Epi of Cancer – Flashcards

Diate 35 Tobacco 30 Infection 10 Reproductive 7

Gastric Cancer

Japan > Russia > Korea > China

Helicobacter pylori

Chronic superficial gastritis -> Chronic atrophic gastritis -> intestinal metaplasia -> dysplasia -> cancer

The process of nourishing or being nourished, especially the process by which a living organism assimilates food and uses it for growth and for replacement of tissues

strongly related with meat and fat consumption; red meat; Total energy intake; Alcohol intake

Fiber, folic acid, methionine, high dietary calcium

Dietary fat intake (not significant or too weak) But monounsaturated fat have inverse association with BC. Energy intake (Height as an indicator(maybe related with IGF-1)) Alcohol (increase endogenous estrogen level)

Fat intake (benign to aggressive) and red meat consumption (strongly associated)

Vitamin E (α-tocopherol) (most significant) Vitamin C Vitamin A (retinol) (also β-carotene, not significant)(for already exposed risks, not protective, for example people smoke are not protected)

Prostate Cancer Colon Cancer Breast Cancer Pancreatic Cancer Endometrium Cancer Gall bladder

Lung cancer Colorectal cancer Stomach cancer Oral Cavity/ Esophagus cancer

4th leading cause of cancer death One of most lethal of all human cancers 5 year survival rate: <6 months From age 40 risk increase, male larger than female Blacks larger than whites Developing country < developed country Mortality continue to increase in Japan Worst prognosis among all cancers

ESTABLISHED: *Smoking (strongest factor) (2 fold) (PAHs, nitrosamines, aromatic amines) *Family history (genetic) (5-10%) *Chronic pancreatitis (important in initiation) *DM (often the first clinical sign) (DM I decrease risk, DM II increase risk) (risk related with high exposure of insulin level) *Obesity SUSPECTED: *Physical inactivity *Occupational exposures (CHC, allergy history, cystic fibrosis, organochlorines, PCBs, pesticides) *Carbohydrate intake

Reverse Causality. Reversal of cause and effect, in which the outcome may be the cause in fact. Protopathic bias is common in retrospective study. The risk factor is actually the result of the disease. So selecting controls, usually exclude those who develop cancer after screening in 2-5 years.

Most common and most rapid increasing (both incident and mortality) cancer among US man (Incidence 27%, 17% life time cancer site of all cancers) 2nd leading cause of male cancer death 1 in 6 men diagnose with PC in lifetime Before 70, Breast cancer more common, after 70 prostate cancer more common

HGPIN High-grade prostate intraepithelial neoplasia

Age Race Family history Diet: diary products, red meat, vegetable oil (saturated fat), calcium (Vitamin D) PROTECTIVE: Phytoestrogens (soy products) Selenium (skeletal and muscle development, immunity, normal function of prostate, regulate apoptosis in Prostate cancer) Vitamine E (reduce DNA damage)? Lycopene (tomato)?

Significant disease burden Preclinical stage is detectable and prevalent Early detection improves outcome (mortality) with acceptable morbidity Screening tests are acceptable to population, inexpensive, and effective Treatment exists for detected disease

Inconsistency in disease progression High prevalence of asymptomatic disease Does screening do more harm than good? No evidence on benefits available from randomized clinical trials Excess cost, morbidity and mortality from treatments

Rare disease: Europe and America > Asian, Male>Female, Blacks>Whites, Low Incidence: M5% F3%, Low mortality: M3% F2%, High survival rate: local55-60% regional 20% Mortality and Incidence among black males still increase the largest until now

85%RCC: Clear cell (80%), papillary (15%), oncocytoma, chromophobe & collecting-duct 12%Transitional Cell Cancer of the renal pelvis (resemble bladder cancer) Wilm Tumor (in children) Other rare malignancy

Average diagnose age: 60 30% no symptoms; 50% by chance by radiology Flank and back pain, anemia, hematuria, weight loss & palpable abdominal mass

Local: Radical or partial nephrectomy; Arterial embolization Metastasis: Radiation therapy; Immunotherapy (IFN-alpha or IL-2); Chemotherapy (not effective for clear cell)

*Genetic predisposition (2%RCC; 2-3 fold 1st degree relative has history of kidney cancer; Von Hippel-Lindau disease - VHL gene- 60% clear cell RCC; age 50) *Smoking (account for 20-30% men, 10-20% woman; RR1.5M 1.3F; cessation 10 years reduce 15-30%) *Obesity (account for 40% RCC in US) *Hypertension, Antihypertensives (diuretics?) (RCC cause HTN or HTN cause kidney injury or alter tubal susceptibility to carcinogens) *Asprin and NSAIDs (Phenacetin used for HTN - pelvis cancer and maybe RCC; meta-analysis: RR=1.2) *Diabetes (not established; associated with HTN and Obesity) *Hormones and reproduction (lower in women; Hysterectomy/oophrectomy, parity(>5) increase risk?; OC use reduce?; HRT no change) *Diet (vege and fruit reduce) (Calori?, meat protein?, alcohol? maybe related with smoking increase) *Solar radiation (change with latitude) *Vitamin D (related with obesity; in RCC low VD related to prognosis; VD receptor polymophism TT at TaqI site - 2.5 fold in Japanese population; ) *End-stage renal disease and duration of dialysis (40 fold); Renal transplantation; Urologic disorders; Ionizing radiation treatment *Occupation (Asbestos?; Trichloroethylene (degreasing) & tetrachroloethylene (dry cleaning)?; Gasoline?; Others? (diesel exhaust, PAH's, printing & dyes, lead, cadmium)

Metabolism & excretion of most components of cigarette occurs in the urinary tract (VHL mut) Loss of renal plasma flow and impaire renal function (promotion of end stage renal disease) Lipid peroxidation Tissue hypoxia

Hypertension & elevated cholesterol levels Diabetes Elevated IGF-I levels * Endogenous sex steroid hormones Diet/physical activity Lipid peroxidation

No. 3 in cancer incidence and mortality among both M and F in US 6% lifetime risk Accounted for 8% of all new cancer diagnoses and 9% of all cancer deaths in 2014 M > F; Blacks > Whites > Asian > Hispanic> Alaska/American native; US East and Mid east (more industrialized area) larger risk;

70%COLON: 35% sigmoid 22% cecum 12% ascending 10% transverse 7% descending 30%RECTUM

Age at diagnose Gender Mucinous tumors Familial cancer syndrome 5FU chemotherapy benefit Ploidy Loss of heterozygosity TP53 mutation Microsatelite instability (MSI)+ CpG island methylator phenotype (CIMP)+

3% Stage 0: No spread of cancer 23% Stage I: Cancer has begun to spread, but is still in the inner lining. 32% Stage II: Cancer has spread to other organs near the colon or rectum. It has not reached lymph nodes. 24% Stage III: Cancer has spread to lymph nodes, but has not been carried to distant parts of the body 13% Stage IV: Cancer has been carried through the lymph system to distant parts of the body. This is known as metastasis. The most likely organs to experience metastasis from colorectal cancer are the lungs and liver.

40% Hereditary with familial risk (3%HPNCC 1%FAP) Adenomatous Polyps （precursor: 93%with CR cancer have AP; related to estrogen excess and endometrial hyperplasia）

Normal epithelium - Loss of APC -> Hypoproliferative epithelium - DNA methylation -> Early adenoma - K-ras mutation -> Intermediate adenoma - SMAD4/DPC4 mutation -> Late adenoma - lose of p53 -> carcinoma - other alterations (c-myc, tyrosine kinase, etc.) -> Metastasis

Increase risk: Adenoma polyps!! (precursor and early lesion of CRC) Tobacco (HCA cause APC; 2 fold in MSI+; related to increase adenomas) Alcohol (Acetaldehyde, through the effect on folate) Reproductive factors Parity (nulliparity increase risk!) (Age at first FTP not related) Anthropometric measures (Height related with IGF-I; BMI 11% attributable risk; >30 2-fold risk; stronger in men and effect on colon cancer) Diet Vegetable Fiber intake heterogeneous effects Micronutrients ↓(Calcium, long chain unsauturated FAP) Meat consumption!! (Fat content; High iron; Ammonia; N-nitroso compounds NOC; HCA and PAH) Hormones (Insulin, IGF-I and II, Leptin, Adeponectin, CRP) Occupation Ionizing radiation Ulcerative Colitis (minor contributor but 20-fold risk; TP53 mutation and MSI) PROTECTIVE FACTORS: Physical Activity? Hormone use: OC use (recent and current users) HRT use (recent user and distal colon in women; estrogen related ) NSAIDs use (inhibit COX1, 2; Effect through control of cellular proliferation/apoptosis; immunologic surveillance, reduced neoangiogenesis; stimulate PPAR; 40-50% reduce adenoma, CRC; short duration and persist for long ) Diet Fiber (redefined as non-starch polysaccharides) Vegetable intake Micronutrients Folate ?(methyl metabolism)

Annual fecal occult blood test FOBT; Flexible sigmoidoscopy/5 years or Colonoscopy/10 years; Start at age 50 or 40 with family history;

Fecal occult blood test (FOBT) (high sensi low speci) Sigmoidoscopy (use with DRE) Barium enema Colonoscopy (high sensi and speci but invasive and expensive) (offer both screen and therapy management) Digital rectal exam (DRE) (detect less than 10% CRC) New tests: Virtual colonoscopy (computerized tomography colonography) DNA stool test (expensive) Proteomics (more expensive)

Virtual colonoscopy is a procedure that uses a series of x-rays called computed tomography to make a series of pictures of the colon. A computer puts the pictures together to create detailed images that may show polyps and anything else that seems unusual on the inside surface of the colon.

A barium enema is a series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series. Moderately sensitive, its use will prob disappear with the advent of virtual colonoscopy if colonoscopy is necessary

Colonoscopy is a procedure to look inside the rectum and colon for polyps, abnormal areas, or cancer. A colonoscope which is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer. Basically it is the same to the sigmoidoscopy whereas it is longer and goes deeper into the ascending colon.

Exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual. It can only detect less than 10% of CRC, not effective.

APC(inherited or acquired) -> impaired APC.. pathway -> Adenoma -> Carcinoma It is associated with the adenoma-carcinoma sequence. This process is now accepted as central to the majority of cancers and an early key event is the mutation of APC. The pathway involves ß-catenin (which both binds E-cadherin and activates transcription) and Tcf (T-cell factor), which is a downstream transcriptional activator gene. A mutant APC or ß-catenin results in failure of proper adhesion-migration of cells and the transcription of a proliferative signal that can operate via c-MYC.

In this pathway the loss of MMR mismatch repair function was caused by hypermethyl of hMLH1. This epigenetic event leads, in turn, to a mutator phenotype. The initial hit is an inherited or acquired mutation in an MMR gene or hypermethylation specifically of hMLH1. This is also a multiple-hit process, the essential part of this pathway is the probability that there will now be a vicious cycle of increasing MSI involving the MMR genes The continuous stimuli will contribute to additional losses of important controllers of DNA and cell integrity, including apoptosis by BAX and cell growth control by TGFbetaRII

Chronic inflamation/loss of epithelia integrity - colonic luminal agents ->p53 mutation - luminal agents ->Aneuploidy ->p53 LOH ->Dysplasia/carcinoma This disease is a minor contributor to the overall population burden of colorectal cancer.However, individuals with ulcerative colitis have about a 20 fold risk. The pathway involves a dysplasia-carcinoma sequence. APC mutations are uncommon and p53 loss can occur early. MSI occurs in the absence of DNA MMR, suggesting perhaps an overwhelming source of mutagenic activity consequent upon the exposure of proliferating cells to the colonic contents.

Decreased Endogenous Estrogen -> Age-related hypermethylation of ER |- HRT ->loss of ER responsive pathways Almost all colon cancers arise from cells in which the estrogen receptor (ER) gene has been silenced by hypermethylation and it is age-related.

2nd most common form of cancer in US (13-14%) 1st mortality of all cancer in US (26%-28%) Most common cancer worldwide and leading cause of death from cancer High incidence from late half of 20th century (1920 smoking start, 20 years later incidence increase largely) Lack detection measures -> low cure rate -> High mortality

Tobacco smoking (predominant cause; 90%; 8-10 fold ever smokers; dose-response; long-term quitters reduce risk) Passive smoking (15% of cancers) Asbestos (silicate type; 5-folds; have interactive effect with smoking) Other environmental agents: PAHs, Beryllium, Nickel, Cobalt, Copper, Chromium, Cadmium, Diesel exhaust Family History (strong; p53, HRAS, KRAS, mutation in Phase I enzymes (CYP1A1, CYP2A1, CYP2E1, CYP2D6) and Phase II enzymes(GSTM1)) Diet: dimethylnitrosamine in meat (2 fold) red meat, diary products Coffee (related with smoking) β-carotene (RCTs show increase risk among smokers! Maybe increase Oxidant Metabolites) Hormones Estrogen and progesterone receptors IGF-I (2-fold) (IGFBP2 decrease risk) Infections (TB, isoniazid - TB drug, Chlamydia pneumoniae) Ionizing Radiation Radon (account for 2-3%/year, radon mines) PROTECTIVE: Diet: Fruit and Vege (15-10% reduction) Tea (preventive Vitamin C (protective Vitamin A Vitamin E (α-tocopherol) (2% reduction) Selenium (protective

70-90% Non-Small Cell Lung Carcinomas (NSCLC) 30-50% Squamous Cell Carcinoma (Male commonest, central origin, manifests early) 35-40% Adenocarcinoma/Bronchoalveolar (Female commonest, peripheral origin, manifests late) 5-15% Large Cell Carcinoma (least common type, peripheral origin) 10-30% Small Cell Lung Carcinoma (most aggressive type, central origin, spreads quickly) (Male: Squamous>Small>Adeno>Large) (Female: Adeno>Small>Squamous>Large)

5-year survival depends on stage at diagnosis: Stage I - 50% Stage II - 30% Stage III - 5-15% Stage IV - <2% All stages - 15%

Chest X-ray and/or Sputum Cytology; Low dose spiral CT;

Usually combination of therapies: Surgery Radiation therapy Chemotherapy (options include a combination of drugs) Targeted therapy (Bevacizumab (Avastin) - VEGF; Erlotinib (Tarceva) - blocks human epidermal growth factor receptor 1 (HER1/EGFR), approved for locally advanced and metastatic NSCLC)

Tumor suppressor gene: DNA repair, Cell-cycle check point control, regulation of transcription, chromatin remodeling and genetic stability Frequency of BRCA1 mut is 0.1~0.2% in general popu (6% BC women has BRCA1/2 mut) Among Ashkenazi Jews 1% (21% BR women have mut) (5%of all BR cases and 60-80% of hereditary cases, most common monogenic disorders, also for prostate and pancreatic cancer, colon cancer maybe)