Cormier: Genetics of Colon Cancer Flashcards

Question

What is a benefit of CT colonography?

Answer 1

detection of non colonic lesions (10% of pts)

Answer 2

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

Answer 3

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

Answer 4

``` estrogen chemopreventative agents (NSAIDS, 5-ASA, statins (?)) ```

Answer 5

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

Answer 6

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

Answer 7

Metabolic syndrome *also linked to obesity!!

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

``` 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) ```

Answer 12

APC/CIN MMR/MIN

Answer 13

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)

Answer 14

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)

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

cetuximab | panitumumab

Answer 23

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

Answer 24

autosomal dominant

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

proximal colon

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

Red meat | Alcohol

Answer 34

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);

Answer 35

progression

Answer 36

uterus | ovary