54. Molecular pathogenesis of colorectal cancer

Question 1

chromosomal instability pathway

Answer 1

normal colon –> mutation/ loss of APC ( FAP) –> low intercellular adhesion, ncreased proliferation –> colon at risk ( for polyp/adenoma) –> kRAS mutation –> unregulated intracellura signaling –> adenoma / polyp –> loss of tumor suppressor genes ( p 53 , DCC) –> TUMORGENESIS —> CARCINOMA

Question 2

Microsatellite instability pathway

Answer 2

mutation or methylation of mismatch repair genes ( eg. MLH1) –> Lunch syndrome and some sporadic CRC ( via serrated polyp pathway )

Question 3

• In the microsatellite instability pathway, what type of mutation is responsible for carcinogenesis in colonic epithelium?

Answer 3

DNA mismatch repair gene mutations, which accumulate (they occur sporadically or are defective in Lynch syndrome)

Question 4

• A man with colonic polyps is found to have colorectal cancer. This process was likely set in motion by the loss of function of which gene?

Answer 4

APC gene (loss of function causes increased proliferation and decreased intracellular adhesion)

Question 5

• The KRAS gene mutation leads to dysregulation of what cellular function?

Answer 5

Signal transduction (the cell will respond abnormally to growth factors, contributing to tumorigenesis)

Question 6

• Both ____ and ____ gene mutations must be present for colonic adenoma formation. The ____ gene mutation alone simply puts the colon at risk.

Answer 6

APC, KRAS; APC

Question 7

• Loss of function of which tumor suppressor genes is often the last step in malignant transformation of colonic epithelial cells?

Answer 7

p53, DCC

Question 8

• What molecular pathway most commonly generates sporadic colorectal cancer?

Answer 8

APC/β-catenin (chromosomal instability) pathway

Question 9

• What three gene mutations must generally occur for colorectal cancer to develop, and in what order do they occur?

Answer 9

In order, they are loss of APC, KRAS, and p53 & DCC (AK-53)

Question 10

• A patient has a family history of Lynch syndrome due to genetic microsatellite instability. Are there any physical signs other than cancer?

Answer 10

There are none, despite the accumulation of mutations (no defined morphologic correlates)

Question 11

• APC gene mutations lead to dysregulation of what cellular function? Can any gross findings be seen on colonoscopy?

Answer 11

Intercellular adhesion (there is decreased intercellular adhesion and increased proliferation); no, as the colon will appear normal

Question 12

• KRAS gene mutations lead to dysregulation of what cellular function? Can any gross findings be seen on colonoscopy?

Answer 12

Intracellular signal transduction becomes unregulated; yes, as colonic adenomas may develop and be visible

Question 13

• In the CRC chromosomal instability pathway, indicate whether each gene in the sequence is a tumor suppressor or a proto-oncogene.

Answer 13

APC is a tumor suppressor, KRAS is a proto-oncogene, p53 and DCC are tumor suppressors