GI Cancers Small Bowel Flashcards
2 most common malignant epithelial tumors in GI tract
adenocarcinoma, neuroendocrine tumor
T/F most neuroendocrine tumors are of the GI tract
T, not a common kind of tumor but most often is GI
Risk factors for adenocarcinoma in the small bowel/colon
age (>50 should screen), diet, environment, obesity, genetics, ibd
Is adenocarcinoma more common in small bowel or colon?
colon
By the time you have an adenocarcinoma, most _____ genes have been knocked out.
APC
Most common sequence of gene knockouts in adenocarcinoma of colon.
85% of colon cancers: point mutation in APC leading to stop codon + 2nd hit of gene rearrangements/loss of chromosome –> 10 years for additional epigenetic/genetic changes before invasive –> metastases (take about 60 years)
_____ are polypoid masses of dysplastic epithelium with no invasion.
adenomas
Tx of adenoma
resection of adenomatous polyp –> can prevent transformation to adenomatous dysplasia and consequent carcinoma
In the colon, when does adenoma become adenocarcinoma
once the polyp invades into submucosa –> no metastatic ability until in that compartment (lymph nodes)
In the small bowel, esophagus, stomach, when does adenoma become adenocarcinoma
when it invades the lamina (lymph nodes closer than in colon so can metastasize)
Genetic components of colon cancer
35% due to genetic predisposition
Dominant: hereditary nonpolyposis colon cancer, familial APC, juvenile SMAD4/ALK3, Peutz-Jeghers LKB1
Recessive: myh
What part of the colon has the highest susceptibility to adenomas?
cecum
Crypt proliferation sequence
stem cells proliferate –> repair replication mistakes/get rid of defective cells –> migrate up –> differentiate –> die
Wnt signaling pathway
When there is no wnt to bind the frizzled receptor, multimeric beta catenin is phosphorylated by the protein group (apc, axin, gsk3b) –> proteosomal destruction of beta catenin –> reduced monomeric and multimeric beta catenin (these two are in equilbrium)
When wnt binds frizzled receptor, there is no phosphorylation of multimeric beta catenin –> increased level of monomeric beta catenin –> nuclear binding to Tcf –> upregulation of genes like cmyc, etc. involved in proliferation
Which cells in GI tract make wnt?
perifibroblastic cells in base of crypt where stem cells reside –> physiologic cell proliferation
Wnt gradient in GI mucosa
highest in the base of crypt where stem cells proliferate and lower at the top of the crypt where cells are differentiating
Functions of beta catenin in GI mucosa
- upregulate proliferation of stem cells
2. bind to intracellular portion of cadherin and involved in cell-cell adhesion
How does colon cancer relate to Wnt?
with knockout of APC and other proteins involved in phosphorylation of betacatenin, can have too much beta catenin –> messed up regulation of cell proliferation in crypts –> adenoma + more mutations = cancer
Staging of colon cancer
TNM
T/F colonoscopy + resection of adenomas reduces risk of colon cancer
T
Through which molecular classification do 85% of colon cancers arise?
chromosomal instability neoplasm (CIN)
Through which molecular do 15% of colon cancers arise (the portion that don’t arise b/c of chromosomal instability neoplasms/CIN)?
microsatellite instability –> germ line HNPCC/lynch syndrome or CpG island methylation (CIMP)
Gains or losses of whole or parts of chromosomes frequently occurring with each cell division resulting in karyotypic cell to cell variability
chromosomal instability = CIN
Uncontrolled methylation of CpG in promoter region leading to gene activation
CIMP= cpg island methylator phenotype
Insertions or deletions in areas of di and tri nucleotide repeats.
MSI = microsatellite instability
CIN arises from collapse of what DNA feature?
fork collapse due to DNA replication stress (decreased dNTP pool,DNA damage blocking replication, inaccessibility due to tertiary structure) leads to breaks and recombination and missing bits of chromosomes
CIMP arises from what DNA feature?
methylation of cytosine in CpG islands in promoter regions is normal but when hypermethylated, can shut off key genes
Microsatellite instability arises from what DNA feature?
normally di and trinucleotide repeats but are prone to slippage leading to deletions via premature stop codons or formation of loops
How does DNA mismatch repair work?
in areas of microsatellite instability, there is a set of MSH and PMS proteins that recognize the errors and repairs them –> hypermethylation or germline hits can knock these guys out
How does base excision repair work?
Guanine can be easily oxidized to look like thymidine –> can disrupt the DNA being made–> MTH1 can remove OH-G from the nucleotide pool and OGG1 can remove it once incorporated into DNA and MYH can remove misincorporated A on complementary strand
- recessive germline hits can knock these guys out
How does familial adenomatous polyposis occur?
germ line APC mutation + somatic hit = Knudson two hit hypothesis –> multiple small bowel adenomas –> each could become a cancer over 10 years –> results in a really high risk of cancer at an early age + extraintestinal manifestations (note that fundic gland polyps don’t increase their risk of gastric cancer)
*rare
3 common extraintestinal manifestations of FAP
desmoid tumors, osteomas, CNS Turcot’s syndrome
Which hits are required in hereditary non-polyposis colon cancer?
original hit in DNA mismatch repair + 2 hits in APC + cancer hits
What mismatch repair genes are implicated in HNPCC?
hMLH1,2,6 and PMS2 –> lynch syndrome
T/F HNPCC are linked to other malignancies
T –> colorectal adenocarcinoma, endometrial, ovarian, pancreatic, etvc
Muirr-Torre Syndrome
HNPCC w/ sebaceous lesions + GI malignancy
Turcot’s Syndrome
GI+brain: GI tumors and GBM (HNPCC) or GI tumors and medulloblastoma (FAP)
Is there a germline mutation that can lead to hypermethylation in states in colon cancer?
no –> in the course of tumor evolution can sporadically acquire the changes necessary to become cancer
which gene _____ is highly mutable in microsatellite instability repair processes.
hMLH1 –> 90% due to promoter hypermethylation –> BRAFV600E is a common mutation in these cases but not germline cases
IHC for mismatch repair proteins
MSH2 and MLH1
Which gene is commonly mutated in excision repair?
myh –> missense mutations leading to somatic transversions –> recessive, caucasian, multiple adenomas like FAP (but no germline mutations in FAP)
Which colon polyps have no malignant potential?
hyperplastic colon polyps (kras)
Are inflammatory/filiform polyps dysplastic?
no
* occur due to IBD repair or sporadically
What is a juvenile polyp?
Most common polyp in pediatrics and is due to SMAD mutations –> usually not individual risky for malignancy …
however, juvenile polyposis which is due to germline SMAD4 mutations has a definite increased risk of cancer
What gene mutations are responsible for 50% of Peutz-Jegher’s Syndrome and how does the syndrome present?
STK11/LKB1 –> mucocutaneous melanin pigmentation, hamartomatous polyps in GI tract, increase risk of all cancers (95%)
What mutations lead to epithelial tumors with neuroendocrine differentation?
MEN
