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GI Week 4 > Colorectal Cancer Overview and Genetics > Flashcards

Colorectal Cancer Overview and Genetics Flashcards

1
Q

CRC is the ____ leading cause of cancer death in the US.

A

2nd leadin gcause

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2
Q

What percentage of the US population will develop CRC and what percentage will develop tumors?

A

5% will have CRC and 50% will develop polyps

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3
Q

Where in the world is CRC most common?

A

the western world - USA, europe, australia, NZ

but not increasing everywhere as places gradually switch to a western diet

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4
Q

What ethic groups have the highest rates of CRC?

A

African american shave highest incidence and present with more advanced disease

but american indians in the great lakes and MN have the highest rate of CRC

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5
Q

Which gender is more ilkely to develop CRC?

A

males

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6
Q

What percentage of CRC will present wiht metastatic disease?

A

30%

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7
Q

Why has there been a recent modest decline in CRC indicence and mortality in the US?

A

improved screening in people over age 50

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8
Q

In what age group is the incidence of CRC increasing?

A

under 50 - those that don’t get screened yet

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9
Q

What percentage of CRC is caused by hereditary syndromes? Sporadic?

A

only 5% are hereditary syndromes

95% are sporadic

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10
Q

At what molecule genetic level, what two types of CRC predominate?

A
  1. APC pathway leading to chromosomal instability

2. Mismatch repair gene pathway that involves microinstability

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11
Q

What is the life risk for carcinoma in sporadic type?

A

only 6%

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12
Q

What is the life risk for carcinoma in FAP?

A

100%

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13
Q

What is the life risk for caricnoma in Lynch syndrome?

A

up to 80%

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14
Q

In what fashion are the familial syndrome sinherited?

A

dominant fashion

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15
Q

True or false: 25-50% of CRC may involve familial susceptibility of some degree even without a familial disorder

A

true

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16
Q

What’s the risk for you if one 1st degree relative gets CRC? Two?

A

10% risk for one

20% risk for two

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17
Q

What is the local site of CRC metastasis

A

mesenteric lymph nodes

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18
Q

What is the most common distant site of metastasis

A

liver

then lung

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19
Q

True or false: proression from normal epithelium to carcinoma usually only takes a few years in CRC?

A

False - it can take as long as 10-15 years (although it varies significantly by tumor and host genetics)

this means there is a huge window of opportunity for diagnosis and treatment

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20
Q

What is the gold standard for CRC screening?

A

colonosopy - 100% acccurate with a 60% reduction rate in mortality

can both diagnose and essentially treat by polyp removal

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21
Q

What are some other options for screening?

A
  1. CT colonography
  2. flex sig
  3. barium enemas
  4. stool DNA and PCR analysis
  5. fecal occult blood
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22
Q

What main analysis do we use to look for microsatellite instability?

A

PCR

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23
Q

When diagnosed in early stages, what is the CRC survival rate?

A

over 90%

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24
Q

What are some general factors that will increase your risk for CRC?

A 
older age
male
obesity and other metabolic syndrome indicators
smoking
lack of exercise
inflammatory bowel disease
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25
Q

What are some general factors that decrease you risk for CRC?

A

estrogen and chemopreventative agnest like NSAIDs, 5-ASA and maybe statins

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26
Q

What are some dietary factors that will increase your risK/

A 
red meat
omega 6 fatty acids and transfats
prcessed meats
alcohol
low caclium and low folate
heterocyclic amines
bile acids
27
Q

What are some dietary factors that will decrease your risk?

A 
marine oils
omega 3 fatty acids
fruits
green leafy veggies
soy and phytoestrogens
fiber, folate, calcium, green tea, garlic, vitamin ACD and E (esp D)
flavenoids, circumin, resveratrol, 
caloric restriction
28
Q

What the special consideration for folate in CRC?

A

It’s probably preventative before CRC develops, but after CRC does arise, folate may act to promote cancer progression

29
Q

How does gut flor affect CRC?

A

it seems that specific gut flora can play a role in obesity and thus affect our CRC risk

30
Q

Which occurs in the promoter region of key genes in CRC - hypomethylation of hypermethylation?

A

both - leading to heritable changes in gene expression (which can functionally act like sequence mutations)

31
Q

What is the classic example of hypermethylation in CRC?

A

hypermethylation and silencing of MLH1 leading to mismatch repair deficiency

32
Q

When does genomic instability typically occur in CRC - early or late in the disease course?

A

probably early - contributes to cancer development

33
Q

Which side of the colon is tpically affected with APC/CIN? MMR/min

A

APC - left side

MMR- right side (has an R in it)

34
Q

What tumor suppressor is typically lost in APC? What signalling pathway increases?

A

lose p53 and increase RAS actiity

35
Q

What is the hereditary syndrome associated with APC?

A

FAP

36
Q

What is the hereditary syndrome associated with MMR?

A

Lynch syndrome

37
Q

Which is more common, APC or MMR?

A

APC - 85% of CRC

MMR is only 15% of CRC

(but all CRC tumors will have many mutations - not just these single ones)

38
Q

Why is APC considered the “gatekeeper” gene in the intestine?

A

because APC loss typically must come first, after which is can proceed thorugh an adenoma-carcinoma sequence over time

39
Q

WHat are two observations that prove this?

A
  1. APC mutations occur at similar rates in both benign and alignant lesions, suggesting they occur early on
  2. APC mutations are seen in th eearliest detectable lesion
40
Q

Why is APC considered a “classic” tumor suppressor gene

A

you need to have a two-hit loss of both copies in order for tumorigenesis to occur

41
Q

How does functional APC resist cancer?

A

regulation of the beta-catenin/Wnt pathway such that when active, it will degrade beta catenin so it can’t act as a transcription factor

aAPC also involved in cell adhesion, migration, cytoskeletal integrity and chromosomal fidelity

42
Q

What is currently the most effective clinically predictive biomarker for CRC?

A

K-ras

it’s a key cell signaling molecule that acts downstream of receptor tyrosin kinases like EGFR

43
Q

Are K-ras mutations (in 40% of CRC) associated with poor or good prognosis?

A

poor prognosis and poor survival

44
Q

What two drugs are ineffective in patients with activating Kras mutations?

A

cetuximab and panitumumab

45
Q

In general, what does chromosomal instability cause?

A

aneuploidy (unusual chromosome number)

detected by karyotype analysis or FISH

46
Q

What is the inherittance pattern of FAP?

A

transmitted in an autosomal dominant fashion as a heteroxygous mutation

RECESSIVE at the cellular level because you need a loss of the good copy before symptoms arise. But they ALWAYS lose the second copy, so the inheritance pattern is autosomal dominant

47
Q

What is the only treatment for FAP?

A

colectomy, but NSAIDS can prevent some polyps

48
Q

How do FAP cancers differ from the sporadic APC/CIN cancers?

A

very similar genetics and morphology, but occur earlier and in far higher numbers

49
Q

Why can two people with FAP have very different outcomes?

A

the APC gene is a big one - so depending on where the germline APC mutation is, presentation will vary

50
Q

When should people with FAP get their first colonoscopy? What happens to the frequency of necessary colonoscopies as they age?

A

stage every 1 year from age 12-45

as you age, the interval can increase

51
Q

Describe attenuated FAP?

A

it’s characterized by a relatively low polyp number with relatively later age for presentation

typically occur with mutations in the APC gene at either extreme amino terminus or carboxy terminus

52
Q

How can two siblings with FAP have completely different presentations? Presumably they get the smae mutations?

A

there are many modifier genes that play a role

53
Q

Again, what is the most common hypermethylation occurence in MMR/MIN pathway CRC?

A

methylator phenotype = hypermethylation of MLH1 ( a mismatch repair enzyme)

54
Q

Which has a better prognosis: APC or MMR?

A

MMR (although 5-FU is less effective)

55
Q

What are the specifid dietary risk factors associated with th eMMR/MIN pathway?

A

high alcohol
red meat
low folate

56
Q

What are three main MMR/MIN target genes in CRC that will contain microsattelites in the coding region?

A

TGF-BR, IGF and BAX

57
Q

What biomarker is used in PCR to look for microsatellite instability?

A

BAT-26

58
Q

What’s another term for lynch syndrome?

A

hereditary non-oolyposis colorectal cancer

59
Q

What are some other tumors you can see with lynch syndrome? Mutation in which mismatch repair gene increases frisk for non-colonic cancers?

A

endometrial, gastric, ovarian, renal, small intestine and urinary tract

MSH2

60
Q

What would trigger a much more severe phenotype in lynch syndrome?

A

if someone inherits a bialleleic inheritance of MMR mutations (so they don’t even need a second hit)

more common in populations where consanguinity is common

61
Q

When should someone with lynch syndrome start colonoscopy?

A

age 20

62
Q

What percentage of the US at-risk population gets preclinical diagnostic screening?

A

only 30%!

63
Q

Back to FAP…what are the most common other cancers/lesions?

A

duodenal cancer

CHRPE (?)

desmoid tumors

64
Q

What protein does cormier love that if you express is you have extension of survival in stae II, III and IV CRC?

A

KCNQ1

GI Week 4 (11 decks)

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