Genetics Flipped lesson 10.PDF

Genetics Flipped lesson 10 – Cancer and Genomic Medicine Cancer Terms - Neoplasm is an abnormal mass of tissue unresponsive to normal growth controls - Neoplastic cells have clonally expanded as a result of somatic mutation (somatic mutation – one that occurs at some point during the life of that ce...

Genetics Flipped lesson 10 – Cancer and Genomic Medicine Cancer Terms - Neoplasm is an abnormal mass of tissue unresponsive to normal growth controls - Neoplastic cells have clonally expanded as a result of somatic mutation (somatic mutation – one that occurs at some point during the life of that cell – not heritable) - Benign – uncontrolled growth of tumour, but cannot metastasize - Malignant tumour (cancer) cells have acquired ability to metastasise (seed other places - spread) Cell Growth/Division (Cancer is closely linked to the cell cycle – most cancers have inactivating mutations in one or more proteins that normally function to restrict progression through the G1 stage of the cell cycle. Virtually all human tumours have inactivating mutations in proteins such as P53 that normally function at crucial cell cycle checkpoints, stopping the cycle if a previous step has occurred incorrectly, or if DNA has been damaged. The categories of these proteins are growth factors, growth factor receptors, signal transduction proteins, transcription factors and cell cycle control proteins) Hallmarks of Cancer (Cancer is a progressive pathology – doesn’t happen overnight. Changes accumulate in cancer cell – hallmarks) Some Cancer Related Genes - Protooncogene (Oncogene(- a proto-oncogene that has mutated to become tumoragenic)) – the accelerator: spped up cancer process - Genes typically involved in growth, proliferation, cell cycle o Tyrosine kinases (Src, ABL) o Growth factors (PDGF-B), o Receptor tyrosine kinases (ERBB2, EGFR, HER2/neu) o Intracellular signalling cascade components (Ras) o Cell cycle regulators (Myc) Some Cancer Related Genes - Tumour Suppressor Genes (TSG) – the brakes: slow down progression - “gatekeeper genes” (e.g. APC, RB1) o inhibit tumour growth, proliferation or cell cycle progression - “caretaker genes” (stability genes e.g. MLH1, MSH2) o stabilise the genome (provide mutational (DNA repair) or chromosomal stability) Protooncogene – Oncogene - Oncogene – a gene that when expressed confers resistance to programmed cell death (accelerates progression) - Proto-oncogene – can become an oncogene following: o point mutation o chromosomal translocation o increase in gene expression (e.g. change in promoter) - Change in just one of the two alleles (of a proto-oncogene to turn it into an oncogene) may result in malignant transformation e.g. epidermal growth factor (EGFR) - Dominant activating/hypermorphic (gain of function) mutation Tumour Suppressor Genes - Products of this family of genes regulate cell cycle or direct cells towards apoptosis – code for: 1. Proteins that repress expression of genes essential for continuation of cell cycle 2. Proteins that prevent cell cycle progression in presence of damaged DNA 3. Proteins that promote apoptosis if DNA is damaged 4. Proteins that promote cell adhesion (prevent metastasis) 5. Proteins involved in DNA repair (BRCA) Tumour Suppressor Genes - Typically need change in both alleles for malignant transformation - Recessive amorph/hypomorphic (loss of function) mutations - Knudson’s two-hit hypothesis: (how tumour suppressor genes are “knocked out” during cancer formation) The Big TS Gene: TP53 - Protein - p53 Gene is TP53 on Ch17 (17p13.1) 393 amino acids Activity depends on forming a tetramer Multiple tumour suppressor functions – growth arrest, apoptosis, DNA repair Hereditary mutation - Li-Fraumeni Syndrome The Big TS Gene : TP53 Mutations Vogelstein’s Tumour Progression Model Breast Cancer - Most common ♀ non-skin malignancy - About 3000 cases/year in Ireland - Life time risk (increased risk with age) o 1/15,000 - 25 o 1/200 - 40 o 1/23 - 60 o 1/11 – 80 - Molecular progression of BC is complex - Different subtypes arising from different pathways - Do men get BC? Yes, but rare (1/1000), <1% of all BC Sporadic Breast Cancer - Majority of BC is sporadic - Risk factors: o Female gender o Oestrogen exposure o Age of menarche/menopause (<12/>55) o Reproductive Hx o Exposure to exogenous oestrogens o Alcohol, obesity, radiation exposure - Family Hx of breast cancer not synonymous with hereditary BC - 13% women have family Hx of BC – most do NOT get BC Common Mechanisms of Genetic Change in Breast Cancer 1. Amplification of DNA sequences 2. Changes in chromosome number (aneuploidy) 3. Epigenetic modification 4. Point Mutations 5. Changes in Micro-RNA regulation 1. Amplification – commonly of oncogenes - Increase in gene copy number - Results in over-expression of proteins - Up to 24 ‘amplicons’ (tandemly repeated copies) in Invasive Breast Cancer - Many genes amplified simultaneously - 17q12-22 (“HER2 amplicon”) contains HER2 and Top2A 2. Changes in Chromosome Number - Common - Advanced tumours - Significance uncertain 3. Epigenetic modification - Common mechanism of genetic change - Reversible - Methylation of DNA and histone acetylation - Regulates expression of many genes e.g. ER, PR, p16, p21, BRCA1 4. Point Mutations - E-cadherin (CDH1) mutated in lobular carcinomas (putative TSG) - Discrete point Mutations are more common in hereditary breast cancer: - BRCA1 and BRCA2 o TSGs, transcriptional regulation, repair of double strand breaks - TP53 o TSG, ‘guardian of genome’ o Mutated in more than 50% of breast cancers - Checkpoint Kinase 2 - CHEK2 o Cell cycle TSG - DNA repair & cell cycle arrest 5. micro-RNAs - Non-coding ss RNA - Contribute to Post-transcriptional gene silencing by binding to mRNA - Altered in breast cancer by e.g. amplification, deletion - Affect expression of many gene products o e.g. ER, p27, Bcl-2 Chromosomal translocations in Cancer - Can create chimeric oncogenes (neomorphic) - E.g. Philadelphia chr (Ph1: (t9;22)) – BCR-ABL in CML o Constitutively active ABL tyrosine kinase - growth signal - E.g. PML-RARa fusion (t15;17) in APML (pictured) o Blocks PML TSG function and retinoic acid induced myeloid differentiation - Can also transcriptionally up-regulate oncogenes - E.g. MYC oncogene in Burkitt Lymphoma (t8;14) or occasionally (t8;2, t8;22) o MYC oncogene moved to IGH (Ig heavy chain) region (Chr 14) o MYC overexpression in lymphocytes (high expression from IGH promoter) o Constitutive B-lymphocyte activation – characteristic lymphoma tumour in jaw Things to Remember 1. Oncogenes develop from protooncogenes through so called “hypermorphic” mutations that result in a gain of function 2. Tumour suppressor genes: Genes that are relevant for the regulation of growth, repair, and cell survival, with malignant transformation supported through (recessive) loss-of-function mutations on both copies of the gene. They typically include DNA repair genes that are responsible for detecting and repairing genetic damage within a cell. 3. Knudson’s wo-hit hypothesis of cancer development: Cancer development involves two successive mutations that affect the two alleles of a tumour suppressor gene. In familial cancer disposition syndromes, a mutation on one allele is inherited, and only one additional hit is required for cancer development. 4. A family history of a common cancer is not a reliable indication of genetic predisposition to cancer 5. There are various mechanisms for the “2nd hit” to occur in cancer, including mutation, amplification, chromosomal rearrangement, epigenetic changes and loss of heterozygosity Question: Knudson's 2 hit hypothesis states that: - Cancer development involves dysregulation of growth signals in 2 cells in the same tissue - Cancer development involves 2 successive mutations affecting the two alleles of an oncogene in the same cell - Cancer development involves simultaneous mutations affecting an oncogene and a TSG in the same cell - Cancer development involves 2 successive mutations affecting the 2 alleles of a TSG in the same cell