Genetics of Colon Cancer - Cormier, Nikcevich, Elliott Flashcards
1
Q
What is the epidemiology of colorectal cancer?
A
- 2nd leading cause of cancer death in US
- (11% of all cancer deaths)
- ~ 143,000 new cases (2,200 in MN)
- 51,000 deaths (800 in MN) yearly; worldwide more than 1 million cases
- 620,000 deaths yearly
- ~ 5% of the US population will develop CRC and ~ 50% will develop tumors
- A significant disease in the western world (USA, Europe, Australia, NZ)
- previously, much less so in Asia & Africa, but rates are increasing everywhere (especially China)
2
Q
What is the racial epidemiology of colorectal cancer?
A
- some differences by race within US:
- African Americans have the highest incidence and present with more advanced disease
- American Indians in Great Lakes & Minnesota have the highest rate of CRC
- men in the USA develop CRC at higher rates than women and also have a higher mortality rates
3
Q
What is the survival rate of colorectal cancer?
A
- 30% present with metastatic disease (~11% 5 year survival)
-
overall 5 year survival rates for CRC = 45-50%
- 50% of “cures” relapse and die from their cancer
- survival rates drop significantly with advanced stages of the disease
4
Q
What are the environmental risk factors that influence the development of colorectal cancer?
A
- obesity is the greatest risk factor for colorectal cancer
- sedentary lifestyle/lack of exercise
- smoking
- influence of dietary factors → poor diet
- can act synergistically, and can interact with selected genetic changes in tumors or with host genetic factors
- particular foods:
- red meat, *w-6 FA, trans fats
- processed meats
- alcohol
- low calcium & low folate
- “Metabolic syndromes” → cardiovascular disease and type-2 diabetes that include: glucose intolerance, insulin resistance, dyslipidemia, obesity & hypertension
5
Q
What factors are protective or decrease the risk of colorectal cancer?
A
- estrogen
- chemopreventative agents
- NSAIDS
- 5-ASA
- statins (?))
- 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
6
Q
What is the basic the genetics of colorectal cancer, both the inherited and sporadic forms?
A
- hereditary syndromes (FAP, Lynch/HNPCC) (~5%) vs sporadic (~ 95%) CRC
- at the molecular genetic level two types of CRC predominate:
- 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
7
Q
What is the key role of the gatekeeper gene APC in both the inherited and sporadic forms of the disease?
A
- APC is a classic tumor suppressor gene (Knudson’s two-hit hypothesis), thus expression of both copies must be lost in tumorigenesis
- APC loss is rate-limiting in adenomagenesis based on two observations:
- 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
8
Q
What is the key role of the gatekeeper gene MLH1 in both the inherited and sporadic forms of the disease?
A
- mismatch repair gene
- mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal
- Defects in MLH1 are associated with the microsatellite instability (MSI) observed in HNPCC
- hypermethylation and silencing of MLH1 - leading to MMR deficiency (primarily in sporadic MIN-associated CRC)
9
Q
What are the various methods for screening for colorectal cancer?
A
-
colonoscopy - gold standard, 100% accurate, 60% reduction in mortality
- endoscopist skill greatly influences effectiveness (recent evidence)
- CT colonography (CTC) virtual colonoscopy under development not as sensitive as endoscopy
- flexible sigmoidscopy and barium enemas still have some utility but are less employed today and less accurate than colonoscopy
- stool DNA - PCR analysis of shed tumor DNA such as APC, p53, RAS, BAT-26, mVIMENTIN >90% sensitivity & specificity
- fecal occult blood - 50% sensitivity (25% adenomas), 98% specificity; 15% reduction in CRC mortality
10
Q
What are the various methods for mutational analysis in colorectal cancer?
A
- Sequencing (esp. NGS)
- protein truncation tests
- immunohistochemistry
- Westerns
- northerns
- gene chips
- PCR for microsatellite instability (MIN) (e.g., BAT-26)
11
Q
What is the most common form of metastases in Colorectal Cancer?
A
- local site of CRC metastasis are the mesenteric lymph nodes
- distant site is most often the liver, next lung, often present as numerous undetectable micrometastases
12
Q
Based on molecular genetics, what are the features of APC/CIN type Colorectal cancer?
A
- complete disruption of APC and/or its pathway (WNT/beta catenin)
- chromosomal instability (CIN)
- mostly left side
- often loss of p53
- increased RAS activity
- hereditary syndrome: FAP (thousands of tumors)
- ~ 85% of all CRC
- poor prognosis (30% survival)
13
Q
Based on molecular genetics, what are the features of MMR/MIN type Colorectal cancer?
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)
14
Q
Why is there a great need for better targeted therapies?
A
- only 50% of individuals in the US > 50 years receive any of the recommended screening tests
- among these those who receive screening the quality is variable
- there are virtually no biomarkers that are useful in predicting response to treatment strategies
- the best one at the present time is the presence of K-Ras mutations
- current treatments for metastatic CRC extends life for months only
- some new treatments offer limited improvement (e.g., VEGFR and EGFR Mabs)
15
Q
How does APC resist cancer?
A
- likely in multiple ways at different stages
- regulation of b-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
