Fundamental Topics in Biology: Cancer 1 PDF

Fundamental Topics in Biology LECTURE BLOCK: Ageing and Disease Cancer 1 Resources: Fundamental Topics in Biology Reading List Dr Pam Scott [email protected]  Fundamental Topics in Biology: Cancer Cancer 1 in...

Fundamental Topics in Biology LECTURE BLOCK: Ageing and Disease Cancer 1 Resources: Fundamental Topics in Biology Reading List Dr Pam Scott [email protected]  Fundamental Topics in Biology: Cancer Cancer 1 includes: Cancer 2 includes:  Cancer Statistics  Hallmarks of  Increases with Age Cancer  What is cancer?  Cancer treatment  Factors contributing to cancer  Mutations and Cancer  Fundamental Topics in Biology: Cancer 1 The aims of the todays lecture:  Understand that cancer is a genetic disease, occurring mainly in the elderly population.  Outline the role of proto-oncogenes and tumour suppressor genes.  Explain why some cancers, for example, retinoblastoma, occur in children Cancer Research at University of Glasgow https://www.beatson.gla.ac.uk/ https://www.gla.ac.uk/schools/cancersciences/ research/units/ https://www.gla.ac.uk/schools/cancersciences/research/ units/paulogormanleukaemiaresearchcentre/ What is Cancer? Cancer is when abnormal cells divide in an uncontrolled way. Some cancers may eventually invade surrounding tissues. All cancers are genetic diseases. https://www.dnalc.org/view/15536-Cell-division-tumor-growth-and-metastasis-3D-animation-with- basic-narration.html  Cancer Statistics: Incidence https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence  Cancer Statistics: Incidence Not one but a large number of different diseases https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared Cancer Incidence Increases with Age https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age#heading-Zero Cancer is a Genetic Disease  Susceptibility to some cancers is familial = GENETIC  Common MUTATIONS found in cancers  Mutagens are also carcinogens  Incidence rate: consistent with 5-6 independent mutations required  Development is multi- stage: eg colon cancer Cancer is a Genetic Disease Germline v Somatic Mutations? Germline mutations Somatic mutations Parent Child Mutation in All cells Somatic egg or affected in mutation (eg, sperm offspring breast) Present in egg or sperm Occur in non-germline Are heritable tissues Cause cancer family Are nonheritable syndromes  Regulators of Poliferation (as an example of a Hallmark of cancer) Some genes encode proteins that STIMULATE cell proliferation: - accelerator in a car: PROTO-ONCOGENES Some genes encode proteins that PREVENT cell proliferation: - brake in a car: TUMOUR SUPRESSOR GENES  Question….. Some genes encode proteins that STIMULATE cell proliferation: - accelerator in a car: PROTO-ONCOGENES Some genes encode proteins that PREVENT cell proliferation: - brake in a car: TUMOUR SUPRESSOR GENES Predict the nature of the CANCER-CAUSING/PREDISPOSING mutations: Gain-of-function or loss-of-function? Dominant or recessive?  Oncogenes Proto-oncogenes: normal cellular genes usually involved in cell growth and/or cell division Cancer Oncogenes: a proto-oncogene that has been activated by mutation or overexpression. Results in a dominant gain of function phenotype. Only one copy to be mutated.  1. Point Mutations Point mutations can convert proto-oncogenes into oncogenes. Proto-oncogene Deletion or point mutation in coding sequence DNA RNA Hyperactive protein made in normal amounts https://www.cancer.gov/research/key-initiatives/ras/about  2. Gene Amplification Gene amplification can convert proto-oncogenes into oncogenes. Proto-oncogene Deletion or Gene point mutation Amplification in coding sequence DNA RNA Hyperactive protein Normal protein greatly overproduced made in normal amounts  3. Chromosomal Rearrangement Chromosomal rearrangement can convert proto-oncogenes into oncogenes. Proto-oncogene Deletion or Gene Chromosome point mutation Amplification Rearrangement in coding sequence or DNA RNA Regulatory Fusion greatly Hyperactive protein Normal protein greatly overproduced sequence causes overproduces made in normal overproduction of fusion protein. amounts normal protein  Oncogenes Number ~250: Only a subset mutated in any given cancer type or individual tumour Category Example Gene Function Growth factor PDGF (platelet-derived growth Induces cell proliferation factor) Receptor tyrosine kinases EGFR (epidermal growth factor Transduce signals for cell receptor) proliferation Signal-transducing proteins Ras Involved in signalling Transcription factors Myc Regulate transcription of genes that induce cell proliferation  Loss of a Tumour Suppressor Gene Some genes encode proteins that PREVENT cell proliferation: - brake in a car: TUMOUR SUPRESSOR GENES Normal gene needed to prevent inappropriate proliferation MUTATION must be LOSS-OF-FUNCTION RECESSIVE Need BOTH copies to be MUTATED Tumour suppressor gene Loss of a gene that normally suppresses or controls cell division Cancer Loss of function: Normally these genes suppress cell division A mutation causes them to lose their function Loss of a Tumour Suppressor Gene: two chance events Most cancers result from mutations in cellular genes. Two types of cancer: - Sporadic more frequent, no hereditary cause - Familial less frequent, hereditary KNUDSON’s TWO HIT HYPOTHESIS  Retinoblastoma LOSS of a single gene – retinoblastoma (Rb) – is a key step in developing a tumour of the retina (Note: Rb mutations are not sufficient but….)  Two-Hit Mutation Model (Retinoblastoma) Sporadic retinoblastoma: 60% of retinoblastoma cases Develops in children with no family history Occurs in one eye WHY? Hereditary retinoblastoma: 40% of retinoblastoma cases Onset typically earlier than sporadic cases Multiple tumours involving both eyes Consistent pedigrees; siblings and offspring develop the same type of tumours Sporadic & Familial (Mendelian) forms of Cancer Knudson’s two-hit hypothesis Sporadic Normal tumour suppressor gene Somatic mutation in one allele Somatic mutation in other allele Single tumours, unilateral, later-onset Two mutations (two-hits) are required for loss of tumour suppressor function Sporadic & Familial (Mendelian) forms of Cancer Knudson’s two-hit hypothesis Tumour suppressor gene Familial containing a germline mutation in one allele – heterozygous for the mutation Somatic mutation in other allele Multiple tumours, bilateral, early-onset Two mutations (two-hits) are required for loss of tumour suppressor function The first “hit” is inherited & the second “hit” is somatic NOTE: homozygous Rb mutants – embryonic lethal Rb – a brake on the G1/S checkpoint Rb p p Rb The key decision point: PROLIFERATION OR NOT? Rb – Functions during the Cell Cycle Non-phosphorylated Rb Bound to E2F p Rb Phosphorylation of Rb Phosphorylated Rb p Rb releases E2F E2F E2F E2F migrates to the E2F nucleus to induce Nucleus transcription Proteins required for cell cycle progression  p53 – The Guardian of the Genome p53 is a transcription factor that regulates the cell cycle, DNA repair and apoptosis Is a tumour suppressor gene Mutations in p53 are implicated in ~50% of human cancers, including cancers of the breast, lung, colorectal and stomach.  Tumour suppressor gene Normal cell cycle-inhibiting pathway – response to DNA damage Tumour suppressors function in many key cellular processes including the regulation of transcription, DNA repair and cell:cell communication. The loss of function of these genes leads to abnormal cellular behaviour.  Tumour suppressor gene Mutant cell cycle-inhibiting pathway – absence of p53  Breast Cancer https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ breast-cancer#heading-Zero  Breast Cancer breast cancer occurs in the cells that line the lobules that manufacture milk or more commonly in the ducts that carry it to the nipple. http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-what- is-breast-cancer  BRCA1 and Breast Cancer Most hereditary cases caused by a BRCA1 or BRCA2 mutation Other genes BRCA1 BRCA2 7-10% Sporadic Hereditar y Loss-of-function allele carried by 1% of the population A TUMOUR SUPPRESSOR AJHG 1998;62:676-89 JCO 2002;20:1480-1490 BRCA1/2 Mutations Increase the Risk of Early-Onset Breast Cancer By age 40 By age 50 By age 70 Population Risk 0.5% 2% 7% Hereditary Risk 10%-20% 33%-50% 56%-87% BRCA1/2 Mutations Increase the Risk of Early-Onset Breast Cancer SPORADIC breast cancer: Older women One tumour One breast (unilateral) FAMILIAL (BRCA1 mutation: heterozygous) Younger women Often multiple tumours Often affects both breasts (bilateral) Similar logic and reasoning for Retinoblastoma tumours in the eyes  BRCA1 Function BRCA1 protein REQUIRED for normal DNA repair Loss-of-function: ( up to ~300,000 mutations per cell division) BRCA1 Mutations in BRCA1 BRCA2 or BRCA2 Accumulation of mutations CANCER  Study Questions.... 1. Why is cancer is normally associated with the elderly population? 2. Why do some cancers, eg familial retinoblastoma, occur in children? 3. What is a proto-oncogene? What role do mutated proto- oncogenes have in cancer? 4. What are the roles of tumour suppressor genes and provide an example? 5. How can a loss-of-function mutation in BRCA1/2 lead to cancer development?