Lecture 21: Neoplasia III

Question 1

CRC staging

Answer 1

1 determinant for outcome

T: tumor depth
N: node involvement
M: metastasis

Question 2

CRC prevention

Answer 2

5-10 yr progression from benign -> malignant polyp -> advanced CRC
- Red flag symptoms
- CRC screening
- Removal of adenoma precursors (size -> polyp danger)

Question 3

CRC screening methods

Answer 3

• Colon-/sigmoidoscopy
• CT colonography
• Fecal Occult Blood Test (FOBT)
• Fecal Immunohistochemical Test (FIT)
• Fecal DNA test (Cologuard)
• Cell free DNA blood test (cfDNA)

Question 4

2 progression paths from normal colon to CRC

Answer 4

1. APC: Adenomatous Polyposis Coli gene
2. KRAS-BRAF-MAPK path: serrated polyp neoplasia

Question 5

APC gene

Answer 5

Cytoplasmic protein in colon mucosal crypt; sequesters beta-catenin for growth, adhesion
- Mx -> Wnt -> division w/o maturation

Question 6

APC gene CRC progression

Answer 6

1. APC Mx -> tubular adenoma dysplasia (Upreg. COX-2, EGFR, hypomethyl.)
2. Advanced adenoma (KRAS oncogene, villous/tubulovillous polyp)
3. Low to high grade dysplasia (cancer w/o invasion, often p53 Mx, nuclear atypia)
4. CRC chr. changes (CIN -> aneuploid, del18q for DCC, SMAD2/4 suppressors)

Question 7

Molecular mechanisms for colon neoplasia progression

Answer 7

1. CIN, aneuploidy
   Serrated path:
2. CpG island methylation (CIMP-H)
3. MMR deficiency -> MSI

Question 8

Serrated polyp neoplasia pathway

Answer 8

1. KRAS or BRAF oncogene Mx -> precursor lesions -> senescence (serrated not dysplastic, hypermature)
2. Hyperplastic polyps: 2 variations
   - KRASmut GCHP
   - BRAFmut MVHP
3. SSA or TSA pathways, depending on SSI

Question 9

KRASmut GCHP

Answer 9

Goblet Cell Hyperplastic Polyp
- Minimal serration
- KRAS Mx

Question 10

BRAFmut MVHP

Answer 10

MicroVesicular Hyperplastic Polyp
- Prominent serration
- BRAF Mx

Question 11

Senescence

Answer 11

Adaptation to oncogene activation causing G1 arrest
e.g. BRAF -> upreg. of p16, p14 cell cycle inhibitors -> senescence
- Can be inactivated by CIMP

Question 12

Classes of serrated polyps

Answer 12

1. Self-limited:
   - Hyperplastic GCHP, MVHP
2. Cancer precursor:
   - Sessile Serrated Adenoma
   - Traditional Serrated Adenoma

Question 13

SSA carcinoma

Answer 13

Sessile Serrated Adenoma
- BRAFmut
- Diploid
- MMR deficit -> microsatellite instability (MSI)
- CIMP-H
- Well-differentiated serrated glands
- Peri/intratumoral lymphocytes

Question 14

TSA carcinoma

Answer 14

Traditional Serrated Adenoma
- BRAF or KRASmut
- CIMP-H of suppressors
- MSS (microsatellite stable)
- Lymphatic invasion