Tumors of the Small and Large Bowel

Question 1

Are adenocarcinomas and neuroendocrine tumors (NETs) derived from different cells of origin?

Answer 1

Apparently not, they just have different mutations that drive different tumor phenotypes.

Question 2

Where are most NETs?

Answer 2

in the GI tract.

Question 3

When should people without other risk factors start getting colonoscopies?

Answer 3

At age 50.

Question 4

6 risk factors for GI cancers? Which one is most important?

Answer 4

Age - most important
Diet
Environment
Obesity
Genetic
IBD

Question 5

Does chronic mucosal injury, eg. from UC, increase cancer risk?

Answer 5

Yup.

Question 6

What happens if you knock out both copies of APC?

Answer 6

Adenoma. Loss of APC is sufficient for adenoma. She emphasized this a lot.

Question 7

About how long, on average, does it take to go from adenoma to adenocarcinoma?

Answer 7

About 10 years.

Question 8

Where must colon tumors get before they can metastasize? How does this contrast from other parts of the GI tract?

Answer 8

The submucosa.

In other parts of the GI tract, tumors can metastasize via lymphatics in the basal lamina.

Question 9

4 autosomal dominant genetic conditions that predispose to colon cancer? What’s affected in each?

Answer 9

Hereditary Nonpolyposis Colon Cancer (HNPCC) - mismatch repair.
Familial Adenomatous Polyposis (FAP) - APC.
Juvenile. SMAD-4.
Peutz-Jeghers. STK-11/LKB-1

Question 10

Most common site for adenomas in the colon?

Answer 10

The cecum.

Question 11

What effect do each APC and Wnt have on beta-catenin?

Answer 11

APC promotes beta-catenin degradation.

Wnt promotoes beta-catenin survival -> acting as transcription factor.

Question 12

What does beta-catenin do?

Answer 12

Promotes cell proliferation.

Question 13

Where in the crypt should there and shouldn’t there be Wnt/ beta-catenin activity?

Answer 13

There should be activity at the base of the crypt (stem cells, etc.).
There should not be activity at the surface epithelium.

Question 14

How does beta-catenin affect adhesion?

Answer 14

It seems to be important in cadherin function.

Question 15

2 major molecular classifications of colon cancer?

Answer 15

Chromosomal instability neoplasms (CIN) - the chromosomes break and rearrange.
Microsatellite instablity - germ line or sporadic.

Question 16

What’s CIMP?

Answer 16

CpG island methylator phenotype: uncontrolled methylation -> gene inactivation.

Question 17

What is microsatellite instability (MSI)?

Answer 17

Insertion or deletions in areas of di- or trinucleotide repeats.

Question 18

What process is thought to lead to chromosomal instability (CIN)?

Answer 18

Fork collapse…. replication fork gets messed up, free ends of DNA stick onto things.

Question 19

3 things that can contribute to fork colllapse / chromosomal instability?

Answer 19

Decreased dNTP pool.
DNA damage that blocks replication.
Alterations in tertiary structure.

Question 20

Name 2 pairs of genes that work to do DNA mismatch repair?

Answer 20

MSH2 and MSH6.

MLH1 and PMS2.

Question 21

What protein removes hyrdroxylated guanine (8-OH-G) from the nucleotide pool?

Answer 21

MTH1

Question 22

What protein removes 8-OH-G after it’s been incorporated into DNA?

Answer 22

OGG1

Question 23

What protein removes mis-incorporated A (caused by 8-OH-G)?

Answer 23

MYH

responsible for an autosomal recessive colon cancer syndrome

Question 24

In what gene do people already have 1 hit when they have FAP? Result?

Answer 24

APC.
Recall 2 hits in APC -> adenoma.
People with FAP have tons of adenomas, thus more chances of progression to cancer.

Question 25

Low yield?: 3 extra-intestinal tumors that people with FAP get?

Answer 25

Desmoid tumors
Osteomas
CNS
- probably just more important that some variants of FAP cause extra-intesintal tumors.

Question 26

What’s the syndrome associated with HNPCC? (genes?) Take-home point about how these tumors behave?

Answer 26

Lynch syndrome. (MLH1 / PMS2, MSH2 / MSH6)

These tumors do go through dysplasia/adenoma before becoming adenocarcinoma, but they do it very rapidly.

Question 27

What’s a way to distinguish between germline vs. acquired mutations in hMLH1?

Answer 27

If aquired (due to hypermethylation), the BRAF V600E mutation will probably be present.

Question 28

Are myh (base excision repair) mutations fairly common?

Answer 28

Yeah.

Question 29

4 types of non-adenoma polyp? Do they have malignant potential (if alone)?

Answer 29

Hyperplastic.
Inflammatory / filliform (result of healing, eg. in UC or CD).
Juvenile (often have mucous cysts, SMAD4 mutation).
Peutz-Jegher (aka Hamartomatous).
No, these don’t have malignant potential. (Juvenile, PJs may if part of syndrome

Question 30

What is Juvenile Polyposis caused by?

Answer 30

Autosomal dominant mutations in SMAD4.

Lots of juvenile polyps, increased cancer risk.

Question 31

What is Peutz-Jegher syndrome? Notable sign?

Answer 31

STK11/LKB1 mutations. Autosomal dominant.
Notable sign: melanin pigmentation spots on mucous membranes.
Hamartomatous polyps throughout GI tract with increased cancer risk.

Question 32

What mutations often drive GI NETs?

Answer 32

MEN mutations

Question 33

Where do GI NETs behave well? Where do they behave poorly?

Answer 33

Appendix: Good (meaning… less aggressive?)

Small intestine: Bad.