Global events in CRC

Question 1

CRCs acquire genetic instability in sterotypic ways that favour the accumulation of hundreds to thousands of ……… …………. .

Answer 1

Somatic abberations

Question 2

About 80% of tumours display widespread chromosomal gains, losses and translocations. These phenomena lead to three genetic alterations - list them

Answer 2

Gene amplifications
Genetic rearrangements
Genetic deletions

Question 3

How many nonsynonymous point mutations do CRCs typically carry?

Answer 3

fewer than 100

Question 4

Chromosomal segregation defects may account for chromosomal instability (CIN), but few specific gene defects are implicated confidently. There are weak associations of CRC with structural changes on which chromosomes?

Answer 4

8 and 18, but specific cytogenetic changes barely influence disease patterns or patient outcomes

Question 5

About 15% of CRC appear to be globally euploid but carry thousands of point mutations and small deletions or insertions near nucleotide repeat tracts. What does euploid mean? What is the term for CRC with these many point mutations/deletions/insertions?

Answer 5

Euploid - a balanced set of chromosomes

These tumours are known as MSI-hi

Question 6

Features and molecular determinants of disease progression in MSI+ tumours differ from those associated with …

Answer 6

CIN

Question 7

BRAF V600E mutations are more common in what type of precursor adenoma?

Answer 7

MSI + precursor adenomas

Question 8

Hypermutability associated with both MSI or CIN results in many changes that are inconsequential or even detrimental to tumours. The presense of a mutaiton does not signify a pathogentic role. List the two features that are used to distinguish driver from passenger mutations

Answer 8

1. Appearance in a high fraction of tumour specimens

2. Ideally, the experimental denostration of its contribution to a malignant property

Question 9

Give two examples of epigenetic mechanisms that may affect CRC. Which is better characterised in CRC?

Answer 9

1. Covalent histone modifications

2. Methylation of cytosine residues in DNA - this is better characterised in CRC

Question 10

What type of content in promoters is a particular target for methylation?

Answer 10

5’-CpG-3’ dinucleotide pairs, in localised areas of high CpG content in promotors

Question 11

What is the effect of CpG methylation in promotors?

Answer 11

Silencing of adjacent genes

Question 12

Do CRCs have lower or higher DNA methylation than normal tissue? By what percent?

Answer 12

Lower, by 8-15%

Question 13

What type of methylation may decrease the fidelity of chromosomal segregation?

Answer 13

Reduced pericentromeric methylation

Question 14

What changes at the IGF2 location increase CRC risk?

Answer 14

Altered methylation or loss of imprinting at the LGF2 locus increases CRC risk. This suggests broad effects of global hypomethylation on cell growth.

Question 15

Do all CRCs demonstrate hypmethylation?

Answer 15

No, a subset shows coordinated hypermethylation of CpG rich promoters

Question 16

What is the phenotypic term for the CRC subset of tumours with hypermethylation of CpG rich promotors?

Answer 16

CpG island methylator phenotype (CIMP)

Question 17

What effect does CIMP phenotype have on two tumour suppressor genes?

Answer 17

CIMP causes transcriptional attenuation of tumour suppressor genes such as H1C1 and Wnt-inhibiting SFRPs.

Question 18

What must CIMP phenotype be differentiated from?

Answer 18

KRAS-mutant CIN disease

Question 19

What 3 features distinguish CpG island methylator phenotype tumours from KRAS mutant CIN disease?

Answer 19

1. Origin in sessile serrated adenomas
2. Strong association with BRAF mutant, right sided MSI hi tumours with MLH1 gene methylation
3. Distinctive gene expression patterns

Question 20

Some features overlap (e.g. MMR and CIMP), but what 3 categories to CRCs tend to fall into?

Answer 20

1. Traditional
2. Alternative
3. Serrated

Question 21

What category of CRC is CIN characteristic of?

Answer 21

Traditional CRC

Question 22

What category of CRC is DNA MMR deficiency characteristic of?

Answer 22

Alternative CRC

Question 23

What category of CRC is CIMP characteristic of?

Answer 23

Serrated CRCs

Question 24

What two classifications did the cancer genome atlas (TCGA) network give CRCs? What are the underlying genetic associations for each group?

Answer 24

1. Non hypermutated, generally CIN+

2. Hypermutated, encompassing MMR and CIMP

Question 25

Give another variant on the classical adenoma-carcinoma sequence. What is the risk of CRC associated with this disease? Why are these patients at risk of CRC?

Answer 25

UC - 10 fold risk of CRC. Probably as a result of ongoing mucosal injury and repair.

Question 26

What two type of lesions do UC associated CRCs tend to arise from?

Answer 26

1. Flat adenomatous plaques

2. Nonadenomatous areas of dysplasia

Question 27

Compared to sporadic cases, (??in UC?), …… mutations occur earlier in the cancer sequence, ….. inactivation is less frequent, and ………… of the …. tumour suppressor gene is more common.

Answer 27

Compared to sporadic cases, (??in UC?), TP53 mutations occur earlier in the cancer sequence, APC inactivation is less frequent, and METHYLATION of the p16INK4a tumour suppressor gene is more common.