Physiology (Digestive 1) Flashcards
Split of GI tract
- Tubular system (Esophogus + Stomach + Small Intestine + Large Intestine/colon + rectum)
- Tube that food goes through
- Non-tubular (Liver + pancreus + Gallblader)
- Puts things into the tube
Layers of the Tubular GI System
In canal of GI tract:
Top - Lumen - Food is here
Mucosa
- Varies organ to origan
Submucosa - Loose connective tissue + Blood vessles)
Muscularis Propia - squeezes the Gi organs (does parastalsis to move food down)
Subserosa - Loose connective tissue
Serosa - Mesothelium
- Missing in some organs
- Interfaces with peritenial cavity
What layer in GI tract variers
Mucosa = Varies organ to origan (rest of the layers is the same throughout GI tract organs)
Because the mucosa does different jobs depedning on where in the process
- Mucosa = closer to the lumen that has the food = it is the varaible part
GI tumorgensis
GI tumorgenesis is similar throughout the GI tract
Start:
1. Normal Epithelium
2. +/- chronic inflamation (often occurs but not always)
- Provessing factor that eads to neoplasia
3. +/- metaplasia - some organs takes on histology of different organs (doesn’t occur in all)
4. Low Grade dysplasia (unversal)
5. High Grade Dysplasia
6. Cancer
Low and high grade Dysplasia
BOTH are universal in process
Cells are still in the basmemt membrane = not cancer yet
Esophogus Function
Convey food to stomach
NO digestion or Absorption
Esophgous Distictive Histology
- Non-keritimizing squamous mucosa in epithelium (different from skin)
- Submucosal glands (lubricate the esophogus)
- Muscularis propia contains skelatal muscle in upper esophogus
- Creates volentray conrtol needed in upper region (smooth would be involentary)
- Adventitia (NOT serosa)
- Because retroperitenal = no serosa
Layers of the esophogus
Squamas epithelium = startified
Dark line at top = where cells proliferate
Infection in esophgus
Esophagitis
Causes:
1. Medications
2. Trauma
3. Allergy
4. Radiation (ex. after cancer)
5. Inefctions
6. Reflux
Infections - have characteristic viral cytopathic effect (Seen on H/E)
CMV Esophogitus
CMV - makes cells big (CMV infected cells) (SEE large pruple circes)
- Get inclusion in cells (Cytoplasmic inclusions)
- Infects endothelial cells (where vessles are NOT on the surface)
IHC - Brown = CMV protein in nulcues (confirms presence of viral proetin)
CMV inclusions = more common in immunosupressive pateints
Viruses in the Esophogus
- CMV
- HSV
HSV Esophigutis
Vicera of epithelium (epithelium is inflamed)
HSV = herpes
herpes Inefction
Seen by 3 M’s
1. Modling - nuclei are shmooshed together
2. Multinucleation in one cell
3. Mergination - viral patches take over nucleus (push nucleic acid to the side)
Esophegeal tumergenesis
Steps:
1. Metaplasia (no neoplasia)
2. Dysplasia (non-invasive neoplasia)
3. Adenocacinoma (invasive neoplasm)
Example Metplasia in Esophogus
Barrets Esophogus
Get squamas epithelial –> intestinal epithelium
- See goblet cells white circles) = defined barretes
Normal Esophogus vs. Barret’s Mucosa
Normal Esophogus - Layers of squamous = normal
Barrets - Esophogus looks like intestinal epitheliam
Normal Intestine vs. Barret’s Mucosa
Images look similar (because get intestial epitheliam in esophgus during barrets)
- normal esophgus + aberrtes = both have goblet cells
High Grade dysplasia arising in Baerrt’s mucosa
When have metaplasia = have risk to gte low grade and then high grade dysplasia
- Cynslodigya displastic barrets = high risk –> can try and fix by removing a perice of the esophogus
Image - Karge nuclei + disorganized nuceli + stalked nuclei
Invasive Carcinoma with associated desmoplasia in Esophogus
Image = Esophogeal Adenocarcima
Desmoplasia = fibrotic stroma –> know cancer has invaded
If resection = know where cancer is by having a small biopsy but you might not know where the cancer is = rely on desmplasia to know that it is canver and not just high grade dysplasia
Risk factors for barets esophogus
- Chronic GERD (Acid goes to esophgus_
- Risk factor for lower barret’s esophogus –> causes adenocarcinomas to be in lower esophgus more often
- ADvancing Age (>50 YO)
- Male
- Tobacco Use
- Central Obesity ( waist >40 inches)
Barret’s esophogus Stats
10% of patients with Barret mucosa have or will develope adenocarcima
- Includes Prevent adenoCA present at intial endoscopy (have barrets and cnacer at first biopsy) AND incident adonoCA develops subquentially
Overall incidence of progression to adenocarcima in Barrets pateints is 0.1-0.3%/year in first 5 years but 9% at 20 years
adenoCA = Adenocarcinoma = poor prognosis
Esophegeal Adenocarcinoma (tumor image)
Adenocarcima and barreys = often at the distal esophogus because often caused by GERD
Barret Mucosa = shows where to biopsy
Image - Pink on right side = stomach + see mass (cancer)
Treatment of Esophegeal Adenocarcinoma
There is a movment to treat endoscopically
Taking out the whole esophgus is a bigger procedure BUT if can do endoscopically it is beneficial
Esophogeal Adenocarcima (Histology)
Functions of the stomach
Overall: mixes and churns food with gastric juices to form chyme
- Begins chemical breakdown of proteins
- released digested food into the duodenum (in SI) as chyme
- Absorbes some fat soluble substances (Ex. alcholol + aspirin)
- Secretes Intrinic factor required to absorb B12 in the SI
- HAs antimicrobial functions
- Stimulates protein digesting enzymes
Layers of the stomach
Lumen = where food is
Muscularis propia - 2 layers of stomach muscle
Gross Anatomy of the stomach
Stomach = has multiple regions with difefrent roles
Middle area = body (fundus)
- makes pepsie + acid + intrisic factor
- Has cheif cells and parietal chells
Antrum
- Tells the body to make acid (regulatory function)
- Has Gastrin-producing endocrine cells (G-cells)
Mucosa of gastric fundus/body
Has:
1. Pits - Lined with mucosa producing cells
2. Glands - Has pareital cells and Cheif cells
Gastric fundic glands
See pareital cells (make Acid) + see Cheif cells (make pepsin)
Key cell in Stomach
Parietal cell
Parietal Cell
Filled with Secretory vesicles
H-K-ATPase Acid secreting pum (“proton pump”
- Basis for proton pump inhibitors to control acid secretion (used for Acid reflux) –> makes stomack condition less acidc = less damage to esophogus
- Activated by Ca+ and cAMP
Mucosa of antrum
Have:
1. Pits
2. Galnds - Have endocriine cells that make gastrin = stimulates acid secretion
Key Players of Acid Secretion
- Acetylcholine
- Gastrin
- Histamine
- Somatostatin
Overall - many cells secrete many thing (verycomplex)
Forms of Gastritis
- Acute
- Chronic includes common and uncommon forms)
Acute Gastritis1
- Acute hemorrahigc gastritis
- Acute infectous gastritis (can be bacterial with H.Pylori or Viral)
Chronic Gastritus
Common Forms:
1. Chemical gastritis - chemical injury to stomach (caused by NSAIDs + bile reflux)
2. Helicobacter Pyloru gastritus - become chronic
3. Autoimmune gastritus
Uncommon forms - many things (not listed)
Helicobacteria Pylori
Curved organisms with flagellae iver gastric epithelium
Helicobacteria Pylori = casues gastritus
Image - see inflamed stroma = look for Helicobacteria Pylori before calling it HP gastritus
Stains for detcting H.Pylori
- Giemsa
- Inset = coccoid forms
2 Immunosatins - shows HP is there - Arrows = Coccoid forms
- Inset = coccoid forms
Consequences of H.Pylori infection
Symptoms:
1. Many people are asymptomatic
2. Dyspepsia (abdominal pain)
3. get Peptic ulcers of the duodenum and antrum
4. get atrophy and intesinal metaplasia of nucosa
5. Increased risk for intestinal adenocarcinoma
6. MALT lymphoma
Have inflmation = risk for adenocarcinoma = get lymphoma of inflamed GI tract
What is H.Pylori associated with
H.Pylori is assoicated with metaplastic atrophic gastritues
Image - red is intesinal metaplasia
Before they had to comepleted a resection of Distal Antrum because Ulcer won’t stop bleeding = need to take out
- Now we know it is caused by HP = an treat the HP = don’ need to take out (prevent surgery for ulcers)
H. Pylori asscoiated with metaplastic atrophic gastritus (hystology)
Similar to metaplasia in Esophogus
See goblet cells = tell you intestinal metaplasia
- have risk for dysplaia and carcinoma
Gastric tumorgensis
- Metaplasia (no neoplasia)
- Dysplasia (non-invasive neoplasia)
- Adenocarcinamo (invasive neoplasia)
Risk factors of Gastric Adenocarcinoma
- Male >60
- H.Pylori infection - get chronic infection –> get metaplasia –> get carcinoma
- Atrophic gut
- Intesinal matplasia* - Atrophic gut
- Chronic atrophic gastrtus* - Atrophic gut
- Pernicous anemia*
- Familail adenomatous poly posis*
- Prior partial gastrectoy
- Nitrate containing foods in diet
- Cigarette smoking
- Endoscopic screening recomended
Gastric adenocarcinoma (intestinal typ)
Looks intestinal because arose from intestinal metaplasia
- See more distict glads
- Has intestinal morphology
Hereditary gastric Adenocarcinoma
Leads to a different Adenocarcinoma
Autosomal Dominent
Gastric cancers develope in youth
Mutated CDH1 gene (E-cadherin) - a tumor supressor gene in epithelial cells (germline mutation)
- get screening and profelactc gasterotimy
Second hit intiates neoplasia
Accounts for up to 40% of family gastic cancer
Gastric adenocarcinma (Diffuse type)
Has a bad prgnosis
Has small cells = easy to miss
Image = diffused AC
- Se siglet cells (circle with mucues inside and nucelus surounding)
Small bowl Function
Function - Absorbe nurteints
- Stomach breaks up food –> then Small intestine absorbs
- SI maximizes surface area so it can absorb more
Small bowl Histology
ALL abount increasing SA
- Glandular mucosa with villous architectire to maximize absorbption
- Villous = fllaments of mucosa stick up
- Submucosal glands in the duodenum (burner’s glands) to neurtolize the gastric acid sectretion
- Burner’s glands = stops gastric acid secretion
- pancreitic juice (digestive enzymes) and bild (emulsifier) enter at duodenal Ampulla of Vater to aid digestion
- Bile = from gall blader
Small Intestine (overall)
Small intestine is divided into:
1. Deodenum (25 cm/9in) - Adjust pH tonicity (has burners glands)
2. Jujunum (280 cm/9 ft) - Digestion and absorption
3. Ileum (350 cm/11.4ft - longest) - Bile salt absportion (has lymphoid aggerates)
Layers of small bowl
Musocsa - has fingers sticking up lined by epihelium to increase Surface Area
Small bowl Mucosal
Have:
1. Crypts
2. Villi
Normal Villia: Crypt ration = 4:1
- Shorter Villi = indictaed certain diseases
Villi = stick up into absorbic epithelium
Villous Epithelium
PAS stain - stains goblet cells + mucin + shows brush boarder
- Brush boader = microvilli stick up
Microvilli
Brush boader = microvilli
- Flagellar stick up = increase surface area
Functional Unit of the Small Bowel
Understand stem cell dynamics
Crypt base = cylcing stem cells
TA compartmet = transitioning epithlium
Top = differentated –> then goes to shed into the lumen
Vils - digestion + absorption
Crypt - secretion
Small intestion job
Overall: Absorption of sugar + protein + fat
Sugar/protein/fat = must be broken down enzymatically into fuctional units before it can be absorbed
Specific transprters in enterocytes mediate absorbption
- Have different trasnprters for different surgars + different for amino acids
- Transporters have a lot of restiction in specificty ; we know many of the transporters
GI tract balance sheet
GI tract is very effecicient - Absorbs 98% of things we take in
Malabsorption
Impaired uptake of any substances by the small intestine
If the smallnintestine has inflation = affects ability to absorb nutrients
Disease:
1. Celiac
Malabsorption syndrome symptomes
- Diapria
- Steotorah (fatty stool)
- Weight Loss
- Deficney states (protein/vitamen dfiecieney)
Celiac Disease
aka Gluten sensitive enteropathy + celiac sprue + non-topical Spure
Overal - inability to tolrate gliadin (alchol soluble fraction of gluten)
- Gluten = in wheat + rye + barley
- chroic autoimmune intestinal disorder
When gluten is ingestid into patients with celiac an immunologically meidated inflamatory response occurs which famages the mucosa of the intestine
- Histologocal chnages - get small bowl atrophy (microvilai are flat) which leads to maldigetion and malabsoprtion
Pathophysiology of celiac disease
Pathohysiology = multidisiplinary disorder
- Need autoantibody
Comination of allergy to glute + innate/adpative immune + genetics
Overall - celiac us an imune disorder that is triggered by the envirnment (gluten) in genetically suceptible individuals
Celiac (histology)
Have:
1. Villous blunting
2. Increased lymphocytes in epithelium (inflamtory disease)
3. Increased plasma cells and lymphocytes in lamina propria (inflamtory disease)
Image -
see flat at the tope
When stop eating gluten = intestne goes back to normal morphology (histology is reversible)
Neoplasia in small intestine
Primar cancers are reare ; metastases are more common
If have adenocarcima in small intestine = often thing it is a metasteses
- If have tumor in dadenus = think it is from primary pandcreotic tumor
Layers of the colon
Mucosa = unique part
Coleractal Mucosa structure
Have crypts that go down (looks like test tubes in a rack)
- Regular achitecture in helathy = crypts
- If ahve infamatpry disease = interupts structure
Coleractal Mucosa (histology)
See crypt is going down
Function of Colon
Fluid absorption (function of mucosa?)
Lubricates stool to move down GI
- have more goblet cells + fewer absorptive cells
Infamatory Bowl disease (overall)
Overall - Chronic inmatory condition of the GI tract
- ofte presnets in patents in teens-twenties ; have second peak from 50-70
Etiology is unknown but they think gentically predisposed hosts have an itestinal mucosal immune reaction to an envirnmental factor iwth the gut microbiota playing a central role
Potential predisposing fcators - Infections + Antibiotics _ NSAID use
Pathogensis of IBD
Multifactoral - includes genetics + enviremnts triggers + mibrobial antigens/adjuvents + effector immune respose
Don’t know the exact cause of IBD or how to prevent it
IBD histopathology
- Muscoal has acute imnatory infiltrate
- Abudendent nuertpphils in epithelium –> causes accute cornus –> crypt (just if in epithelium)
- Cyrptisis and crypt abcesses
- Abudendent nuertpphils in epithelium –> causes accute cornus –> crypt (just if in epithelium)
- Basal Plasmacytosis - plasma cell on bottom of cypt (shows it is IBD)
- Crypt distortion (not organzied) - shows it is IBD
- Goblet cell depletion
- Paneth cels metaplasia
many things can cause nuetrophils to come + cyrptisis = also need chronic injury to get crypt distoration + plasma cells
Types of IBD
- Ulcerative colits - mucosal ulceration in colon (onl mucosa is inflame)
- Chrons disease - Tranmural inflamation (Illetis + illeocolitis + colitus)
- Inflmaation in entire wall of GI tract
- Other Colites - Other things cause inflamation in colon
- Ex - microsopic colitis + diversion colitus + diverticular colitus + pouchitis)
Ulcerative colitus vs. Chron’s diseae
Ulerative cholitis:
1. Diffuse mucoasl inflimation limited to colon
2. Afefcts colon (affects rectum and things more proximal)
3. May involove all or part of the rest of colon
Chrons:
1. Patchy transmural inflammation
2. May affect any part of GI
IBD + carcinoma
IBD can set up inflamation –> leads to cracinoma = pateints have survelnce to check for inflamtion and Dysplasia
Large Intesinve neoplasia
Colorectal carcinoma = colon cancer
- rectum = most distal part of colon
- Most comon cancer of GI tract
- hird highest incidence and cayse f cancer deaths
Colon tumorgensis
Colon tumorgensis = prototyouc example of precnacer-cancer sequence (see genetics of multistep tumorgenesis)
Different types of precancer represent different genetic pathways of tumorgensis
Image - Colon Adenocarcinoma
Colonic Adenocarcinoma
See Polyp (Precancer) + Mass (Cancer)
Colonoscopy = good –> finds precancer and removes the precancer at the same time
Types of Polyps in colon
2 types = have different genetic paths
- Tubular Adenoma - Multistep CRC carcinogensis model
- Sessile serated Adenoma - Microsatolite instability pathway
Tubular Adenoma
Neoplastic ; pre-malignent
- Most common neoplasmic polyp
Have low grade dysplasia
Histology:
1. Have high nucelus:cytoplasm ration (bigger nuclei)
2. Nucear elongation
3. Nucleo psuedostartification (bunch up on each other)
4. Nucleat changes extend to surface
Multistep Colorectal carcinmoma Carcinogensis
Multistep Colorectal carcinmoma Carcinogensis = tumor progression model
- Have step wise progression ofr precancer neoplasia dirven by different mutation in ecah step
First hit = APC at 5q21(germline or somatic in neoplastic cell)
- Have loss of function of both alleles
Sesile serrated adenoma
2nd path for colon cancer to take
Histology:
Cytosolic pertuesion = different
Crypt = dialted at the bases (“boots”/”flash”)
Microsatilite instaility pathway
Cancer arises through mutations in genes that contro; DNA repair = get more fusion mutaions = hits other cancer genes
Start - Mutation in gene regulating growth and apoptosis = get cancer (MLH1, MSH2 gene etc.)
Familial Adenomatous polyposis
Have germline mutation in APC (in 1 allele)
Fits Knudson’s two hit hypothesis for tumor supressor genes
Affect pateints ahve one inherited mutated allele ; 2nd hit occurs in the neoplasm
Familial Adenomatous polyposis (images)
Have MANY polyps
- SO many adenomas = one is likley to get mutations it needs to get cancer
- Have heterozygosity in polyps
Treatment - usually take out colon
Lynch Syndrome
Non-herditary polyposis syndrome (affects microsalitile pathway)
Autosomoal dominant inheritance pattern (only need one allele)
Germline mutaions in mismatch repair genes (MLH1, MSH2, MSH6, PMS2)
Inherite one defcetive allele ; second hit happens in neoplasm
Have Accelerated carcinogensis because mutation rae is higher (X1000 increased mutation rate) –> more likley to get mutation in genes that cause tumorgensis
Other cancers - endometriu + stomach + overy + uterus + brain + small bowl + hepatobiliary tract + opancreus + skin
Alfred Warthin
His seamstress said she will die from colon cancer bevause eveyrone in her family did
First family decsrived with Lynch syndorme
Lifetime risk of colorection CA
If have APC Colon cancer = test for MSI to see if can do immunotherapy
sporatic (under 10%) - 10% MSI ; 80% APC
- cancer with MSI = uniqley suceptive to immunotherapy (Use PDI)
- More sporatic via APC
Lynch - 100% MSI (risk is 50% in end)
- All MSI changes
FAP - 100% APC (All get cancer)
Function of Pancreus
Makes degestive enzymes –> Puts enzymes into the duedenum
Pancerus
See Head - leads into the deuadenum
Pancreus = retroperiteneal = under paretenium = not a lot of nerves = less symptoms = diagnosed late
Anatomy of Pancreus/Blood vessels
See head + dumps into the duadenum
Superior mesonteric aretry/vein
- Located next to the pancreus
- Reason for pancreus is hard because the pancreus is next to big vessel
Pancreus Histology
Acini - makes digetive enzymes –> puts enzymes into digetive ducts –> enzymes go to the duedenum
Islets - Have Langerhans cells
What is normal pancreus composed of
Normal pancreus is composd mostly of Acinar Cells
Bid part of cpryt because makes enzymes???(Slide 97)
Islats of langerhands
Make insulin and glucagon –> sceretes to blood through duct
Pancreus function
Acinar cells - scerete pancreotic enzymes into pancreotic duct (Exocine - out)
Islets of langerhands - Secretes hormones into blood vessles (enodcrine - in)
- Secrete insulin + glucagon = controls blood surgar level
Types of Pancreatitus
- Acute (short + self inflcited)
- Glands will usualy return to nomal if underlying cause of inflmation is resolved
- Chronic
- Irreversible destruction of pancreitic parenchyma
Acute = emergency vs. chronic is not an emergencey
Causes of Acute Pancreatitus
Most common:
1. Alchol (65% in US
2. Biliray tract disease (Gallstones cause obstrcution)
Also have some less common causes (obscurtion of pacreitic duct systems due to tumors + drugs + trama + infections + genetic
Genetic causes of Acute Pancreatitus
- Mutation in Cationic trypsinogen (PRSS1)
- Recurrent attacs of pancreatitis since childhood
- Most common is R122H mutation - Prevents protylitic inactivation of Trypsin (digestive enzyme) = can’t stop making trypsin = autodigest pancreus
- Recurrent attacs of pancreatitis since childhood
- Mutation in protease inhibitor SPINK1
- Normally prevents trypsin-catalyzed premature activation of zymogens
- Mutation causes excess trypsin acivity
- Mutation in cystsic firbosis transmembrane regulator (CFTR)
Chronic Pancretitis
Overall: Irreversible destruction of pancreotic paranchyma
- Leads to exocine insufincey (no Acinar cells)
- Leads to Endocrine insufincey (late)
Most common cause = Alchol abuse
Recurrent acute pancreatitis can result in chronic pancreatitus (caused by pancreus divisum + hereditary pancretitus + anatomical abnormalities)
NOT life threatening emergencey BUT 50% mortaility rate by 20 years
Histology of chronic pancreatitis
Key features:
1. Paranchymal fibrosis
2. Loss of Acini (replaced with firbrosis)
3. Variably dialted ducts
4. “Englarged” islaets (look enlarged because eveyrthing else is gone)
5. Chronic inflamation
Complications of chronic Pancreatitus
- Plural effusions
- Pain from perineral fibrosis
- pancreotic calcification
- Acites
- Stones in Pancreotic duct
- Diabetes
- Pancreotic cyst
- Fast malabsorption (sterorrehea + decreased vitamen K) - not making enzyme needed to absorb fat
PDAC
Has glandular morphology
Symptoms:
1. Painless onstructive juancice (if the tumor is at the head of the pancreus blocking gallblader)
2. Back pain
3. Weightloss/Cachexia
4. Trouseau sign migratory thromboplhebits (blood clots that move around body)
5. New onset of diabetes
ALL are late symotoms (only 10-15% are resectable tumore)
Profiling tumore
Tumor profile after surgery - done on tissue in surgery but the pancreus isonly 10% of pateints = need to keep in min wgere that is from and how that affects disease spectrim (think if it is represnetaive of the spectrum of disease)
PDAC pathologic features
- Grossly firm + white + poorly defined mass
- Microscopically they form glands and scerete mucin
- Called ductal (Ductal different? - slide 109)
- Intense desmoplastic repsonse (fibrotic)
- Poorly vascrularied
PDAC image
White = mass ; Yellow = pancreus
PDAC histology #1
See intense desmoplastic response (fibrosis)
- took tissue and did multiple anylsysis BUT majority of the tumor is fibrosis not cancer = need to pay attention to the cells that are there (Example - for DNA sequenceing might not afefct but for proteomics or expression it does affect = need to pay attention
See lighter circle - glands = cancer
PDAC histology #2
See Perinueral invasion (invaded nerves)
- Invades locally
PDAC histology #3
See invasion into veins
- Metastisis = invades in vessels = cancer spreads
PDAC metastisis
Metastisis = common in PDACbecause the cacer invades into the veins
- Liver = most common location of metastisis (because portal vein)
- Pateints with metastisis to the lungs = better prognosis than metastis to the liver
PDAC metastisis to liver
image - cross scetion of liver from pateint with metastic pancreitic cancer
In image - red is nomal ; rest is liver metastis
PDAC Epidemeology
Risk factors:
1. Age - PDAc is a disease of elderly (80% beteen 60-80 YO)
2. Blacks > whites
3. Ashkenazi jews > gentiles
4. Smoking - cuase s20% of Pancreoic cancer (doubles risk)
5. Family histpry - 10% of pateints have family history
6. Diet - High in meats + low in fruits and vegtibles
7. Obesity
8. Diabetes - risk factor + symptom of disease (hard to seperate between the two)
9. Chronic pancreatitus - risk factor + symptom of disease
10. non-O ABO blood group
BRACA increases risk
- most germline mutations = not known
What is Pamcretotic cancer
Pancreotic cancer is fundementally a genetic disease
Somatic mutation in somatic neoplastic cells = get cancer
Genetic an Epigenetic events in Pancreotic cancer
- Mutaions (intergenic mutations) - point mutations
- Large deletion
- Aplifications - CNVs
- Genetic instability/chrmothripisis - chromsome shatters and then is put back together weird
- Mitocndrial mutations
- DNA methylations
How do we get mutations that cause pancreotic cancer?
- Inherit mutated allele (BRACA2)
- Do something to damage DNA (ex. smoking)
- By change - 6 Billion BP in every cell –> can get error in cell divsion
- Bad luck that the mutation is bad
Types of pancreitic leisons
- PanIN - Small lesions (don’t see on imaging)
- Get dysplasia –> high grade dyspalsia
- Low rise for pray?
- IPMN- Large cystic (do see on imaging)
Genetic progression towards invasive pancreatic cancer
Telemere shortening (earliest chnage) –> P16 –> p53/SMAD4/BRAZ2
- at p53 = get high grade transition to carcinoma
Complex clonal evolution of precancers
NOT always linear
Precancer = poly cloncal
- Have mant clones in precacer –> one clone expands –> eventually get mutations that leads to progression
Multifocal precancers cancer
Precancers are multifoacal
Image - 3D live image
- See different precusers in different colores
- have >10 precacers in one tissue
- Everyone has many precancers
- Not uncomon to have many precancers but abnormal to have pregressions (progression)of precancer to cancer)
Role of inflamation
In some organs precancers are proceeded by inflamation and metaplasia
Inflamation roles in chronic infection is not as definedbut think inflamation is needed for neoplasm to happen
