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GI- Week 4 > Cormier: Genetics of Colon Cancer > Flashcards

Cormier: Genetics of Colon Cancer Flashcards

1
Q

What is cancer?

A

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

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2
Q

What is the cancer stem cell hypothesis?

A

s

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3
Q

What is the second leading cause of death in the US?

A

CRC

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4
Q

In Minnesota, who has the highest rate of CRC?

A

American Indians

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5
Q

Do men or women have higher rates of CRC?

A

men

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6
Q

Why is CRC increasing world wide?

A

poor diet
life style
OBESITY

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7
Q

What prevents CRC?

A

diet
life style changes
early detection and prevention

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8
Q

What is linked to a modest decline in CRC incidence?

A

screening

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9
Q

What accounts for 95% of CRC?

A

Sporadic CRC

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10
Q

What accounts for 5% of CRC?

A

Hereditatry syndromes:

FAP, Lynch/HNPCC

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11
Q

What are the two types of CRC at the molecular level?

A

1) APC pathway that involves chromosomal instability (CIN)
2) mismatch repair (MMR) gene pathway that involves microinstability (MIN); both of these classes have hereditary syndromes and sporadic forms; in discussing CRC genetics we will focus on these two classes.

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12
Q

What is the most severe CRC?

A

FAP

*Still are opportunities for intervention

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13
Q

What percent of CRC shows familial clustering?

A

50% (increased familial susceptibility)

10% risk - one 1st degree relative
20% risk - two 1st degree relatives
50% risk for FAP and HNPCC - 1st degree relative

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14
Q

What is the local site of CRC metastasis?

A

mesenteric LN (staging related to how many LN have been sampled)

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15
Q

What is the MC distant site of metastases for CRC?

A

Liver, next lung

*many are present as undetectable micrometastases

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16
Q

Why is there a large window of opportunity for dx and tx of CRC?

A

progression from normal epithelium to carcinoma can take as long as 10-15 years

*early stage dx has huge impact on prognosis and survival

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17
Q

What type of testing is used for CRC?

A

Screening

Mutational analysis

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18
Q

CRC screening: colonoscopy

A

gold standard,
100% accurate,
60% reduction in mortality;
some recent data suggests endoscopist skill greatly influences effectiveness

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19
Q

CRC screening: colonography

A

(CTC)/virtual colonoscopy under development; not as sensitive as endoscopy

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20
Q

CRC screening: flexible sigmoidoscopy and barium enemas

A

still have some utility but are less employed today and less accurate than colonoscopy

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21
Q

CRC screening: stool DNA-PCR analysis

A

PCR analysis of shed tumor DNA such as APC, p53, RAS, BAT-26, mVIMENTIN >90% sensitivity & specificity

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22
Q

CRC screening: Fecal occult blood

A

50% sensitivity (25% adenomas), 98% specificity; 15% reduction in CRC mortality

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23
Q

What are the MC types of mutational analysis?

A

sequencing
immunohistochemistry
gene chips
PCR for microsatellite instability

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24
Q

What percent of CRC cases could be prevented by early detection of adenomas?

A

80%

diagnosed in early stages CRC has a >90% survival rate

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25
Q

What is a benefit of CT colonography?

A

detection of non colonic lesions (10% of pts)

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26
Q

What is the mutational genetic testing strategy in suspected disease families?

A

always test the proband first; if mutation is identified family members can be tested with 100% accuracy, leading to presymptomatic diagnosis and possibly pharmacological intervention

in ~ 20% of cases no mutations are found, preventing family testing but not ruling out inherited CRC syndromes; requires continued screening of all family members

27
Q

What are RFs for CRC?

A 
older age
male 
obesity (& other metabolic syndrome indicators)
smoking
lack of exercise
inflammatory bowel disease
28
Q

What decreases risk for CRC?

A 
estrogen 
chemopreventative agents (NSAIDS, 5-ASA, statins (?))
29
Q

What are dietary RFs for CRC?

A 
red meat, *-6 FA, trans fats
processed meats
alcohol 
low calcium & low folate
heterocyclic amines
bile acids
30
Q

What decreases risk for CRC?

A

marine oils, w-3 FA (DHA, EPA),
fruits, green leafy veggies, cruciferous
soy & phytoestrogens
fiber, folate, calcium, green tea, garlic, vitamins A,C,D,E
flavinoids, curcumin, resveratrol, caloric restriction

31
Q

There is a strong link between CRC and what syndrome?

A

Metabolic syndrome

*also linked to obesity!!

32
Q

How to gut flora affect CRC?

A

recent studies indicate that specific gut flora play a role in obesity: lean people have a different flora profile than obese people and the flora profile of infants can predict which of these children are likely to be obese later on

33
Q

How does epigenetics relate to CRC?

A

both hypermethylation and hypomethylation in the promoter regions of key genes is observed in CRC - leading to heritable changes in gene expression, comparable to sequence mutations

34
Q

What is a classic exapmle of hypermethylation associated w/ CRC?

A

classic example is hypermethylation and silencing of MLH1 - leading to MMR deficiency (primarily in sporadic MIN-associated CRC); other targets include APC, IGF2 and CDKN2A

CpG island methylator phenotype (CIMP) is reported in ~ 20% of CRC’s, linked to MSI CRCs

35
Q

CRC is associated w/ defects in DNA repair systems such as:

Form of genomic instability

A 
mismatch repair (MMR genes such MLH1), 
base excision repair (BER such as MUTYH), 
double strand break repair (BrcaI, MreII, BLM, ATM) and mechanisms that ensure proper segregation of chromosomes during mitosis (genes such as Chk2, Bub1 & Bub2)
36
Q

What are the two main classes of CRC based on molecular genetics

A

APC/CIN

MMR/MIN

37
Q

APC/CIN

A

complete disruption of APC and/or its pathway (WNT/beta catenin)

chromosomal instability (CIN)

mostly LEFT side

often loss of p53

Increases RAS activity

hereditary syndrome: FAP (thousands of tumors)

~ 85% of all CRC

POOR prognosis (30% survival)

38
Q

MMR/MIN

A

complete loss of mismatch repair (MMR) (mostly MLH1 or MSH2)

microsatellite instability (MIN)

mostly RIGHT side

methylator phenotype common

hereditary syndrome: Lynch (a sub-type of HNPCC, 1 or several tumors)

~ 15% of all CRC

BETTER prognosis (90% survival)

39
Q

Why is APC considered a gatekeeper gene?

A

APC loss must come first, which is why APC is considered a “gatekeeper” gene in the intestine

proceeds through an adenoma-carcinoma sequence over time (usually several years or more)

loss of p53, increase in RAS activity, and large-scale chromosomal instability (CIN) occur later, aiding cancer progression

40
Q

Why is APC loss rate limiting in adenomagenesis?

A

1) APC mutations occur at similar rates in benign and malignant lesions
2) APC mutations are seen in the earliest detectable lesions, some only a single crypt in size

41
Q

What type of TSG is APC?

A

APC is a classic tumor suppressor gene (Knudson’s two-hit hypothesis), thus expression of both copies must be lost in tumorigenesis

*Large gene

42
Q

How does APC resist cancer?

A

likely in multiple ways at different stages

regulation of -catenin/Wnt pathway is well-known and probably its most important function

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

43
Q

What happens to beta catenin w/ the loss of APC?

A

loss of APC leads to buildup of B-catenin, induction of growth stimulatory genes, cell proliferation and cancer

44
Q

What is the most effective clinically predictive biomarker in CRC?

A

K-Ras

45
Q

What is K-Ras

A

key cell signaling molecule that acts downstream of receptor tyrosine kinases such as EGFR;

46
Q

How do K-Ras mutations relate to CRC?

A

activating K-Ras mutations occur in ~ 40% of CRC and K-Ras mutations are associated with poor prognosis and poor survival

47
Q

What drugs are ineffective in treating pt’s with K-Ras mut?

A

cetuximab

panitumumab

48
Q

What is CIN (chromosomal instability?

A

CIN precedes and causes aneuploidy, defined as unusual chromosome number

in APC/CIN CRC, numerous large scale chromosomal changes (including translocations, large scale deletions and insertions) are observed, at a rate up to 100 x greater than normal

APC may be involved in regulation of CIN

CIN is detected by karyotype analysis/FISH

49
Q

How is FAP transmitted?

A

autosomal dominant

50
Q

What characterizes classic FAP

A

thousands of polyps in left colon that manifest by age 15, with cancer by mid-30’s, colectomy is only effective treatment but NSAIDs can prevent some polyps

51
Q

What does the FAP phenotype depend on?

A

site of germline APC mutation - most severe is truncation mutation between codons 1250 and 1464 with hotspot at 1309, with extracolonic diseases also site dependent

52
Q

What is attenuated FAP?

A

characterized by relatively low polyp number (1-100), later age for presentation (polyps ~ 44, cancer ~ 52 years)

53
Q

What causes AFAP?

A

caused by mutations in APC gene that occur at either extreme amino terminus (< codon 157) or extreme carboxy terminus

54
Q

Where are AFAPs usually located?

A

proximal colon

55
Q

What are modifier genes?

A

host genetic factors can influence phenotype, both tumor incidence and development and response to therapy

evidence from FAP: one sibling can manifest classic FAP while a different sibling with an identical severe polyposis mutation can present an AFAP-like disease

56
Q

What represents hte great majority of CRC? When does it arise?

A

sporadic APC/CIN

on average in 60’s

sporadic nature is likely overestimated because inherited genetic contributions are complex

in genes and morphology very similar to FAP, extensive CIN and LOH

57
Q

MMR-deficient/MIN pathway represent waht percent of CRC?

A

15%

58
Q

What is hte mutator phenotype associated with MMR def/min pathway?

A

microsatellite instable high (MSI-H); (note that CIN CRC is referred to as either MSI-L (low) or MSS (stable))

59
Q

What dietary RFs are related to MMR def/MIN pathway?

A

Red meat

Alcohol

60
Q

What is the inheritance pattern for Lynch Syndrome (HNPCC)?

A

autosomal dominant

patients inherit a single mutant copy of a MMR gene (MLH1, MSH2) and lose the second copy by genetic or epigenetic changes (LOH, two-hits required);

61
Q

Does MMR affect progression or initiation?

A

progression

62
Q

What other cancers are associated w/ FAP?

A

duodenal

63
Q

What other cancers are associated w/ HNPCC?

A

uterus

ovary

GI- Week 4 (12 decks)

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