Cancer Epidemiology PDF

 CANCER EPIDEMIOLOGUE CARCINOGENESIS : Epidemiology Study : of the distribution and patterns of disease -...

 CANCER EPIDEMIOLOGUE CARCINOGENESIS : Epidemiology Study : of the distribution and patterns of disease - w/ their causes within populations. along , ↳ cornerstone of public health research + informs policy decisions. ↳ informs evidence-based medicine through id. risk factors + targets for preventive medicine. can allow id of causes complex though. - -. · relies on systematic + unbaised approach to data collection. · concerned we frequency & pattern of disease. o used for search of determinants (causes). v large databases prod. complex analytical statistical ·. + + methods used to process data. ↳ data available Much of publically Most common cancers : (word Top 5 causes of death : 1) Lung 1) Lung 2) Breast 2) Liver 3) colorectum 1) colorectum 4) Prostate 4) Breast 5) Stomach 5) stomach. TOP 5 in the UK : Top 5 most common deaths : 1) Breast 1) Lung 2) Prostate 2) Bowel 3) 3) Prostate Lung u) Bone 4) Breast st Melanomaskin cancer. 5) Pancreas.  consider w/ incidence things to : detection more detection. + reporting more test · - = · Risk factors/cause - may differ by region e.. g things to conside w/mortality : availability of health Screening + · detection resources early - availability of effective · treatment Exp to risk factors ·.. INCIDENCE & DEATHS : deaths. these data shown side could study · incidence side · or by · related but tells us different things. commonly. Incidence : of disease prevalence ~ tells us about levels dependent · also on detection. Eg. : screening for early disease may a incidence statistics - but w/effective treatment =>↓ deaths. · TOP 5 in the UK : Top 5 most common deaths : 1) Breast 1) Lung 2) Prostate 2) Bowel 3) 3) Prostate Lung u) Bone 4) Breast st Melanomaskin cancer. 5) Pancreas. to changes in chart positions reflects relative survival chances for patients w/ dif. types of cancer. Relative Survival chances : measured as 1 5 and 10 years survival - , · (i. e. % Of patients arive still I , 5 or 10 years after diagnosis. ) for of often 1 Survival varies greatly between diff. types of cancer a no. inc complex reasons stage at detection at efficiency of current -. treatments. 10 these rates are what Clinicians + researchers to improve. working Epidemological data has allowed to see that : J to UK cancer incidence is a steadily. to predicted to continue rising. age standardised rates. 1 But :. mortality ↓ · Worldwide predicted Age factor a larger + is is defo. a in Cancer risk. AGE as a RISK Of CANCER : CHILDHOOD : Small numbers of tumour types occur in , mainly embryonal tissues (blastomas) + Leukaemias. YOUNG ADULTS : tumours uncommon , main of bone , Lymphoma germ cell tumours. MIDDLE TO OLD AGE : ↑ Incidence of epithelial neoplasms. Lo = ) of accumulating genetic changes rea. for 'multi-step causation of neoplasia  COLORECTAL CANCER : CAUses/RISKS : - many factors interplay to influence risk - isolating 1 is tricky · age · diet rich in fat and low in fibre · history of inflammatory bores disease hereditary predisposition · · familial historial of bowel cancer also strong risk factor + presence of polyps. · studies indic. diet as a key cause : -v. hard to conduct as so many facets to diet + lifestyle that interplay (tre + fre) to alter cancer risk. EPIC study : · European Prospective Investigation into Cancer and Nutrition. ↳ 23 centres in 10 European countries - 521k ppts. ↳ ppI. recruited from 1992-1999 and studied since then. ↳ > 67k developed cancer. ↳ have been able to corroborate findings of smaller studies to make new discoveries. t %:. findings from Epic + infl. WHO's decision to make processed meet as class human carcinogen. Lo study expanded to look at other aspects of disease - e.g cardio - vascular disease.  LUNG CANCER : · incidence 4 in women-but ↓ similar rate smoking rate to males ↑ rates seen in the oldest age groups + relates to carcinogen > - exposure in earlier life , before smoking rates were much lower. CARVICAL CANCER : > Australia aims by 2035 W/UK following to eliminate and globally by - 2100. ↑ detection of (in disease) reflects pre-malignant Situ · stage the significant↓ in disease deaths. Lo CV Cancer is entirely preventable disease success of cancer screening - and prevention. · Although overall ↓ in incidence + mortality - can be a disease of younger women. ↳ Last 20 years ↑ : rate in women < 35.  CARCINOGENESIS : CARCINOGEN : Substance capable of causing cancer in living tissue'. Coin 3-step model : Subs that can cause initiation and/or propagation]. Initiation - Propagation - Progression. Lo different types + classified into groups depending on their likelihood of causing cancer. to can be : physical , chemical , biological > classification depends on the - weight of evidence that can - show something to be defo. , probably or possibly causing cancer. > X mean al in the same category - have same carcinogenic dency 16 main categories : I for each 3 categories. 1) Chemical carcinogens 2) Dietary factors -Chemical 3) Biological u) viruses & Biological 5) Physical 6) Exposure J Physical to imising radiation CHEMICAL: Lo many id. by exposing animals to the agents. lo many of them work by causing damage to DNA in cells. Source Associated Tumour Type : : Polycyclic Tars , cigarette smake , Skin + Lung Cancer. hydrocarbons BBQ'd food. Aromatic Rubber -Dye industry + , Bladder Cancer & others amines cooked Meat Stomach Colorectal Diet (smoked meats) + Nitrosamines Tobacco , cancer. Vinyl Chloride manufacture , food-packaging angiosarcoma of liver Alkalyting Mustard gas chemoth ( ??) ,. - agents Dietary Factors proving links is dif cult They have diverse modes of action - depends on their chemical nature Some examples: To understand links - need to understand what is meant by risk. Move by WHO/IARC classifying red meat as class 1 carcinogen Simply re ected the weight of evidence to show there is a de nite link with cancer risk Biological Carcinogens several viruses known to increase risk of certain cancers Molecular mechanism by which viruses cause neoplastic transformation vary Example; ○ Human papilloma virus (HPV) known to cause ~90% of cervical cancers ○ HPV produces proteins - E6 + E7- that inactivate the protein products of tumour suppressor genes ○ This allows cells to escape normal cell cycle regulation ○ Screening for CV cancer now focuses on detection of HPV ○ A HPV vaccine has been in widespread in UK - 2008 fl fi Several viruses known to increase risk of certain cancers no. of biological molecules - e.g hormones and growth factors - have carcinogenic potential This also means that these molecules can be used as therapeutic targets Example: ○ Oestrogen can stimulate proliferation of breast and endothelium ○ Can predispose to development of breast and endometrial cancer in animals ○ Some human tumours depend on hormones like oestrogen for continued growth ○ Some breast cancers can be treated by drugs which bind to oestrogen receptor (ER) ER positive patient is likely to respond to the ER-blocking drug 8 ER negative ER positive Considering the ‘Hallmarks of cancer’ when looking at e.gs. below self suf ciency in growth signals; insensitivity to anti-growth signals; evading apoptosis, sustained angiogenesis, and potentially invasion and metastasis. Physical Carcinogens Asbestos has been shown to cause mesothelioma - type of lung tumour Was used for: ○ Roo ng ○ Natty threads ○ Vehicle brakes ○ Insulation Inhalation of asbestos bres: ○ Causes chronic in ammation and wounding response in the outer lining of lungs ○ Some bres coated with proteins as part of this injury responses - ‘asbestos bodies’ ○ The deposition of scar tissue impairs lung function ○ This damage to the tissue increase the risk of mesothelioma ○ Incidence has been increasing due to historical exposure fi fi fi fl fi Physical carcinogens; Ionising Radiation causes DNA damage If not repaired properly —> can lead to mutations If mutations occur in oncogenes or TSGs may => cancer Example: ○ Repeated exposure to X-rays increases risk of tumours of bone marrow and skin ○ Prolonged exposure to UV light in sunlight increases risk of skin tumours ○ Ingestion of radioactive iodine increases risk of thyroid cancer ○ Inhalation of radioactive dust or gas increases risk of lung cancer Effect of carcinogen exposure - the 3 step model following exposure to a carcinogenic agent there can be a long latent period before neoplasia develops ○ This latency - can last decades - occurs for no. Reasons (knowing some cancers take years to develop) ○ Carcinogenesis occurs in a multi-step fashion ○ Timing of carcinogen exposure and subsequent changes has to be perfect ‘Cancer is a disease of evolution, genes, culture, diet, lifestyle and old age’  3 - STEP MODEL OF CANCER DEVELOPMENT Initiation Promotion Progression · Initiation : irreversible genome alteration Promotion : clonal expansion of the initiated cell (i. e stimulation of growth. Progression : Stable alteration of an initiated cell. ↳ gaining ability to invade + metastasise > chemical and physical - many things biological - - , can cause initiation + promotion by altering Cellular DNA. to these alterations occur in oncogenes and /or tumour Suppressor genes (TSGs) the 3 steps achieved by permenant alterations in specific genes and TSGs. oncogenes V  ONCOGENES : > - mutated versions of normal genes (proto-oncogenes - reg. cell death). oncogene: any mutated " gene that contributes to neoplastic transformation · neoplastic = benight malignant · change cell => benign or malignant cells oncogenes activated in cancer > - > - they promote cell growth + survival. e at promoter region g. for cell cycle reg. · Mutations can : ↑ - alter gene expression levels (transcription) (ie. 4 MRNA prod. ) or alter structure of resulting protein -. Lo makes it more active : e. g. ↓ cell death + ↑ all growth. · many mutations > Constitutive activation (constantly active). many common oncogenes promote mitosis/progress through cell cycle · OR death evasion of signals. Lo this can 'hit the gas' from normal tissue homeostasis. oncogenes activated by genetic changes : inc. Point Mutations : may = production of an abnormally functioning protein product e g as.. Deletions : from a few base pairs - loss of an entire chromosome e. g : V-erbB + oncogene activated by that. gene amplification = : excessive production of oncogene product e. g HER-2[mecopies chromosomal translocations : gene activated inappropriately by another e promoter region g: c-myc. ↳ can push cell proliferation  mode of action of oncogenes : ↑ production of cell growth factor ↑ expression of growth factor receptors Mutant transcription factor production over-production of factors that prevent cell death Active oncogenes found in tumours thought to be early events in marignant transformation. ** need to know 2-3 for exam. to they are tissue specific. rea energy + more materials SUMMARY. : so selective adv. as more energy avail for cell ploviteration. often promote : often repress : Net outcome : cell growth cell death - - - cell Survival - differentation CELLS MORE  Tumour Suppressor Genes (TSGs) : · Mutated versions of normal genes · TSG : I growth regulatory genes which , if their function is lost - contribute to neoplastic transformation. > they show loss of function in Cancer - -Often negatively regulate cell growth & Survival , or promote differentiation Knudson's 'Two kit Hypothesis' : a cell can initiate tumour when it contains two mutant alleles only > a - ↳ who inherits mutant allele must experience somatic mutation a person a in the 2nd allele to initiate tumourigenesis. two mutant alleles red. for initiation or promotion to occur ↳ explains why people who inherit 1 mutant allele develop cancer at a younger age.  if cell checks > - to mitosis. can progress Example : Retinoblastoma gene (Rb discovered malignant tumour of in Childhood-retinoblastoma · in a refine cycle progression (mitosis > inhibits - cell > function altered in almost all cancers. - to other cancers associated inc : Lung , breast and bladder cancer. p53 gene (TP53) "prob. Most common genetic abnormality in Neoplasia > - deleted / mutated in more than 50 % of human tumours. Regulates · cell cycle progression · known as 'guardian of Genome' - role in DNA damage response. Lo functional p53 : stops a cell of Mitosis if DNA abnormal = pushed to cell death. · key regulator of apoptosis (programmed cell death). APC gene (APC ↳ Adenomatous polypsis cri ↳ Multifunctional protein product invered in : U to Mutated in -90 % of All Colorectal Cancers. polypsis (FAP). ↳ inn. of a single inactive copy > = familial adenomators Ap : byearly 20s 1000's of benign tumours (posyps) colon. - in - by early 30s May have progressed to malignant cancer - - by 40- almost all FAP patients will have malignant cancer if untreated. Treatment : Surgical removal of Cocon.  Oncogenes TSGS · Cancer preventing genes · promoting genes cancer · usually gain of function · usually loss of function in in tumours tumour. ploiferation ; · · often promote cell often prevent cell ploriferation ; inhibit apoptosis ; or block cell promote apoptosis ; or induce differentation cell differentiation Eg : ras , myc Sch2 , Eg. : Rb , p53 , APC. THE HALLMARILS OF CANCER : LoHanahan model the key features of + Weinberg - proposing malignant tumour cells. (but some features also apply to benigh Cells all) · not. · the 6'Hallmarks' are acquired by tumour cells dre to : 1. gain of function of oncogenes 2. Loss of function of TSGs. 3. Action of selective pressure (avail Of O2. , space , immune system). self-sufficiency in growth signals · intensitivity of anti-growth signals · Tissue invasion & metastasis Limitless potential for replication sustained angiogenesis · Grading apoptosis. Self-sufficiency in growth signals : cells need constant to stay Guire (to proliferate). signals inc. external signals from 'growth factors' these often act by allowing progression through ' cell cycle Lo Cancer cells gain abivity to grow + divide independently of these external signals. if mutated > - switches all pathways - I I ! I ! ! on pushing all ↓ I ! poliferation t i & ! ↓ ↳ reg. B-catenin act. or Switches over expressed on => ↑ D1 ) D14 ) = = Cell p. = cel pot. ↑ when high : will push cells to S-phase => through cell cycle => division  Intensitivity of anti-growth signals : limit division cells receive signals to cell growth + also veg by. 'growth factors'. no Cancer cells become resistant to these ↳ growth inhibitor signals funneled through the retinoblastoma protein (pRB) ↳ which prevents the innapropriate transition from 61-S-phase. Tissue invasion and metastasis : Meta-change I Stasis place - ·. Malignant adjacent · tumours invade normal tissue · they may then spread to other parts of body. · this metastatic Spread = ~90 % of all cancer deaths. · Process driven by the tumour microenvironment (env around tumour) largely. and NOT by further mutations.  Tissue invasion and metastasis : · detachment from tumour mass · motility more through Stroma/mesenchyme (using old DNA from e.g WBC). · · intravasation (invasion of Cancer cells through basement membrane ( · extravasation (leakage) Limitless replicativePotential : · normal cells reach the 'Hayflick Limit (Senescene · forms part of aging process. by disabling pRB pS3. ↳ the Hayflick limit overcome + ↳ the counting device for cell doublings is the telomere : loses DNA at the tips of every chromosome during each cell cycle. · ↳ many cancers show an unregulation of thomerase · the enzyme maintaing telomears.  sustained angiogenesis : / genesis angio-vessel beginning. · - as tumours hypoxia (dep of oxygen). · => grow. ↳ Hypoxia induces vascular endothelial growth factor (VEGF) prod. oncogene · normal cells. > - · VEGF stimulates endothelial cell proliferation and migration · new blood vessels (capillaries) are formed. ↳ provide tumou w/ oxygen. green : Capillaries red : hypoxia. trading apoptosis: -> form of programmed cell death. in normal unwanted/damaged · tissue : removes cells nomeostasis achieved in tissues through balance of proliferation apoptosis · - · Cells W/damaged DNA - normally undergo apoptosis (p53) In Cancer see changes : , 1 4 rates of cell. proliferation. ↓ rates 2 of apoptosis. 3 ↓ celluar differentiation.  this is progression part of the 3-step model MULTISTEP NATURE OF CANCER : · distinction between bengin imp their relationship. + malignant is. - ↳ Maignant tumours - usually derived from bengin tumours = Malignant progression. allows observation of development as multistep process. ~ cancer · det nature of a tumour influences patient prognosis + treatment Begin tumours often are the prosecursors of Malignant cancers. i Normal endothelial cells. mutation confers freedom from growth control = proliferation further mutations confer - ↑ growth adv. (dif mutations). = clones · capabilities as dif. more mutations forming a mixed population - clones cells to (become invasive). progress malignancy  Cancer timescale: degree of cellular abnormality - tenign. bengin pre-malig Progression : tumours become less well differentiated. & more aggressive > - propersity to spread around. ↳ less diff = aggressive < differentiation : more aggressive. emergence of sub-populations of cells W/ new genetic abnormalities growth control becomes more abnormal & cells become invasive large tumours composed of Sets of slightly different cells (tumour heterogeneity mutations that favor tumour Survival or spread are chosen by natural selection This is 'evolution in microcosm'. new model old-model - too simp  In tumours Clonacity : Explains why the primary tumour may respond to therapy but metastatic lesions X Explains how after initial good response to treatment , tumours emerge that are resistant to therapy. these then dominate the tumour (natural selection). HISTOLOGICAL DIFFERENCES : · normal nuclei capsulated > - more variation = more aggressive. encapsulated nucleus takes · · larger nuclei majority of space. · uniform looking vary in snape/size. Benign tumours : CLINICAL FEATURES : Prognosis : Usually good - complications may occur. Compression of adjacent tissues 9 , adverse if : lo blockage of Lumen leg gut/airways). ↳ confined space (eg tumours of the brain). to impossible to surgically remove 2. Disease die to uncontrolled release of hormones : ↳ tumours of cells w/ endocrine function. leg tumours of thyroid gland , adrenal grand , etc... ). interferes wi 3 organ function (eg Leiomyoma (fibroids) of the uterine myometrium. Luterus wall) ].  Malignant tumours : CLINICAL FEATURES : Prognosis : variable , may be poor ↳ not confined to site of origin (primary tumour Lo =) invasion of tissue at expense of local tissues surrounding. lo cells can become detached I diff part of body W/ more to. metastatic spread (development of 10 tomous). to also disruption of normal tisse + cells at new site (like 10 tumours). MULTI-STEP MODEL : CRC (conorectal cancer) - provides paradigm for the model lo most follow described nath of a well initiation , promotion + progression. > - X find any genetic mutations caused by environment around tumour. wer INITIATION PROMOTION PROGRESSION  CRC : Colorectal CANCER : Benign colorectal polyps - ADENOMAS : Lo non-invasive ↳ grow out into the comen - form posyps. lo -90 % of TSG APC. adenomas form due to loss ↳ as more genetic changes occur= > may progress to become invasive. colonoscopy Microscope DIAGNOSIS : ↳ by histopathologists. Chistopathology Lab). looking for : ↳ changes from normal tissue architecture ↳ changes to cells (eg size of nucleus]. ↳ Type tumour present ? of to has tumour invaded , how far ? " how abnormal does tumour look ? TUMOUR TYPE - nomenclature ↳o named after derived from Cancer' cells that they = malignant. ↳ benign /malignant have separate names. Example : Malignant epithelial tomous 1 Carcinoma Glandular (columnar) epithelium recieves prefix : 'adeno- & more cancer names Bangin = adenoma/Malignant = adenocarcinoma  PROGNOSIS : Lo GRADE and STAGE Capplies to malignant tumours]. GRADE : how abnormal tumour cells look under microscope - aggression STAGE : size of tumour and whether it has SPREAD ( + howfar). · both important for prognosis + choice of treatment. GRADE : by looking degree of · assessed at : ↳ (tobusel formation gland lo pleomorphism (variability in size + shape of cells and /or nuclei) ↳ numbers of mitoses. · Often refers to degree of cellular differentiation : Grade aX undetermined Grade cannot be assessed G1 well differentiated Cancer cells similar to normal cells and divide slowly (low grade) Gl moderately differentiated Cancer cells look more abnormal than normal cells and (intermediate grade) slightly faster division 43 poorly differentiated Cancer cells look very different to normal cells and (high grade) tend to divide quickly · 94 undifferentiated Anaplastic - lack differentiation and very rapid (high grade) division  Cell differentiation in tumours : In after cell division from Stem cell + normal cells assume specific function. ↳ involves development of specialised structures. legmicrovilli or ciric]. => differentiation stem cells undifferentiated · - fully mature cells highly differentiated. · - Neoplastic cells commonly fail to achieve fully differentiated State * (selective adv. to not differentiate = rea. energy + more materials - can spend on cellular division to grow instead]. In BENIGN tumours : In MALIGNANT tumours : differentiated · Degree of differention varies · generally well : reflect cells of the tissue of which differentiated well/moderately/poorly · ↳ they are derived from · no differentiation - anaplastic · often retain function · differentiation relates to behaviour ↳ e.. benign endocrine g tumours prognosis. secrete hormones. poorly differentiated · usually = more aggressive.  BUSPLASIA : imp. in neoplasia ↳ abnormal cell growth/differentiation. · benign tumours assessed for their degree of dysplasic (line grading). · dysplasia in non-neoplastic tissues - a measure of Cancer risk. ↳ e borrel disease Barret's oseophagus ; CIN.. inflammatory g. , · graded as mild , moderate or severe oesophageal dysplasia Dysplasia I risk of Cancer. Cervical Intraepitnitial neoplasia  STAGE : ↳ stying describes severity or extent of a cancer. · knowing stage helps plan treatment and estimate prognosis various tests needed to determine stage : exams Staging systems ophysical evere + imaging procedures continue to change. · ~ lab. tests pathology reports · surgical reports. · Tumour TNM system stage :. 1 Size or extent of Tumour (1). 2 Whether cancer cells have spread to nearby lymph nodes (N) 3. Whether distant metastasis (M) has occurred to other parts of body. Tumour : Nodes : Mestastasis Tumour staging : CRC : T stage : det by. how many layers of bonel wall the tumour has spread through. > - D S N stage det. by histological examination of regional lymph nodes removed by surgeon. Mstage rea. many diff-tests incl. images , blood , etc... TNM Stage is then expressed as numerical stage used to determine prognosis ·. Duke's used Clinicians. staging still by some ·