Week 10: Genes and Cancer PDF

1/29/2025 Week 10 Genes and Cancer based on eBook Chapter 10 What is Cancer? A phenotype produced by the environment and a person’s genotype Group of diseases affecting many different cells and tissues in the body Tw...

1/29/2025 Week 10 Genes and Cancer based on eBook Chapter 10 What is Cancer? A phenotype produced by the environment and a person’s genotype Group of diseases affecting many different cells and tissues in the body Two main characteristics: 1 – Uncontrolled cell division 2 – Ability of cells to spread (metastasis)  1/29/2025 What is Cancer? Improvements in medical treatments have increased life expectancy Also increased risk of cancer 1/2 men and 1/3 women will be diagnosed in Aus 30% of deaths in Australia Major cause of death in developed countries Age is the biggest risk factor Risk of developing cancer increases with age Early diagnosis leads to better treatment and outcomes  1/29/2025 What causes Cancer? Several different causes: 1 – Genetic predisposition 2 – Mutagenic chemicals 3 – Some viruses 4 – Chromosomal changes 5 – Environmental factors 6 – Time Mutation is the starting point for all cancers Most cancers are sporadic Accumulation of mutations over time Environmental factors can speed things up >2 mutations required  1/29/2025 Some cancers are familial Some cancers run in families These have helped identify cancer genes Inherit one mutated gene, then normal gene mutates too - Loss of Heterozygosity (LOH) Other mutations are normally also needed Sporadic vs Familial Sporadic Mutation Mutation Two normal copies One copy mutated Second copy mutated Familial Mutation One copy mutated Second copy mutated at birth  1/29/2025 Inheritable susceptibilities Disorder Gene Chromosome OMIM Early onset familial breast cancer BRCA1 17q21.3 113705 Familial adenomatous polyposis FAP1 5q22.2 175100 Lynch Syndrome I MSH2 2p21 120435 Li-Fraumeni Syndrome LFS1 17p13.1 151623 Multiple endocrine neoplasia I MEN1 11q13.1 131100 Multiple endocrine neoplasia IIA MEN2A 10q11.2 171400 Neurofibromatous type I NF1 17q11.2 162200 Neurofibromatous type 2 NF2 22q12.2 101000 Retinoblastoma RB1 13q14.2 180200 Von Hippel-Lindau disease VHL 3p25.3 193300 Wilms tumour WT1 11p13 194070 Progression of Cancer All cancers start in a single cell Mutations accumulate over time, until eventually it becomes cancerous Once formed cancer cells divide continuously Further mutations accumulate and the cancer may become more aggressive Cancer cells become invasive and can colonise new areas  1/29/2025 Types of Cancer Carcinoma – skin or tissues that line our internal organs Sarcoma – connective or supportive tissue Leukaemia – blood and blood-related cells Lymphoma and myeloma – immune system Brain and spinal cord – central nervous system Also classified by location Some mutations disrupt the cell cycle Many cancers start in epithelial cells They are constantly being renewed Mutations alter the cell cycle controls Uncontrolled cell division  cancer  1/29/2025 G1/S Checkpoint Cell proceeds to S The Cell Cycle phase or enters inactive G0 state G1 Interval of cell growth before DNA replication S (chromosomes Interval of cell unduplicated) growth when DNA replication is Each daughter cell completed starts interphase (chromosomes duplicated) M Checkpoint G2 Cell monitors Interval following attachment of DNA replication; spindle fibers to cell prepares to chromosomes divide G2/M Checkpoint Cell monitors completion of DNA synthesis and DNA damage Cell Cycle Checkpoints G1/S Checkpoint Primary checkpoint Cell either enters S phase or enters a non-dividing state (G0) Checks internal and external conditions are ok – size, nutrients, growth factors, DNA quality  1/29/2025 Cell Cycle Checkpoints G2/M Checkpoint Checks that all DNA has been copied and any mistakes have been repaired Pauses here to repair damage Apoptosis (cell death) if unfixed Cell Cycle Checkpoints M Checkpoint Checks that chromosomes lined up across the cell Checks that chromosomes are attached to spindle fibres from each end of the cell Apoptosis if not corrected  1/29/2025 Cell Cycle Checkpoints Help to prevent passing down damaged DNA Checkpoint regulation genes Tumour-suppressor genes Genes that decrease or stop cell division Mainly work in G1/S or G2/M Mutations result in uncontrolled division Proto-oncogenes Start or maintain cell growth/division Drive cell division in response to signals received In cancer these are normally permanently switched on - oncogenes  1/29/2025 Tumour-suppressor genes Retinoblastoma Retinoblastoma 1 (RB1) is a tumour-supressor gene Change of activity can result in retinal, bone, lung and bladder cancer Retinoblastoma affects the eye’s retina Familial (usually both eyes) or sporadic (single eye) Most commonly diagnosed in children 1-3 years old  1/29/2025 Familial vs Sporadic Retinoblastoma Retinoblastoma RB1 is on chromosome 13q1 Codes for a protein called pRB, which binds the transcription factor E2F RB1 on at G1/S  pRB produced and binds to E2F  Stops cells moving through the cycle RB1 off at G1/S  pRB not produced to bind E2F  Genes switched on and cell progresses  1/29/2025 Role of RB1 pRB Active pRB Inactive pRB binds pRB pRB P pRB P to E2F cannot bind E2F E2F E2F cannot bind E2F free to bind to promoters promoters E2F Promoter No gene expression Gene expression Cell remains in G0 phase Cell moves into S phase Proto-oncogenes Switch on or maintain cell division Many mutations can result in changes to an oncogene  1/29/2025 Ras proto-oncogenes Family of proto-oncogenes that code for signal transducers – relay messages ras protein at the cell surface, switched on by growth factors A single base mutation at one of two sites can cause cancer Ras mutations GGC CAA val arg CGA GTC  1/29/2025 Ras mutations DNA repair and genome stability All cancers result in some form of genomic instability Aneuploidy, loss of chromosomes, duplications, deletions, inversions, etc Result from a loss of the ability to repair damage Progressive over the life of the cancer  1/29/2025 DNA damage Many different ways to damage DNA All generally cleared up quickly DNA repair problems Damaged DNA repair genes lead the cell towards cancer  1/29/2025 Breast Cancer and DNA repair Mutations in the BRCA1 or BRCA2 genes ~85% lifetime risk of breast cancer in females, 7% in males Also increased risk of ovarian cancer in females and prostate cancer in males BRCA1 and BRCA2 are DNA repair genes Both are tumour-suppressor genes Both genes encode nuclear proteins (work within the nucleus) Detect DNA damage at checkpoints and repair double strand breaks  1/29/2025 BRCA1 DNA repair mechanism Histones close to break become phosphorylated Other regulatory molecules add ubiquitin to nearby histones Modifications signal to Rap80 Recruits BRCA1 to site of damage BRCA1 stops cell cycle and fixes DNA Mutated BRCA1 cannot bind Rap80 BRCA2 DNA repair mechanism Break is detected and enzymes are drawn to the site Digest a bit from each strand leaving ssDNA ends BRCA2 binds to Rad51 and takes it to the ssDNA Coats ssDNA with Rad51 proteins BRCA2 helps align damaged DNA to homologous chromosome for repair  1/29/2025 BRCA-related Genome Instability Normal cell karyotype BRCA-mutation cancer cell karyotype BRCA mutations Accounts for 15-20% of hereditary breast cancers Only 5-10% of breast cancers overall Cancer type Normal risk BRCA1 BRCA2 mutation mutation Breast - women 12% 65% 45% Ovarian 1.3% 39% 15% Prostate 14% 25% 65% Breast - men 0.01% 1% 6%  1/29/2025 The pathway to Colon Cancer >6 mutations required to form cancer Genetic and environmental factors Mostly sporadic, ~5% inherited Autosomal Dominant inheritance Familial Adenomatous Polyposis (FAP) Hereditary Nonpolyposis Colon Cancer (HNPCC) Familial Adenomatous Polyposis (FAP) Accounts for ~1% of all colon cancers 100% lifetime risk of developing colon cancer Associated with chromosomal instability Requires 5-7 mutations Order of mutations is important also  1/29/2025 Familial Adenomatous Polyposis (FAP) Multiple polyps start to grow in the large intestine in the teenage years Number of polyps increases with age If not removed polyps become cancerous Average age of cancer diagnosis – 39 Familial Adenomatous Polyposis (FAP) Inherit one copy of mutated APC gene APC is a tumour-suppressor gene Cells partially evade cell cycle controls Many polyps develop, each a clone Normal Colon FAP colon  1/29/2025 Familial Adenomatous Polyposis (FAP) APC mutations alone are not enough Mutations to one copy of the K-RAS gene (proto-oncogene) Turns the polyps into adenomas – non-cancerous Mutations in further genes push the adenomas to develop finger-like growths p53 mutations finally make the cells cancerous Later mutations allow the cancer to move and colonise other areas FAP Progression 1. Mutation to APC 2. Mutation to K-RAS 3. Loss/mutation of other genes 4. Loss of function of p53 Chromosome 5q 12p 18q 17p Other Alteration Mutation Mutation Deletion Deletion Mutations Gene APC K-RAS DCC p53 Normal Polyp Intermediate Late Colon Metastatic colon adenoma adenoma cancer cancer epithelium with villi  1/29/2025 Hereditary Nonpolyposis Colon Cancer Mutations in 7 different genes lead to HNPCC Mutations in MSH2 and MLH1 cause 90% Both are DNA repair genes Hereditary Nonpolyposis Colon Cancer Mutation carriers have a 70-90% lifetime cancer risk Average age of diagnosis – 40-50years Not associated with polyp formation Genetic screening of family members Yearly colonoscopy from age 20 Increased risk of other cancers – stomach, pancreas, endometrial and ovarian  1/29/2025 Hereditary Nonpolyposis Colon Cancer Faulty DNA repair genes causes destabilization of the DNA Result in large-scale changes to repetitive DNA regions – microsatellites 2-6bp sequence, repeated in tandem Repeat number can differ on chromosome pairs Do not code for proteins Highly mutable AATC AATC AATC AATC AATC AATC AATC AATC AATC Hereditary Nonpolyposis Colon Cancer Damage to DNA repair genes increases mutation rate in microsatellites Change number of copies as well as sequence Creates instability in the genome Increased mutation of nearby genes - APC  1/29/2025 Chromosomal re-arrangement and cancer Several cancers are associated with translocations Chronic Myelogenous Leukaemia (CML) Translocation between chr9 and chr22 Philadelphia chromosome  1/29/2025 Chronic Myelogenous Leukaemia (CML) Disrupts two genes C-ABL and BCR C-ABL cell signaling, DNA damage response, apoptosis BCR turns genes on and off Hybrid gene leads to uncontrolled cell division Cancer is a Genomic disease Accumulation of mutations throughout the genome DNA sequencing, family studies, GWAS are helping identify cancer-causing changes Aim to develop a catalog of cancer mutations  1/29/2025 Better identification of cancer genes Genes in normal tissue can be compared to genes in cancerous tissue Identifies which mutations have occurred One study of 13,000 genes showed an average of 90 differences Different types of mutations identified in breast and colon cancer Disease-specific tumours showed different mutations Cancer gene mutations 100 KEY 90 Breast cancers Colon cancers 80 70 Percent of tumors with mutation 60 50 40 30 20 10 0  1/29/2025 Epigenetics and cancer DNA and histone modifications can lead to cancer Epigenetics and cancer Allows cells to proceed through the cell cycle uncontrolled or with damaged DNA Mutations and cells increase --- cancer  1/29/2025 Historical cancer therapy Chemotherapy or radiation used in the past Non-specific – other cells may be affected Unpleasant side-effects Chemotherapy Anti-cancer drugs to destroy cancer cells Injection, oral or cream application Given for several reasons – cure, relapse reduction, tumour shrinking Lots of different side effects possible, often transient  1/29/2025 Radiation therapy X-rays used to prevent cancer cells from multiplying External or internal Treatment times vary Given for several reasons – cure, tumour shrinking, prevention of metastasis, assist other treatments Side effects related to the area of the tumour Hormone therapy Some cancers are hormone-dependent Slow the growth of hormone receptor positive cells Tablets or injections Sometimes surgery also required Side effects are often milder, but can be permanent  1/29/2025 Immunotherapy Helping the immune system fight cancer Checkpoint inhibitors – allow T-cells to recognise cancer cells Immune stimulants – reawaken the immune system CAR T-cell therapy – T-cell training Oncolytic virus therapy – viruses infect the cancer cells Targeted therapy Affects only cancer cells Small molecular inhibitors – drugs that enter the cell Monoclonal antibodies – designed to cell surface markers  1/29/2025 Targeted cancer therapy Personalised medicine is the goal Targeted therapy for CML BCR-ABL hybrid gene produces a new protein Protein binds ATP Gleevec mimics ATP and binds to BCR-ABL preventing cell division Gleevec  1/29/2025 Zero Childhood Cancer Commenced with a National clinical trial in 2017 Specifically for children with high-risk cancer Identify minute information about each tumour 70% showed improvement Now expanded to all children in Australia (0-18) Environmental effects on cancer Viruses, chemicals, radiation, diet, smoking, sun exposure, etc can all damage DNA  1/29/2025 Viruses and cancer 15% of cancer associated with viruses HPV16 and HPV18 can cause cervical cancer Viral E7 protein blocks pRB –  cell division Other environmental agents - smoking 75-85% of smokers develop cancer, 20% total cancer Most cancers have low survival rates Passive smoking, snuff and chewing tobacco also increase cancer risk  1/29/2025 Other environmental agents - sun Sunlight or tanning beds – 95-99% of skin cancers 2 in 3 Australians will develop skin cancer More likely to develop cancer with fair skin UV light causes mutations in the DNA Reducing your risks