Colorectal Cancer, Lynch syndrome, FAP Flashcards
(35 cards)
What risk factors are associated with CRC?
Strong (RR>4.0): advancing age (>50), country of birth, hereditary syndrome (FAP, Lynch), long standing IBD
Moderate (RR 2.0-4.0):
high red meat diet, previous adenoma/CRC, pelvic irritation
Modest (RR 1.1-2.0): high fat diet, obesity, smoking, alcohol, cholecystectomy
What protective factors are associated with CRC?
Moderate (RR<6):
physical activity, aspirin/NSAIDs, colonoscopy
Modest (RR0.9-0.6):
high fiber diet, high fruits/vegetables, high calcium, high folate, hormone replacement therapy
How do colon cancers develop?
normal –> polyp (adenoma) –> cancer
transition from normal to cancer takes about 5-10 years in the general population
polyp removal leads to CRC prevention
polyps are a surrogatemarker (they grow larger before developing into cancer)
tubular adenoma (80% of all polyps)
Describe the correlation between survival and state of CRC.
Stage I- Localized; confined to primary site
Stage II- regional; ranges from invading muscle layer to spreading to nearby organs
Stage III- regional; spreads to regional lymph nodes
Stage IV- distant; cancer has metastasized
resectable at stages I-III
Describe how we talk about the two sides of the colon.
splenic flexure marks the proximal (right) from the distal (left) colon
How does the tumor location influence the likely presenting symptoms of CRC?
Ascending cecum (25% of cancers)- occult bleeding, anemia
Descending colon (5% of cancers)- obstructive symptoms, overt bleeding
Rectum (20% of cancers)- tenesmus (spasm of the rectum), pain, bleeding
HOWEVER the most common symptoms is no symptoms
What is a sessile serrated polyp?
can progress to CRC
often flat, pale, difficult to detect even with excellent prep, usually found in proximal colon
have ill defined borders that need to be assessed for complete resection
account for15-20% of all CRCs
What are the pathways of colon carcinogenesis?
Chromosomal instability (60-70%) Microsatellite Instability (15%) CpG Island Methylation (15-20%)
Describe the progression from normal mucosa to carcinoma in chromosomal instability carcinogenesis.
normal –(APC)–> early adenoma –(K-ras)–> intermediate adenoma –(DCC/18q genes)–> late adenoma –(p53)–> carcinoma (MSS)
Describe the progression from normal mucosa to carcinoma in microsatellite instability carcinogenesis.
normal mucosa –(loss of DNA mismatch repair genes or key target genes such as TGFbetaRII)–> carcinoma (MSI)
Describe the progression from normal mucosa to carcinoma in CpG Island Methylation carcinogenesis.
normal mucosa –(DNA methylation inhibits key gene expression or BRAF oncogene mutation)–> carcinoma (MSI-High)
How much colorectal cancer is familial?
2/3 is sporadic
1/3 has some family history (some genetic and some non-geneitc)
5% is Lynch
1% is FAP and other adenomatous polyposes
1% is hamartomatous polyposes
What screening tests are available for CRC?
stool based screenings: Fecal Occult Blood Test (Guaiac), FIT (ELISA), FIT-DNA (Cologuard)
Colonoscopy
Sigmoidoscopy
What is the recommended timeline for colorectal screenings?
Age >45 and asymptomatic: colonoscopy every 10 years sigmoidoscopy every 5 years CT colonography every 5 years FOBT (high sensitivity) every year FIT (high sensitivity) every year Multi-target stool DNA (high false positive) every 3 years screening through age 75 if life expectancy >10 years age 75-85 individualized age >85 discouraged
What are the kinds of polyposis syndromes?
adenomas (FAP, MAP)
hamartomas (Peutz-Jeghers, Juvenile Polyposis, PTEN syndromes like Cowden’s and BRRS)
Serrated (serrated polyposis syndrome)
Mixed (HMPS)
What is Familial Adenomatous Polyposis?
AD
mutations in the APC gene (tumor suppressor)
most mutations are protein truncating and disrupt the ability of APC to bind to beta-catenin
30% have no fhx of FAP or CRC (de novo)
do not get polyps until teenaged years
How does FAP present?
colon (hundreds of adenomas)
stomach (fundic gland polyps- often with LGD)
duodenum (adenomas, esp. ampularry)
jejunum/ileum (adenomas, less common)
other locations (benign: osteompas in the mandible, skull, long bones, desmoid tumors, soft-tissue tumors, CHRPE lesions; malignant: brain medulloblastomas, thyroid, hepatoblastoma younger than 3)
What is attenuated FAP?
much more common later age of onset uaually <100 adenomas (often <5 mm in size) mostly in the proximal colon rectum is usually spared UGI lesions present (gastric/duodenal) CHRPE and desmoids are rare APC gene mutations (5' and 3' end)
Describe the AJ mutation for FAP.
I1307K
DO NOT get polyps BUT get CRC
2x higher than GP risk
Describe the pathophysiology of APC mutations.
APC normally acts to phosphorylate B-catenin, thereby targeting it for destruction
lack of functional APC permanently uncouples the B-catenin binding complex and causes unregulated intracellular accumulation of B-catenin
thus constitutive expression of c-myc and of the cyclin D1 gene
proliferation increases and is unregulated and apoptosis is suppressed
these effects represent the early steps of the carcinogenesis process and explain the growth advantage observed in cells lacking APC function
What is MUTYH-Associated Polyposis (MAP)?
AR
MUTYH gene (biallelic inactivation)
most common mutations are G382D and Y165C
monoallelic inactivation: CRC>adenomas
How does MAP present?
colonic adenomas: oligopolyposis of 5-100 adenomas; also have hyperplastic and sessile serrated polyps; average age 45-60 years
extracolonic manifestations: duodenal adenomas, gastric cancer, osteomas, CHRPE
looks very much like FAP
What is the mechanism of MYH polyposis?
base excision repair is damaged
oxidative damage to Guanine prefers to bind to adenine rather than a cytosine, which should be caught after the first replication by MYH, however if it is not it goes on to the second replication wrong and propagates the mutation
APC gene is prone to oxidative damage
Contrast Lynch syndrome and FAP.
FAP: tumor initiation is fast, but tumor progression is normal
Lynch: tumor initiation is normal, but tumor progression is accelerated
