Colon Cancer

Question 1

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

Answer 1

Next generation sequencing

Question 2

Moore’s Law statement

Answer 2

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

Question 3

depth of coverage

Answer 3

of sequences/reads at a given site

Question 4

variant allele fraction

Answer 4

For a given mutation/variant

The percent of sequence reads that contain the mutation

Question 5

Components of a cancer genome panel

Answer 5

Translocations

Copy # variants

Somatic variants (sequence mutations)

Question 6

nullisomy

Answer 6

homozygous deletion

Question 7

Copy Number Assessment plot

Answer 7

Plotted as log₂( tumor / normal ) vs chromosome #

Question 8

Driver mutation

Answer 8

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

Question 9

Most cases of colon cancer are. . .

Answer 9

sporadic.

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

Question 10

__% of colon cancer cases have a hereditary component.

Answer 10

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

Question 11

Risk factors for CRC:

Answer 11

• Family history (slight effect)
• chronic IBD
• heavy alcohol use
• diet rich in red meat and unsaturated fat and refined starch, low in vegetables

Question 12

Drugs that show a modest protective effect against CRC

Answer 12

Antiinflammatories!

Aspirin and NSAIDs

Question 13

Most CRC deaths are preventable by. . .

Answer 13

early detection

This is why colonoscopy is so important

Question 14

Polyp

Answer 14

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

Question 15

Hyperplastic polyps

Answer 15

Particularly small, ~5 mm in size or less.

Histologically characterized by distended goblet cells and serrated glands. Genearlly considered to be more benign polyps.

Question 16

Adenomatous polyp

Answer 16

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.

Question 17

Foci of ___ can often be detected within adneomas.

Answer 17

Foci of carcinoma can often be detected within adneomas.

Question 18

While hyperplastic polyps are typically benign, . . .

Answer 18

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

Question 19

Juvenile hyperplastic polyposis syndrome

Answer 19

predisposes to development of many hyperplastic polyps in chilren.

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

Question 20

CIMP

Answer 20

CpG island methylation phenotype

Question 21

Familial adenomatous polyposis

Answer 21

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

Question 22

Genes which frequently lead to colon cancer when mutated at the germline level

Answer 22

APC

PTEN

MSH and MYH (DNA repair)

POLD/POLE (proofreading domains of DNA polymerases)

LKB1/STK11

Question 23

Only about ____ of all CRC cases are associated with defined highly penetrant cancer syndromes

Answer 23

Only about 5% of all CRC cases are associated with defined highly penetrant cancer syndromes

Question 24

APC sequence diagram

Answer 24

Question 25

Turcot syndrome

Answer 25

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

Question 26

APC vs APC/C

Answer 26

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

Question 27

APC in Wnt signaling

Answer 27

Question 28

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

Answer 28

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

Question 29

β-catenin’s binding partners for transcription

Answer 29

Tcf / Lef

Question 30

Prominent among the critical proteins encoded by β-catenin/TCF-regulated genes are. . .

Answer 30

. . .many genes which act as feedback inhibitors of Wnt signaling.

AXIN2, DKK1, NKD1, APCDD1, and WIF-1

Question 31

APC loss of function as a dual-hit

Answer 31

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

Question 32

AXIN2 dual role

Answer 32

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.

Question 33

Min

Answer 33

Multiple intestinal neoplasia, mouse line.

Germline truncated APC

Question 34

Dnmt1 and Dnmt3

Answer 34

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.

Question 35

MYH

Answer 35

Encodes the protein MutYH, a part of the base excision repair pathway. Mutation causes MAP (MYH associated polyposis), predisposes to CG-to-AT transversions.

Question 36

LKB1/STK11

Answer 36

Negative regulator of mTOR. Tumor suppressor gene.

Question 37

CDK8

Answer 37

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

Question 38

Mediator complex in relation to Cyclin-CDKs

Answer 38

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.

Question 39

16% of CRCs display a ____ phenotype.

Answer 39

16% of CRCs display a hypermutated phenotype.

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

Question 40

Fecal screening tests

Answer 40

Can detect blood in small fecal samples.

Question 41

Standard guaiac fecal occult-blood test

Answer 41

Detects peroxidase activity of heme and is not specific for human blood.

Only 33-50% sensitivity for colon cancer

Question 42

Specialized guaiac occult-blood tests

Answer 42

Like Hemoccult SENSA and others

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

Question 43

Fecal immunochemical test

Answer 43

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

Question 44

Barium enema examination

Answer 44

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

Question 45

CT colonography

Answer 45

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

Question 46

Of at-risk patients who go for colonoscopy,. . .

Answer 46

0.5-1% of patients have colon cancer, and 5 to 10% have an advanced neoplasm which may be removed intraoperatively.

Question 47

Colonoscopy is not recommended routinely for patients over ___.

Answer 47

Colonoscopy is not recommended routinely for patients over 75

Question 48

Approximately ___% of mutated cancer genes are dominantly acting

Answer 48

Approximately 90% of mutated cancer genes are dominantly acting

Question 49

p53 mutation is usually a ___ event in colon cancer.

Answer 49

p53 mutation is usually a late event in colon cancer.

Question 50

Effects of gender on CRC rates

Answer 50

None detectable! Men and women have very similar colons.