Colorectal cancer Flashcards
(31 cards)
Overview of cancer
genetic disease in which single clone of cells accumulate heritable changes that result in cancer phenotype
CRC disease burden
- 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
Sporadic colon cancer
disease of old age
General categories of CRC
Hereditary syndromes (FAP, Lynch) --> ~5% (autosomal dominant) Sporadic --> ~95%
Molecular level of CRC types
- APC pathway –> chromosomal instability CIN
- Mismatch repair –> microinstability MIN
- both have hereditary and sporadic forms
Metastasis
local site of CRC metastasis are mesenteric lymph nodes
- distant site is often liver
- rectal cancer spreads to lungs because of IVC drainage
Testing for CRC
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
CRC Screening
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
Mutational genetic testing is suspected family disease
always test proband (person to seek medical attention first) first!
- if mutation identified, family members can be tested with 100% accuracy
Environmental factors in CRC
diet plays a particularly major role
- can act synergistically and interact with selected genetic changes in tumors
Increased risk of CRC
- old age, male, obesity, smoking, lack of exercise, IBS
- red meat, omega-6, alcohol, low calcium and folate, heterocyclic amines, bile acids
Decreased risk of CRC
- estrogen, chemopreventive agents (NSAIDs, statins?)
- marine oils, omega-3, fruits & veggies, soy, fiber, folate, calcium, garlic, vitamins, flavinoids
Special note on folate
generally it appears to prevent CRC –> but once CRC has arisen, folate acts as cancer promoter
epigenetics and CRC
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
What is characteristic of all CRC?
genomic instability –> occurs early and contributes to development of cancer
- can be MMR, base excision repair, proper segmentation of chromosomes
APC pathway/CIN
- 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
MMR/MIN pathway
- complete loss of MMR (MIN)
- mostly right side
- methylator phenotype common
- Lynch
- 15% of CRC –> better prognosis
Key role of APC in CRC
APC loss is the rate-limiting step in adenomagenesis
- classic tumor suppressor gene (2-hit hypothesis)
How does APC resist cancer?
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
K-Ras mutation
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
CIN
precedes and causes aneuploidy
- detected by karotyping and FISH
Familial Adenomatous Polyposis
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
Modifier genes
host genetic factors can influence phenotype –> both tumor incidence and development
MIN
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
