Colon Cancer Flashcards Preview

HMS Oncology > Colon Cancer > Flashcards

Flashcards in Colon Cancer Deck (50):
1

Technology which made cancer genomics a possibility for the clinic rather than just research labs

Next generation sequencing

2

Moore's Law statement

The price of x developing technology will decrease by half every 18 months

3

depth of coverage

# of sequences/reads at a given site

4

variant allele fraction

For a given mutation/variant

 

The percent of sequence reads that contain the mutation

5

Components of a cancer genome panel

Translocations

Copy # variants

Somatic variants (sequence mutations)

6

nullisomy

homozygous deletion

7

Copy Number Assessment plot

Plotted as log2( tumor / normal ) vs chromosome # 

8

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

9

Most cases of colon cancer are. . .

sporadic.  

 

There is slight heritability for colon cancer, but no clear Mendelian pattern.

10

__% of colon cancer cases have a hereditary component.

~25-30% of colon cancer cases have a hereditary component.

11

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

12

Drugs that show a modest protective effect against CRC

Antiinflammatories!

 

Aspirin and NSAIDs

13

Most CRC deaths are preventable by. . .

early detection

 

This is why colonoscopy is so important

14

Polyp

Generic term for any localized lesion protruding above the surrounding mucosal surface of the colon

15

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.

16

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.

17

Foci of ___ can often be detected within adneomas.

Foci of carcinoma can often be detected within adneomas.

18

While hyperplastic polyps are typically benign, . . .

. . . they correlate with increased risk of adenoma, likely due to shared underlying factors.  

19

Juvenile hyperplastic polyposis syndrome

predisposes to development of many hyperplastic polyps in chilren.

 

Also has a substantially increased risk of adenoma and colorectal carcinoma.

20

CIMP

CpG island methylation phenotype

21

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

22

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

23

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

24

APC sequence diagram

25

Turcot syndrome

Combination of colorectal polyposis with brain tumors (particularly pediatric medulloblastoma)

26

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

27

APC in Wnt signaling

28

____ % of sporadic colorectal adenomas and carcinomas have somatic mutations inactivating APC

80% of sporadic colorectal adenomas and carcinomas have somatic mutations inactivating APC

29

β-catenin's binding partners for transcription

Tcf / Lef

30

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

31

APC loss of function as a dual-hit

APC loss-of-function both:

1.  leads to lack of need for extracellular input for β-catenin-mediated transcription

2.  leads to loss of upstream inhibitory effects normally executed by feedback inhibitors produced by β-catenin signaling

32

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.

33

Min

Multiple intestinal neoplasia, mouse line.  

Germline truncated APC

 

34

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.

35

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.

 

 

36

LKB1/STK11

Negative regulator of mTOR.  Tumor suppressor gene.

37

CDK8

A component of the Mediator Complex.  Associates with Cyclin C.  

38

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.

39

16% of CRCs display a ____ phenotype.

16% of CRCs display a hypermutated phenotype.

 

These may contain as many as ~700 nonsilent mutations per cell

40

Fecal screening tests

Can detect blood in small fecal samples.

41

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

42

Specialized guaiac occult-blood tests

Like Hemoccult SENSA and others

 

High sensitivity than the standard test, reaching ~50 to 75% sensitivity.

43

Fecal immunochemical test

Tests for human hemoglobin, albumin, and other blood components.  More specific than standard guaiac blood tests, and with 60-85% sensitivity.

44

Barium enema examination

Useful for outlining late-stage cancerous lesions, but of little use for detecting important early cancer precursors

45

CT colonography

Low sensitivity and specificity.  Of little clinical value despite its use.

46

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.

47

Colonoscopy is not recommended routinely for patients over ___.

Colonoscopy is not recommended routinely for patients over 75

48

Approximately ___% of mutated cancer genes are dominantly acting

Approximately 90% of mutated cancer genes are dominantly acting

49

p53 mutation is usually a ___ event in colon cancer.

p53 mutation is usually a late event in colon cancer.

50

Effects of gender on CRC rates

None detectable!  Men and women have very similar colons.