GDPbio: Genome based prediction of Diseases and Personal medicines using Bioinformatics

G.P.S. Raghava | Department of Computational Biology | IMTECH | CRDD | Team Members | Contact | FAQ
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Diseases and Genes
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Personal Genomes
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What is Cancer ?
Cancer is a class of diseases in which a group of cells display uncontrolled growth, invasion and sometimes metastasis. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Cause of cancer
Cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may randomly occur through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers is usually affected by complex interactions between carcinogens and the host's genome. Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

The abnormalities which cause cancer are often self-amplifying, some of them are:
  1. Mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly
  2. Mutation in signaling (endocrine) machinery of the cell can send error-causing signals to nearby cells
  3. Mutation might cause cells to become neoplastic, causing them to migrate and disrupt more healthy cells
  4. Mutation may cause the cell to become immortal, causing them to disrupt healthy cells forever
Chemical carcinogens are another major cause of cancer. Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with many forms of cancer, and causes 90% of lung cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma. Many mutagens are also carcinogens, but some carcinogens are not mutagens. Some of the chemical carcinogens are:

Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals may promote cancers through stimulating the rate of cell division. Faster rates of replication leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a mutation.
Tobacco another carcinogen cause of cancer in the lung, larynx, head, neck, stomach, bladder, kidney, oesophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide.
Some More Causes
  1. Ionizing radiation: Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. It is estimated that 2% of future cancers will be due to current CT scans.
  2. Viral or bacterial infection: Cancers can be caused by infection with pathogens. Many cancers originate from a viral infection, they are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. They appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the virus carries an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserts near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements then cause overexpression of that proto-oncogene. This induces uncontrolled cell division. Because the site of insertion is not specific to proto-oncogenes and the chance of insertion near any proto-oncogene is low, slowly-transforming viruses will cause tumors much longer after infection than the acutely-transforming viruses.
    Vaccines: In 2006, the U.S. Food and Drug Administration approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts.
  3. Hormonal imbalances: Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.
  4. Immune system dysfunction: HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer.
  5. Heredity: There are a number of recognised syndromes where there is an inherited predisposition to cancer, often due to a defect in a gene that protects against tumor formation. The examples are:
    • Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
    • Turcot syndrome (brain tumors and colonic polyposis)
    • Inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
    • Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
    • Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
    • Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors) due to mutations of p53.
    • Tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
In addition to mutations, there are still another causes such as aneuploidy(the presence of an abnormal number of chromosomes) may involve either gain or loss of one or more chromosomes through errors in mitosis; genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material; translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location (A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase), they all lead to cancerous state. Small-scale mutations such as point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Cancer Classification
Cancers are classified by the type of cell that resembles the tumor. The general categories of cancer are given as below:
  1. Carcinoma: Malignant tumors derived from epithelial cells e.g., breast, prostate, lung and colon cancer.
  2. Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
  3. Lymphoma and leukemia: Malignancies derived from hematopoietic cells
  4. Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
  5. Blastic tumor or blastoma: A tumor which resembles an immature or embryonic tissue. Many of these tumors are most common in children.
Signs and symptoms
The cancer symptoms can be divided mainly into three groups:
  1. Local symptoms: These include unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.
  2. Symptoms of metastasis: They are enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
  3. Systemic symptoms: These include weight loss, poor appetite, fatigue and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.
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