Genes involved in DNA repair mechanisms 2 Basic concepts in cancer Ca...

Chapter 09 Cancer Genetics Dra Verónica Veses Jiménez Chapter overview Basic concepts in cancer. Molecular basis of cancer: – Oncogenes – Tumor suppressor genes – Genes involved in DNA repair mechanisms 2 Basic concepts in cancer Cancer is a group of genetic disorders of somatic cells that causes the cells to escape from normal controls of cell division and apoptosis. Cancer is therefore defined as the uncontrolled growth of cells, called neoplasia. Cancer cells are not inhibited by contact with other cells and can form tumors. Sometimes the cells can invade and spread to distant sites of the body (metastasis). 3 Definitions A tumor is a non-specific term, it means abnormal mass of cells. They can be subclassified in: Benign tumors are non-malignant, usually localized, and do not spread to other parts of the body. Most benign tumors respond well to treatment. However, if left untreated, some benign tumors can grow large and lead to serious disease because of their size. Malignant tumors are cancerous growths. They are often resistant to treatment, may spread to other parts of the body and they sometimes recur after they were removed. 4 Hallmarks of cancer Hanahan and Weinberg. Cell. 2011 5 Cancer classification Classification by type of tissue affected Classification by cell: Carcinoma Adenomatous cells – epithelial cells – ductal or glandular cells – 90% of all tumors Squamous cells Sarcoma – Flat cells – connective tissue Myeloid – 2% of all tumors – Blood cells Leukemia Lymphoid – circulatory or lymphatic – Lymphocytes or macrophages – 8% of all tumors 6 Common cancers worldwide Lung (2.09 million cases) Breast (2.09 million cases) Colorectal (1.80 million cases) Prostate (1.28 million cases) Skin cancer (non-melanoma) (1.04 million cases) Stomach (1.03 million cases) Data from WHO, 2021 7 Causes of Cancer Formation of a cancer (oncogenesis) may be due to: – A viral infection (one fifth of all cancers worldwide are caused by viral chronic infections, such as human papillomavirus and hepatitis B virus) – Exposure to environmental mutagens – Genetic changes such as chromosomal or genetic spontaneous mutations Usually, there is a combination of genetic and environmental factors. 8 Environmental mutagens that can cause cancer: physical carcinogens, such as ultraviolet and ionizing radiation. chemical carcinogens, such as: – asbestos – components of tobacco smoke – aflatoxin (a food contaminant) – arsenic (a drinking water contaminant)… 9 Radiation UVB rays can damage DNA and is associated with over 90% of skin cancers, including melanomas Radon has been associated with lung cancer amongst people who work in the mines Electric and magnetic fields from power lines, mobile phones and appliances have not been proven contributors to the incidence of cancer or leukemia nuclear radiation is of sufficient energy to ionize molecules and therefore is carcinogenic 10 Chemical occupational carcinogens There is a proven relationship in: – Skin cancer in tar workers – Cancer of the bladder in aniline dye workers – Lung cancer in asbestos workers 11 Tobacco Tobacco use is the single most important risk factor for cancer causing about 20% of global cancer deaths and around 70% of global lung cancer deaths. It is causally related to lung cancer, upper respiratory tract, esophagus, bladder, pancreas. It is probable cause of stomach cancer, liver, kidney, colon and rectum. Recent studies show that smokers with short telomeres are at higher risk than people with short telomeres that have never smoked and smokers with long telomers. 12 Genetic basis of cancer Mutations associated with cancer usually involve: Proto-oncogenes, whose products typically stimulate cell proliferation. Their mutations, somatic and dominant, turn them into oncogenes, which stimulate cell division. Tumor suppressor genes, whose products inhibit the proliferation normally. Genes involved in DNA repair systems, whose products ensure accurate replication and genome maintenance. 13 Oncogenes An oncogen is a mutant gene whose altered function or expression results in abnormal stimulation of cell division and proliferation. Oncogenes have a dominant effect at a cellular level. When activated or overexpressed, a single mutant allele is sufficient to initiate the change in phenotype of a cell from normal to malignant. Up to 50 oncogenes have been identified so far. 14 Classes of activated oncogenes Class Example Type of cancer I. Growth factors Sis Glioma II. Receptor of Growth Ret Multiple endocrine Factor adenomatosis III. Intracellular signaling pathways: - Cytoplasmic tyrosine Abl Chronic myelogenous kinase leukemia - G protein signaling K-Ras2 Pancreatic cancer - Phosphoinositide 3- PTEN Breast cancer, glioma kinase IV. Transcription factors Myc Burkitt Lymphoma V. Telomerase Telomerase Many VI. Antiapoptotic Bcl2 Chronic lymphocytic proteins leukemia 15 Mechanisms of activation of proto-oncogenes Mechanism Type of gene Result activated Regulatory Growth factor Increased mutation genes expression Structural Growth factor Allows autonomy mutation receptors, signal- of expression transducing proteins Translocation, Transcription Overexpression gene factors amplification 16 Case study: Chronic Myeloid Leukemia 95 % of CML patients show the Philadelphia chromosome, a smaller-than-normal chromosome 22 within the malignant bone marrow 17 Philadelphia chromosome Results from a reciprocal translocation between chromosomes 9 and 22 As a result of the translocation the ABL proto- oncogen is translocated from its normal site at 9q34 to chromosome 22q11 creating a hybrid gene BCR-ABL that causes cell transformation 18 Tumor suppressor genes When they are functional they negatively regulate cell-cycle progression, couple DNA damage recognition to cell-cycle control, promote apoptosis or play a role in cell adhesion. Mutation of tumor suppressor genes (TSG) causes cancer through loss of function of both alleles of the gene. At least 30 TSG have been identified so far, including p53, BRCA1, BRCA2, APC, and RB1. 19 Comparison of the effects of mutations in tumor suppressor genes and proto-oncogenes Oncogenes are dominant mutations Tumor suppressors genes are recessive Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings. 20 P53: a key tumor suppressor gene The product of the tumor suppressor gene p53 is a protein of 53 kilodaltons. More than half of all human cancers harbour p53 mutations and have no functioning p53 protein. The p53 protein prevents a cell from completing the cell cycle if its DNA is damaged or the cell has suffered other types of damage. When the damage is minor, p53 halts the cell cycle until the damage is repaired. If the damage is major and cannot be repaired, p53 triggers the cell to commit suicide by apoptosis. 21 RB1 The Rb protein function is to prevent cells from entering S phase of the cell cycle by binding to a transcription factor called E2F. This prevents E2F from binding to the promoters of proto-oncogenes as c-myc and c-fos. Transcription of c-myc and c-fos is needed for mitosis so blocking the transcription factor needed to turn on these genes prevents cell division. 22 Inactivation of RB1 gene If the two copies of the RB1 gene are inactivated the patient will develop retinoblastoma, the commonest malignant eye tumor of childhood. It can occur in two forms: familial or sporadic 23 Familial vs sporadic retinoblastoma Familial retinoblastoma: multiple tumors in the retinas of both eyes occurring in the first weeks of infancy. Familial retinoblastoma occurs when the fetus inherits from one of its parents a chromosome 13 that has its RB locus deleted (or otherwise mutated) Sporadic retinoblastoma: a single tumor appears in one eye sometime in early childhood before the retina is fully developed, after two separate mutation occur de novo in each copy of chromosome 13 somatically 24 The two-hit hypothesis by Knudson (1971) 25 DNA repair genes DNA repair systems exist to correct DNA damage due to environmental mutations and mismatch bases incorporated during DNA replication. Inherited defects of either system can result in an increase frequency of cancer, such as: – Mutations in BRCA1 and BRCA2: increased frequency of breast and ovarian cancer – Mutations in MSH2, MLH1, PMS1 and PMS2 (mismatch repair systems): increased frequency of non-polyposis colon cancer. 26 GENETICS IN COMMON CANCERS Hereditary cancer syndromes When a cancer occurs as a part of a hereditary cancer syndrome, the initial cancer-causing mutation is inherited through the germline and is present in every cell of the body It is estimated that around 5% of colorectal and breast cancer arise as a result of an inherited cancer susceptibility gene 28 Familial versus hereditary cancer Hereditary cancer Familial cancer Apparently autosomal dominant More cases of a specific type(s) of transmission of specific cancer type(s) cancer within a family than statistically Earlier age of onset of cancers than is expected, but no specific pattern of typical inheritance Multiple primary cancers in an individual Age of onset variable Clustering of rare cancers May result from chance clustering of Bilateral or multifocal cancers sporadic cases First degree relatives of mutation carriers May result from common genetic are at 50% risk to have the same mutation background, similar environment and/or Those who do not have the familial lifestyle factors mutation have the general population risk Does not usually exhibit classical for cancer features of hereditary cancer syndromes 29 Features suggesting inherited cancer susceptibility Several close relatives with a common cancer Several close relatives with related cancers Two family members with the same rare cancer An unusually early age of onset Bilateral tumors in paired organs Synchronous or successive tumors Tumors in two different organ systems in one individual 30 BREAST AND OVARIAN CANCER 31 Breast cancer Breast cancer is a very common type of cancer. About 5% of breast cancers are hereditary. Hereditary forms of breast cancer are inherited in a dominant pattern, and often have an early onset and are bilateral. The population risk for breast cancer is 1 in 10, however, it increases to 1 in 4 for patients with a sister diagnosed with breast cancer younger than age 40 years. Several genes have been implicated in familial breast cancer, like BRCA1 and BRCA2. 32 BRCA1 and BRCA2 BRCA1 is located at 17q21 and BRCA2 is located at 13q12 The main function of these genes is double-strand break repair of DNA. They are tumor suppressor genes 33 BRCA1 and BRCA2 mutations Faulty BRCA1 and BRCA2 genes are rare. Between 45 to 90% of women with a BRCA1 or BRCA2 gene mutation will develop breast cancer during their lifetime. Both these genes also increase the risk of ovarian cancer BRCA1 increases the risk of colon cancer, male breast cancer and prostate cancer. 34 Other mutations in inherited breast cancer Faults in TP53 and PTEN are even rarer than BRCA1 and BRCA2 mutations. The TP53 gene normally controls when a cell divides. It causes breast cancer as part of a rare cancer syndrome called Li-Fraumeni syndrome. It causes less than 1% of all breast cancers diagnosed. Mutations in PTEN (a tumor suppresor gene) cause a rare condition called Cowden syndrome. It increases the risk of breast cancer. 35 Li-Fraumeni syndrome It is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The cancers most often associated with Li-Fraumeni syndrome include: – breast cancer – osteosarcoma – soft tissue sarcomas – brain tumors – leukemia – adrenocortical carcinoma,… 36 Genetic cause of Li-Fraumeni syndrome It is inherited in an autosomal dominant pattern It is associated mainly with mutations in TP53 (some cases associated with CHEK2) TP53 stands for Tumor Protein 53. The p53 protein is located in the nucleus, where it binds directly to DNA. When the DNA in a cell becomes damaged, this protein plays a critical role: if the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis It plays an essential role for regulating cell division and preventing tumor formation, and therefore it has been nicknamed the "guardian of the genome” 37 COLORECTAL CANCER 38 Colorectal cancer Population risk for colorectal cancer is 1 in 50. It is estimated that 5 to 10 % of diagnosed colorectal cancers are hereditary. For patients with one first degree relative affected the risk increases to 1 in 17. There are several familial syndromes that can predispose to colorectal cancer. 39 Familial Adenomatous Polyposis (FAP) FAP is caused by a mutation in the APC gene, a transcriptional regulator. It is a rare disease that causes 1 % of total colorectal cancers. It is inherited in a autosomal dominant pattern The mutation can cause hundreds of non cancerous (benign) growths called polyps to develop in the bowel at a young age. Over time, these polyps can develop into a cancer. The average age of bowel cancer in people with FAP is 35 years. 40 MYH associated polyposis (MAP) MAP is caused by mutations in the MYH gene, involved in base excision repair. It is much rarer than FAP (familial adenomatous polyposis). It is inherited in a autosomal recessive pattern. People with MAP develop polyps and are likely to develop bowel cancer under the age of 50. 41 Lynch syndrome or hereditary non polyposis colon cancer (HNPCC) It is caused by mutations in the MLH1, MSH2, MSH6 and PMS2 genes. These genes are involved in DNA mismatch repair. Lynch syndrome accounts for between 2 to 5 % of total colorectal cancers. Between 70 to 90 % of people with Lynch syndrome will develop bowel cancer. Most of the bowel cancers occur under the age of 50. People with Lynch syndrome also have an increased risk of developing other cancers including womb and ovarian cancer in women, stomach, small bowel and gallbladder. 42 Peutz Jeghers syndrome It is linked to a mutation in STK11. It is inherited in a autosomal dominant pattern. Peutz Jeghers syndrome increases the risk of bowel cancer as well as other types of cancer. Patients with this syndrome also have melanin spots on lips and perioral regions. 43 MELANOMA 44 Melanoma Melanoma is a type of cancer that occurs in the skin. The main cause of melanoma is too much exposure to ultraviolet light, from sunlight or from artificial sources such as sun beds. About 1 in 10 people (10%) who have melanoma have a strong family history of the disease. 45 Familial atypical multiple mole melanoma syndrome Researchers have found that familial atypical multiple mole melanoma syndrome (FAMMM) increases the risk of developing melanoma. People who have FAMMM have more than 50 moles and at least one close relative has been diagnosed with a melanoma. Some families with FAMMM are also at a higher risk of developing pancreatic cancer. 46 CDKN2A The gene CDKN2A has been linked to familial cases of melanoma. CDKN2A participates in cell cycle regulation. Its mutations are inherited in an autosomal dominant pattern. Research suggests that the risk of melanoma linked to the CDKN2A mutation varies depending on other factors such as environmental UV light and other genetic factors. 47  References WHO information on cancer: http://www.who.int/mediacentre/factsheets/fs297/en/ Hallmarks of cancer: the next generation. Hanahan D and Weinberg RA. Cell. 2011; 144(5):646-74. Robert L. Nussbaum, 2007. Thompson & Thompson Genetics in Medicine. 7th Edition. Saunders. Peter D Turnpenny, 2011. Emery's Elements of Medical Genetics. 14th Edition. Churchill Livingstone. Saunders Elsevier , 2007​. 48 References II Edward S. Tobias, 2011. Essential Medical Genetics. 6th Edition. Wiley-Blackwell. Genetics Home Reference. US National Library of Medicine – https://ghr.nlm.nih.gov 49