Colon Cancer Flashcards
Technology which made cancer genomics a possibility for the clinic rather than just research labs
Next generation sequencing
Moore’s Law statement
The price of x developing technology will decrease by half every 18 months
depth of coverage
of sequences/reads at a given site
variant allele fraction
For a given mutation/variant
The percent of sequence reads that contain the mutation
Components of a cancer genome panel
Translocations
Copy # variants
Somatic variants (sequence mutations)
nullisomy
homozygous deletion
Copy Number Assessment plot
Plotted as log2( tumor / normal ) vs chromosome #
Driver mutation
Any mutation that gives a cell a growth advantage over other cells lacking the mutation.
May be in an oncogene OR a TSG, and there may be many
Most cases of colon cancer are. . .
sporadic.
There is slight heritability for colon cancer, but no clear Mendelian pattern.
__% of colon cancer cases have a hereditary component.
~25-30% of colon cancer cases have a hereditary component.
Risk factors for CRC:
- Family history (slight effect)
- chronic IBD
- heavy alcohol use
- diet rich in red meat and unsaturated fat and refined starch, low in vegetables
Drugs that show a modest protective effect against CRC
Antiinflammatories!
Aspirin and NSAIDs
Most CRC deaths are preventable by. . .
early detection
This is why colonoscopy is so important
Polyp
Generic term for any localized lesion protruding above the surrounding mucosal surface of the colon
Hyperplastic polyps
Particularly small, ~5 mm in size or less.
Histologically characterized by distended goblet cells and serrated glands. Genearlly considered to be more benign polyps.
Adenomatous polyp
Also called an adenoma. Believed to give rise to most cases of CRC.
Grossly, adenomas are larger than hylerplastic polyps. They may be described as pedunculated (with a stalk), sessile (flat), or semisessile.
Histologically, dysplasia and glandular architecture are analyzed to grade the adenoma. Attached is a section of a sessile serated adenoma.
Foci of ___ can often be detected within adneomas.
Foci of carcinoma can often be detected within adneomas.
While hyperplastic polyps are typically benign, . . .
. . . they correlate with increased risk of adenoma, likely due to shared underlying factors.
Juvenile hyperplastic polyposis syndrome
predisposes to development of many hyperplastic polyps in chilren.
Also has a substantially increased risk of adenoma and colorectal carcinoma.
CIMP
CpG island methylation phenotype
Familial adenomatous polyposis
Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium (CHRPE)
Mutation in APC
Genes which frequently lead to colon cancer when mutated at the germline level
APC
PTEN
MSH and MYH (DNA repair)
POLD/POLE (proofreading domains of DNA polymerases)
LKB1/STK11
Only about ____ of all CRC cases are associated with defined highly penetrant cancer syndromes
Only about 5% of all CRC cases are associated with defined highly penetrant cancer syndromes
APC sequence diagram
Turcot syndrome
Combination of colorectal polyposis with brain tumors (particularly pediatric medulloblastoma)
APC vs APC/C
APC = Adenomatous polyposis coli, part of the β-catenin degradation complex.
APC/C = Anaphase-promoting complex / cyclosome, E3 ubiquitin ligase for Cyclin B and Securin
APC in Wnt signaling
____ % of sporadic colorectal adenomas and carcinomas have somatic mutations inactivating APC
80% of sporadic colorectal adenomas and carcinomas have somatic mutations inactivating APC
β-catenin’s binding partners for transcription
Tcf / Lef
Prominent among the critical proteins encoded by β-catenin/TCF-regulated genes are. . .
. . .many genes which act as feedback inhibitors of Wnt signaling.
AXIN2, DKK1, NKD1, APCDD1, and WIF-1
APC loss of function as a dual-hit
APC loss-of-function both:
- leads to lack of need for extracellular input for β-catenin-mediated transcription
- leads to loss of upstream inhibitory effects normally executed by feedback inhibitors produced by β-catenin signaling
AXIN2 dual role
AXIN2 both acts as a Wnt feedback inhibitor, and can promote EMT and invasive phenotypes via other interactions.
When APC loses its function, AXIN2 will accumulate but will have no effect on Wnt signaling, and so it will promote EMT and invasion aberrantly.
Min
Multiple intestinal neoplasia, mouse line.
Germline truncated APC
Dnmt1 and Dnmt3
DNA methyltransferases
Epigenetic regulators which induce silencing of genes. Revealed to have contributions to polyposis pathogenesis in Min mice and APC LoF patients.
Reveals a strong role of epigenetic silencing in the colon cancer phenotype.
MYH
Encodes the protein MutYH, a part of the base excision repair pathway. Mutation causes MAP (MYH associated polyposis), predisposes to CG-to-AT transversions.
LKB1/STK11
Negative regulator of mTOR. Tumor suppressor gene.
CDK8
A component of the Mediator Complex. Associates with Cyclin C.
Mediator complex in relation to Cyclin-CDKs
Certain Cyclin-CDKs associate with the mediator complex of nearly all RNA Pol II-dependent genes in order to convey information about the state of the cell as part of the decision on whether or not to transcribe.
16% of CRCs display a ____ phenotype.
16% of CRCs display a hypermutated phenotype.
These may contain as many as ~700 nonsilent mutations per cell
Fecal screening tests
Can detect blood in small fecal samples.
Standard guaiac fecal occult-blood test
Detects peroxidase activity of heme and is not specific for human blood.
Only 33-50% sensitivity for colon cancer
Specialized guaiac occult-blood tests
Like Hemoccult SENSA and others
High sensitivity than the standard test, reaching ~50 to 75% sensitivity.
Fecal immunochemical test
Tests for human hemoglobin, albumin, and other blood components. More specific than standard guaiac blood tests, and with 60-85% sensitivity.
Barium enema examination
Useful for outlining late-stage cancerous lesions, but of little use for detecting important early cancer precursors
CT colonography
Low sensitivity and specificity. Of little clinical value despite its use.
Of at-risk patients who go for colonoscopy,. . .
0.5-1% of patients have colon cancer, and 5 to 10% have an advanced neoplasm which may be removed intraoperatively.
Colonoscopy is not recommended routinely for patients over ___.
Colonoscopy is not recommended routinely for patients over 75
Approximately ___% of mutated cancer genes are dominantly acting
Approximately 90% of mutated cancer genes are dominantly acting
p53 mutation is usually a ___ event in colon cancer.
p53 mutation is usually a late event in colon cancer.
Effects of gender on CRC rates
None detectable! Men and women have very similar colons.
