Multistep models of colorectal tumorigenesis

Question 1

The …………-……….. sequence best models the genetic basis of CRC?

Answer 1

Adenoma-carcinoma sequence

Question 2

CRCs invariably arise within benign precursor polyps. List the four features these polyps show.

Answer 2

1. Epithelial overgrowth
2. Dysplasia
3. Abnormal differentiation
4. Sometimes, foci of tissue invasion

Question 3

What type of polyps are the most significant risk for development of CRC?

Answer 3

Pedunculated polyps >1cm

Question 4

A pedunculated polyp >1cm harbours a …..% risk of progressing to CRC over …. years. Endoscopic removal of these adenomas reduces CRC incidence and mortality.

Answer 4

15% over ten years.

Question 5

The prevalence of polyps in the US is estimated to be ….% at age 70. This dwarfs the 6% lifetime risk of developing CRC because few adenomas progress to invasive cancer, and the successive abberations that promote invasion take … to …. decades to accumulate.

Answer 5

50% at age 70.

1-3 decades to accumulate

Question 6

What are the two types of serrated CRC precursor lesion forms?

Answer 6

• Serrated adenomas with cytologic dysplasia

- Sessile serrated adenomas without cytologic dysplasia

Question 7

A serrated adenoma with cytologic dysplasia may evolve into what type of CRC with what underlying genetic abnormality?

Answer 7

Common CRCs with chromosomal instability and KRAS mutation

Question 8

A sessile serrated adenoma without cytologic dysplasia may evolve into what type of CRC with what underlying genetic abnormality?

Answer 8

CRCs with microsatellite instability (MSI-hi), BRAF mutation, and abundant CpG island methylation.

Question 9

Approximately ….% of CRCs arise within serrated lesions, retain a serrated epithelium with characteristic ……… ……………., and carry a relatively ……. prognosis.

Answer 9

8%, nuclear morphology, poor prognosis.

Question 10

Cancer progression has both genetic and epigenetic underpinnings. What is meant by the terms genetic and epigenetic in this context?

Answer 10

Genetic = somatic mutations
Epigenetic = unrelated to altered DNA sequence

Question 11

Alterations in several classes of genes drive tumours. List three.

Answer 11

1. Oncogenes
2. Tumour supressor genes (including those that assist with repair of damaged DNA)
3. Epigenetic modifiers - those that help control other genes.

Question 12

Selected mutations appear at high frequencies in different tumour types and stages, allowing for the assignment of typical sequences, although mutational …… can vary and most tumours do not carry ….. ………… .

Answer 12

Selected mutations appear at high frequencies in different tumour types and stages, allowing for the assignment of typical sequences, although mutational ORDER can vary and most tumours do not carry EVERY ALTERATION .

Question 13

Few specific mutations correlate strongly with particular ………. …….., or …….. …….. . Most affect multiple cellular functions

Answer 13

Few specific mutations correlate strongly with particular histologic features, or patient survival . Most affect multiple cellular functions.

Question 14

Particular …………… do define CRC subtypes, and response to certain therapies

Answer 14

genotypes

Question 15

Where do MSI-hi tumours tend to arise? Are the associated with good or poor prognosis?

Answer 15

The ascending colon

Good prognosis

Question 16

In stage II MSI tumours, which adjuvant treatment provides little benefit?

Answer 16

5-fluorouracil

Question 17

Which mutations account for approximately half of all cases?

Answer 17

KRAS and BRAF

Question 18

How do KRAS and BRAF mutations affect response to adjuvant therapy?

Answer 18

KRAS and BRAF limit response to epidermal growth factor receptor antibodies (EGFR antibodies). They are contraindications for this treatment.