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Investigating Cancer. Cancer. Cancer is the second leading cause of death in the United States, 2nd only to heart disease. ½ of all men and one-third of all women in the US will develop cancer during their lifetimes. Although cancer is a term that encompasses more than 100
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Cancer • Cancer is the second leading cause of death in the United States, 2nd only to heart disease. • ½ of all men and one-third of all women in the US will develop cancer during their lifetimes. Although cancer is a term that encompasses more than 100 different diseases and affects different people differently, all cancer cells share one important characteristic. Cancer cells are abnormal cells in which the processes that regulate normal cell division are damaged. Most cancers are initially recognized when signs or symptoms appear. Once cancer is suspected, it can be further investigated through medical tests including X-rays, CT scans, and MRI scans. Finally, the definitive diagnosis requires the histological examination of a tissue specimen, called a biopsy. Once a diagnosis is confirmed, treatment can begin. The more that is known about the cancer, the more effective the treatment can be.
What is cancer? • All cancers derive from single cells that have acquired the characteristics of continually dividing in an unrestrained manner and invading surrounding tissues. • Cancer cells behave in this abnormal manner because of changes in the DNA sequence of key genes, which are known as cancer genes. Therefore all cancers are genetic diseases. Human melanoma cell undergoing cell division Credit: Paul Smith & Rachel Errington, Wellcome Images
Cancer information • 1 in 3 people in the Western world develop cancer and 1 in 5 die of the disease • There are approximately 200 types of cancer, each with different causes, symptoms and treatments • Cancer Statistics 2019 • An individual's risk of developing cancer depends on many factors specifically: • age • lifestyle • genetic make-up Cancer Research UK http://info.cancerresearchuk.org/cancerstats/incidence/?a=5441
Cancer can originate almost anywhere in the body. 1. Carcinomas, the most common types of cancer, arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this type in the United States. 2. Sarcomas are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle. 3. Lymphomas are cancers that arise in the lymph nodes and tissues of the body’s immune system. 4. Leukemias are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream. 5. Melanomas, the most serious type of skin cancer, develops in the cells (melanocytes) that produce melanin — the pigment that gives your skin its color. Melanoma can also form in your eyes and, rarely, in internal organs, such as your intestines.
Different Kinds of Cancer Leukemias: Bloodstream Some common carcinomas: Lung Breast (women) Colon Bladder Prostate (men) Lymphomas: Lymph nodes Lung Breast (women) Colon Bladder Prostate (men) Some common sarcomas: Fat Bone Muscle
Naming Cancers Cancer Prefixes Point to Location Prefix Meaning adeno- gland chondro- cartilage erythro- red blood cell hemangio- blood vessels hepato- liver lipo- fat lympho- lymphocyte melano- pigment cell myelo- bone marrow myo- muscle osteo- bone
Example of Normal Growth Dead cells shed from outer surface Epidermis Cell migration Dividing cells in basal layer Dermis
The Beginning of Cancerous Growth • During the development of skin cancer, the normal balance between cell division & cell loss is disrupted. • The basal cells now divide faster than is needed to replenish the cells being shed from the surface of the skin. Underlying tissue
Tumors (Neoplasms) • The gradual increase in the # of dividing cells creates a growing mass of tissue called a tumor (neoplasm). Underlying tissue
Invasion and Metastasis 1 Cancer cells invade surrounding tissues and blood vessels 2 Cancer cells are transported by the circulatory system to distant sites 3 Cancer cells reinvade and grow at new location
Malignantvs Benign Tumors Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time
Why Are Malignant Tumors Dangerous? Brain Melanoma cells travel through bloodstream Liver Melanoma(initial tumor)
Cancer cells have altered genomes Karyotype illustrating structural abnormalities in cancer Credit : Mira Grigorova and Paul Edwards, Department of Pathology, University of Cambridge, unpublished Source: www.path.cam.ac.uk/~pawefish/BreastCellLineDescriptions/HCC38.html
What is a mutation? • Germline mutation • A change in the DNA sequence that can be inherited from either parent • Somatic mutation • A change in the DNA sequence in cells other than sperm or egg • The mutation is present in the cancer cell and its offspring, but not in the patient’s healthy cells
Mutations & cancer genes • Cancer genes are causally implicated in oncogenesis • Mutations in cancer genes can occur somatically or can be inherited. • Mutations in some cancer genes can be inherited from parents, in which case they are present in every cell of the body. Such people are at a higher risk of developing cancer. • Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children.
Importance of somatic DNA changes in human cancer Both Inherited Somatic Only 5 –10% of cancer cases have a clear hereditary component, e.g. BRCA1 and BRCA2 in breast cancer Even in those cases where susceptibility is clearly inherited, somatic changes are required for cancer to develop
Cancer genes • There are two types of cancer genes: • Tumour suppressor genes • Oncogenes • To date, we know of approximately 400 somatic “cancer genes” * but there are almost certainly more to be found • COSMIC is a catalogue of somatic mutations found in cancer genes in human tumours and is available at: http://www.sanger.ac.uk/genetics/CGP/cosmic/ *(COSMIC v47release. July 2010)
These genes normally function to PREVENT cell growth/division Tumour suppressor gene TS Cancer
Genes which normally function to PROMOTE cell growth/division in a controlled manner Oncogene Ras Cancer
Examples of mutations Sequence 1 Sequence 2 Type ACTCGTTAGGCA Substitution ACTCCTTAGGCA ACTCGTTAGGCA ACTCGGCA Deletion ACTCGTTAGGCA Insertion ACTCGTTATCAGGCA ACTCGTTAGGCA Inversion ACTTTGCAGGCA ACTCGTTAGGCA Duplication ACTCGTTAGTTAGGCA
Cancer progression: A cell begins to divide more rapidly than it’s neighbours and a localised mass of cells forms. Benign Tumor: cell begins to divide more rapidly than it’s neighbours and a localised mass of cells forms. In situ cancer: A cell begins to divide in an uncontrolled way. Invasive cancer: tumor gets bigger and cells begin to invade surrounding tissue. In this case the illustration is showing the tumor arising from a cell within a villi of the large intestine, expanding outwards into the surrounding area. Metastatic cancer: Tumor cells travel to other parts of the body through the bloodstream and deposit in other organs leading to secondary tumors, known as metastasis.
Stages of Cancer • In situ—Abnormal cells are present but have not spread to nearby tissue. • Localized—Cancer is limited to the place where it started, with no sign that it has spread. • Regional—Cancer has spread to nearby lymph nodes, tissues, or organs. • Distant—Cancer has spread to distant parts of the body. • Unknown—There is not enough information to figure out the stage.
External causes of cancer: ultraviolet radiation www.flickr.com: lastexit
External causes of cancer: tobacco smoke
Biological factor: virus • HPV is a cause of cervical cancer • Proteins from the virus activate and deactivate cancer genes • The role of HPV in cervical cancer has led to the development of vaccines HPV in cervical epithelium Credit: MRC NIMR, Wellcome Images
Biological factors can also be linked with cancer. For example, Human papilloma virus (HPV) is recognised as a cause of cervical cancer. • HPV is a sexually transmitted virus which has more than 100 different strains. Thirty of these can cause cervical cancer and genital warts. • When HPV enters cells of the cervix proteins made by the virus activate and inactivate oncogenes and tumour suppressor genes respectively. It is like a machine for turning on lots of cancer genes. The image shows a lesion in a human cervical epithelium infected with human papilloma virus (HPV16). Early viral proteins (green) bind to and re-organize the keratin filaments (red) towards the edge of the cell. Cell nuclei are stained with Dapi (blue).
In 2007, there were more than 550,000 new cases of cervical cancer, and approximately 260,000 deaths from cervical cancer worldwide. The overwhelming majority of these women were in developing countries, where cervical cancer screening programmes are often unavailable and healthcare infrastructure weak. • The role of HPV in cervical cancer has led to the development of vaccines against HPV. Vaccination against HPV dramatically reduces cases of cervical cancer. The development of the vaccine is regarded by cancer experts as a stunning advance in the prevention of cancer. A HPV vaccine is available and vaccination and screening programs are being introduced in the UK. Since 2008, the vaccine has been offered to 12- to 13-year-old girls (school year 8). A three-year catch-up programme was started in 2008 and offers the vaccine to older girls aged 13-18 years old.
Activity • The KRAS gene codes for a signalling molecule • Mutations in KRAS are present in many cancers, including pancreatic cancer • You have to look for the mutations by comparing healthy DNA sequence with tumour DNA sequence • Not all of you will find a mutation
If you find a mutation EXAMPLE ONLY
How to use the codon wheel Start from the centre and move outwards
Heterozygous mutations Normal DNA sequence A double peak indicates a mutation on one chromosome and not the other i.e. a heterozygous mutation A DNA change in cancer T → A BRAF gene mutation Nature 417, 906-7 (June 2002)
Results Amino Acid Healthy DNA Tumour DNA Healthy Amino Tumour Amino Number Sequence Sequence Acid Acid G ( glycine ) V ( valine ) GGT GTT 12 D (aspartic acid) G (glycine) GGC GAC 13 D (aspartic acid ) D (aspartic acid) 30 GAC GAT Q (glutamine ) R ( arginine ) 61 CAA CGA A (alanine) P (proline) 146 GCA CCA ) D (aspartic acid D (aspartic acid) 173 GAT GAC
How common? AA 12 13,894 AA 13 2,111 AA 61 212 AA 146 33 Source: COSMIC July 2010
RB1: tumour suppressor gene Source: COSMIC July 2010
What’s the impact? • KRAS helps to transmit external growth signals to the cell nucleus, driving normal cell growth. It is: • Activated when it binds GTP • Inactivated or “switched off” when GTP is hydrolysed to GDP
