Cancer and Genetics

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  • Cells either grow and divide with restraint ...or not! The many kinds of malignant growth that the term "cancer" represents all have one lethal attribute in common:
    The cells of the malignancy go through the cell cycle without restraint.
    These cells "defy" the control mechanisms that lie with them.
    What Is the Connection Among Cancer, the Cell Cycle, and Genetics?
    There are many protein molecules involved in the cell cycle, each is the product of a single gene. When there is a mutation in one of these genes, it can:
    increase the likelihood that a cell will become cancerous and eventually, through repeated, unrestrained division, overtake the normal cells, become malignant; and
    possibly spread, or metastasise throughout the body.
    Cancer can develop at almost any stage in life. There are some forms of cancer that develop very early, such as retinoblastoma (a cancer of the eye); others tend to develop in childhood, such as various forms of leukaemia, a cancer of the blood; and, of course, there are many forms that develop during adulthood.
    In each case, cancer is the result of a mutated gene, or a series of mutated genes, that lead to unregulated cell growth and haphazard controls over cell proliferation.
  • Food—diet appears to be related to cancer in terms of what we eat and what we don't eat.
    There are a number of foods and food additives that have been suggested as cancer-causing agents, however, their links have not been established and some have been disputed; coffee and artificial sweeteners are two examples of publicised potential carcinogens that are no longer considered to be cancer-producing.
  • Electromagnetic radiations from power lines, mobile phones and microwave ovens are significantly below levels needed to ionise biological molecules and cause mutations resulting in cancer.
  • LD was an otherwise healthy 9-month-old when his mother first noted that his left eye begun to turn out when he was tired. At the next routine examination, the pediatrician was not comforting, indicating to the parents that she was unable to complete her customary examination of the back of LD's left eye. A detailed ophthalmologic examination under general anesthesia revealed a single whitish elevation of the retina characteristic of retinoblastoma. Further evaluation (MRI, X-rays) showed no evidence that the tumor had spread in the orbit or had metastasized to other parts of the body. The plan was to treat LD with a course of radiation therapy.
    The parents were stunned to learn that their son has a cancer of the eye that  may have been inherited from one of them. LD's parents then underwent ophthalmologic examination, which indicated that neither parent was affected. A three-generation pedigree was obtained: LD's father remembers being told that he had an aunt who died in childhood after going blind, but he did not know the cause. The family history also included a paternal uncle with prostate cancer. LD has an older brother and sister, both without any signs of eye problems or other significant medical concerns.
  • JR, a healthy 38-year-old mother of three and of European ancestry (Scottish, Irish, English, German, and Polish), sought genetic counselling and testing because of a family history of breast cancer:
    Her mother was diagnosed with breast cancer at 36 years of age and died 10 years later.
    Her maternal grandmother was diagnosed with breast cancer at 57 years of age and died 7 years later.
    At the time of the genetic counselling session, the family history was found to include a paternal grandmother who was diagnosed with pancreatic cancer at 88 years of age and a paternal grandfather who was diagnosed with melanoma at 78 years of age:
  • A family history may or may not indicate that a woman has an inherited susceptibility for cancer present in her family. Most cases of breast cancer are sporadic. Only 5% to 10% of all breast cancer cases are hereditary. Efforts to identify the genetic basis of familial breast cancer reached fruition some five years ago, when the breast cancer susceptibility genes BRCA1 and BRCA2 were identified through positional cloning. Germline mutations in either of these genes account for 20-60% of breast cancer cases in families where multiple individuals are affected (2-6% of all cases). Mutations in about four other genes, some identified and some unknown, are predicted to account for the remainder of familial risk
    In familial cancers, several members of an extended family are affected with the same or related types of cancer, although a definite pattern of inheritance is not obvious.
    Certain families may have multiple members affected with cancer; however, this does not necessarily indicate the presence of inherited cancer. As many as 1 in 5 breast cancer patients have a positive family history—at least one other similarly affected family member.
    Because cancer in general, and breast cancer in particular, is a common occurrence, chance alone may account for more than one family member being diagnosed with breast cancer. More than one family member with breast cancer could presumably occur because of shared exposure to a cancer-causing environmental agent. If such agents exist that increase the risk of breast cancer, they have not been identified.
  • Recently it has been shown that DNA damage stimulates BRCA1 association with BARD1, and that together these repress the polyadenylation of mRNA transcripts. According to the model, BRCA1 and BARD1, along with destroying the polymerase, would prevent the aborted transcript from being processed. It is possible that the suppression of RNA processing is part of the destruction of the polymerase, or alternatively that the capped RNA at the site of the DNA lesion provides a signal in the repair pathway.
  • The Myc gene was originally identified in the avian myelocytomatosis virus.
  • Cancer and Genetics

    1. 1. The Genetics of Cancer
    2. 2. Newspapers, magazines, radio, and television are reporting discoveries and breakthroughs attributing one form of cancer or another to a specific gene. Cancer of the breast, colon, prostate, and many other sites in the body are being connected to specific genes... But the meaning of this isn't always clear. •What does it mean for you if your mother has or had breast cancer... or an aunt and two cousins have colon cancer? •What does it mean for your children if you've been diagnosed with cancer of the endocrine glands or some other organ? Cancer in the media
    3. 3. cancer is a disease of the cell cycle
    4. 4. Types of genes which may mutate to cause cancer: • Tumour suppressor genes • oncogenes • DNA repair genes • telomerase • p53
    5. 5. The environment: Some environmental agents associated with cancer are: • Viruses • Tobacco smoke • Food • Radiation • Chemicals • Pollution
    6. 6. Viruses Viruses—mostly in the form of DNA viruses—have been causally linked to cancer. • human papillomaviruses—primarily types 16 and 18, which are sexually transmitted—have been linked to cervical cancer; • more than 25 other types of papillomaviruses have been linked to cancer as well • hepatitis B and C—linked to cancer of the liver • human immunodeficiency virus (HIV)—linked to Kaposi's sarcoma and lymphoma • retroviruses—linked to cancers in animals other than humans
    7. 7. Tobacco smoke • is associated with 50% to 60% of all cancer deaths • is causally linked to cancers of the lung, upper respiratory tract, oesophagus, bladder, pancreas • is probably a cause of cancer of the stomach, liver, kidneys, colon, and rectum
    8. 8. Food • is connected to 50% to 60% of cancer deaths • is causally linked to cancers of the lung, upper respiratory tract, oesophagus, bladder, pancreas • is probably a cause of cancers of the stomach, liver, kidneys, colon, and rectum
    9. 9. Radiation • UVB from the sun can damage DNA and is associated with more than 90% of skin cancers, including melanomas • radon has been associated with lung cancer among those who work in mines; general levels of radon have not posed a significant cancer threat • electric and magnetic fields from power lines and household appliances have not been demonstrated contributors to the incidence of cancer or leukaemia • radio frequency electromagnetic radiation from mobile phones or microwave ovens has not been linked to cancer. • nuclear radiation is of sufficient energy to ionise molecules and is therefore carcinogenic.
    10. 10. Chemicals • benzene (myelogenous leukaemia) • arsenic containing pesticides (lung cancer) • polychlorinated biphenyls (liver and skin cancers) • mineral oils (skin cancer) • mineral fibres (lung cancer and mesothelioma) Chemicals, many of which have been historically linked to the workplace, have been successfully limited through public health efforts, because they have been associated with a variety of cancers. Examples of common chemicals that fall in this category are:
    11. 11. Pollution Pollution has been difficult to document as a contributor to human cancer. However, long-term exposure to high levels of air pollution may increase lung cancer risk by as much as 25%.
    12. 12. Cancer terminology Classification by tissue type: • carcinoma epithelial cell 90% of all tumours derived from ectoderm (mostly) or endoderm (some) • sarcoma connective tissue 2% of all tumours derived from mesoderm • leukaemia circulatory or lymphatic 8% of all tumours derived from mesoderm Classification by the type of cells: • Adenomatous cells ductal or glandular cells • Squamous cells flat cells • Myeloid blood cell • Lymphoid lymphocytes or macrophages
    13. 13. Cancer terminology Classification by the site of origin of the tumour: • Breast: carcinoma of ductal, medullary, papillary, etc. cells • Lung: small cell, bronchioloalveolar, squamous, large cell carcinomas • Bone: osteosarcoma, Ewing's sarcoma • Eye: retinoblastoma • Lip, tongue, mouth, nasal cavity: squamous cell carcinoma • Lymphocytes: acute lymphocytic leukaemia, chronic lymphocytic leukaemia, Hodgkin's lymphoma • Ovary: adenocarcinoma, choriocarcinoma, teratoma, Brenner tumour • Testis: seminoma, teratocarcinoma,
    14. 14. Cancer terminology Benign tumours • are generally slow growing and enclosed in a fibrous capsule • are relatively innocuous, although their location can make them serious (such as a tumour located in the brain) • are not considered cancerous (that is, they are not malignant) • are given names that usually end in "oma" (although a melanoma is a malignant skin cancer) Malignant tumours • proliferate rapidly, invading neighbouring tissues • can metastasise, or spread, to other sites of the body • are named using the conventions of tissue, cell type, and origin e.g. A tumour of the bone is an osteoma if benign and an osteosarcoma if malignant
    15. 15. Tumour suppressor genes • The gene’s normal function is to regulate cell division. Both alleles need to be mutated or removed in order to lose the gene activity. • The first mutation may be inherited or somatic. • The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area.
    16. 16. Knudsen’s “two hit” hypothesis
    17. 17. retinoblastoma
    18. 18. retinoblastoma • Retinoblastoma (RB) is a malignant tumor of the developing retina that occurs in children, usually before the age of five years. • All forms of retinoblastoma represent a mutation in the gene RB1 located in in the region 13q14.1-q14.2. • The gene is about 180 kb in length with 27 exons that code for a transcript of only 4.7 kb. • individual mutations are heterogeneous: 20% are deletions larger than 1kb; 30% are small deletions or insertions; 45% are point mutations. • mutations have been found in 25 of the 27 coding exons and in promoter elements. • Genotype-phenotype correlation: most mutant RB1-alleles show premature termination codons and are associated with almost complete penetrance (>95%) and high expressivity (more than 6 individual retinoblastoma foci per individual and, therefore, most often involvement of both eyes); some rare mutant alleles that code for proteins with retention of parts of the functions of the wild-type protein or that result in diminished amounts of wild- type transcript are associated with incomplete penetrance (<75%) and low expressivity (mean of less than 2 tumor foci)
    19. 19. RB1 • Is regulated by phosphorylation by Cdk2 • Hypophosphorylated form binds and sequesters E2F (and viral proteins such as E7 from human papilloma virus-16) • It also interacts directly with the product of the ABL gene and participates in several regulatory and feed back loops even involving its own transcription.
    20. 20. Breast Cancer “Why do so many of my relatives have breast cancer...is this just plain bad luck or what?”
    21. 21. breast cancer • her age, • family history, • age at which she began menstruating, • whether she has given birth and her age at the time of the first birth, and • whether or not a breast biopsy was performed in the past. Within the general population, there is an 11% chance that any woman will develop breast cancer over her lifetime. For any one individual, this risk may be increased or decreased by a variety of factors:
    22. 22. breast cancer
    23. 23. But its more complicated than that!
    24. 24. oncogenes • Cellular oncogene c-onc • Viral oncogene v-onc • Proto-oncogene, activated by mutation to c-onc
    25. 25. Proto-oncogene activation
    26. 26. Types of proto-oncogene • Growth factor e.g. SIS oncogene (PDGF)
    27. 27. Types of proto-oncogene • Growth factor receptor e.g. tyrosine kinase receptors
    28. 28. Types of proto-oncogene • G proteins e.g. ras
    29. 29. Types of proto-oncogene • Nuclear transcription factors e.g. MYC
    30. 30. p53 • suppresses progression through the cell cycle in response to DNA damage • initiates apoptosis if the damage to the cell is severe • acts as a tumour suppressor • is a transcription factor and once activated, it represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control
    31. 31. Transformation is a multistep process
    32. 32. Transformation is a multistep process
    33. 33. Colorectal Cancer • 11% of cancer- related deaths • Tumor progression may take 10-35 years • Adenomatous polyp develops into carcinoma
    34. 34. Chromosome changes in colorectal cancer Cancer karyotype Stable karyotype
    35. 35. reading URLs: • http://www.infobiogen.fr/services/chromcancer/Kprones/RbKprID10031.html • http://cgap.nci.nih.gov/ • http://www.intouchlive.com/home/frames.htm?http://www.intouchlive.com/cancergene • http://bioinformatics.weizmann.ac.il/hotmolecbase/entries/p53.htm Books: • Concepts of Genetics, Klug and Cummings, chapter 23 • Molecular Biology of the Cell

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