Colorectal cancer

Question 1

Overview of cancer

Answer 1

genetic disease in which single clone of cells accumulate heritable changes that result in cancer phenotype

Question 2

CRC disease burden

Answer 2

• 2nd leading cause of cancer death in US –> 11%
• significant in western world
• African-Americans have highest incidence (low screening rates)
• men develop CRC at higher rates than women

Question 3

Sporadic colon cancer

Answer 3

disease of old age

Question 4

General categories of CRC

Answer 4

Hereditary syndromes (FAP, Lynch) --> ~5% (autosomal dominant)
Sporadic --> ~95%

Question 5

Molecular level of CRC types

Answer 5

1. APC pathway –> chromosomal instability CIN
2. Mismatch repair –> microinstability MIN
   - both have hereditary and sporadic forms

Question 6

Metastasis

Answer 6

local site of CRC metastasis are mesenteric lymph nodes

• distant site is often liver
• rectal cancer spreads to lungs because of IVC drainage

Question 7

Testing for CRC

Answer 7

progression to carcinoma may take 10-15 years –> have a large window of opportunity for diagnosis and treatment
- strong evidence that screening asymptomatic individuals decreases CRC incidence and mortality

Question 8

CRC Screening

Answer 8

Colonoscopy --> GOLD STANDARD
CT colonography --> may need to biopsy anyway --> can miss flat lesions and rectal tumors
Flexible sigmoidoscopy, barium enema
Stool DNA - PCR analysis
Fecal occult blood

Question 9

Mutational genetic testing is suspected family disease

Answer 9

always test proband (person to seek medical attention first) first!
- if mutation identified, family members can be tested with 100% accuracy

Question 10

Environmental factors in CRC

Answer 10

diet plays a particularly major role

- can act synergistically and interact with selected genetic changes in tumors

Question 11

Increased risk of CRC

Answer 11

• old age, male, obesity, smoking, lack of exercise, IBS

- red meat, omega-6, alcohol, low calcium and folate, heterocyclic amines, bile acids

Question 12

Decreased risk of CRC

Answer 12

• estrogen, chemopreventive agents (NSAIDs, statins?)

- marine oils, omega-3, fruits & veggies, soy, fiber, folate, calcium, garlic, vitamins, flavinoids

Question 13

Special note on folate

Answer 13

generally it appears to prevent CRC –> but once CRC has arisen, folate acts as cancer promoter

Question 14

epigenetics and CRC

Answer 14

hypermethylation and hypomethylation in promoter regions of key genes have been observed –> leading to heritable changes in gene expression –> can either increase or decrease expression

Question 15

What is characteristic of all CRC?

Answer 15

genomic instability –> occurs early and contributes to development of cancer
- can be MMR, base excision repair, proper segmentation of chromosomes

Question 16

APC pathway/CIN

Answer 16

• complete disruption of APC and its pathway (Wnt/beta-catenin) –> APC loss MUST come first (gatekeeper)
• CIN
• mostly left side
• often loss of p53, increased RAS activity
• FAP
• 85% of CRC –> poor prognosis

Question 17

MMR/MIN pathway

Answer 17

• complete loss of MMR (MIN)
• mostly right side
• methylator phenotype common
• Lynch
• 15% of CRC –> better prognosis

Question 18

Key role of APC in CRC

Answer 18

APC loss is the rate-limiting step in adenomagenesis

- classic tumor suppressor gene (2-hit hypothesis)

Question 19

How does APC resist cancer?

Answer 19

likely multiple ways

• regulation of beta-catenin and Wnt pathway is well known and its most important function
• loss of APC leads to build up of beta-catenin and induction of growth, cell proliferation and cancer

Question 20

K-Ras mutation

Answer 20

currently most effective clincal predictive marker

• it’s a key signaling molecule that acts downstream of receptor tyrosine kinase such as EGFR
• K-ras mutation associated with poor prognosis and survival

Question 21

CIN

Answer 21

precedes and causes aneuploidy

- detected by karotyping and FISH

Question 22

Familial Adenomatous Polyposis

Answer 22

autosomal dominant as heterozygous mutation in APC –> need loss of heterozygosity (2-hits)

• thousands of polyps by 15 y.o.
• can have attenuated form where it has later presentation

Question 23

Modifier genes

Answer 23

host genetic factors can influence phenotype –> both tumor incidence and development

Question 24

MIN

Answer 24

errors in DNA replication occur normally and are repaired by MMR, when MMR genes are defective, slippage occurs and mutations become fixed
- detected by PCR

Question 25

Lynch Syndrome

Answer 25

HNPCC –> autosomal dominant, inherit single mutant copy of MMR gene –> 2nd hit (LOH)

• MMR defects primarily affect progression not initiation
• high risk for other cancers

Question 26

Carcinoembryonic antigen (CEA)

Answer 26

glycoprotein that can be detected in serum and is marker of CRC progression

Question 27

Clonal evolution hypothesis

Answer 27

all tumor cells have equal probability of driving cancer progress

Question 28

Cancer stem cells hypothesis

Answer 28

tumors contain very small fraction of epigenetically programmed cancer stem cels

Question 29

Clonal evolution of cancer stem cells hypothesis

Answer 29

cancer stem cells acquire new changes that permit them to drive cancer process

Question 30

Diagnostic Genetic Testing

Answer 30

establish if diagnosis is genetic

- based on personal history

Question 31

Predictive Genetic Testing

Answer 31

purpose –> risk and surveillance assessment

• Family history EXTREMELY important
• need to have 1st degree relative with known gene mutation