Colorectal Cancer, Lynch syndrome, FAP

Question 1

What risk factors are associated with CRC?

Answer 1

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

Question 2

What protective factors are associated with CRC?

Answer 2

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

Question 3

How do colon cancers develop?

Answer 3

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)

Question 4

Describe the correlation between survival and state of CRC.

Answer 4

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

Question 5

Describe how we talk about the two sides of the colon.

Answer 5

splenic flexure marks the proximal (right) from the distal (left) colon

Question 6

How does the tumor location influence the likely presenting symptoms of CRC?

Answer 6

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

Question 7

What is a sessile serrated polyp?

Answer 7

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

Question 8

What are the pathways of colon carcinogenesis?

Answer 8

Chromosomal instability (60-70%)
Microsatellite Instability (15%)
CpG Island Methylation (15-20%)

Question 9

Describe the progression from normal mucosa to carcinoma in chromosomal instability carcinogenesis.

Answer 9

normal –(APC)–> early adenoma –(K-ras)–> intermediate adenoma –(DCC/18q genes)–> late adenoma –(p53)–> carcinoma (MSS)

Question 10

Describe the progression from normal mucosa to carcinoma in microsatellite instability carcinogenesis.

Answer 10

normal mucosa –(loss of DNA mismatch repair genes or key target genes such as TGFbetaRII)–> carcinoma (MSI)

Question 11

Describe the progression from normal mucosa to carcinoma in CpG Island Methylation carcinogenesis.

Answer 11

normal mucosa –(DNA methylation inhibits key gene expression or BRAF oncogene mutation)–> carcinoma (MSI-High)

Question 12

How much colorectal cancer is familial?

Answer 12

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

Question 13

What screening tests are available for CRC?

Answer 13

stool based screenings: Fecal Occult Blood Test (Guaiac), FIT (ELISA), FIT-DNA (Cologuard)
Colonoscopy
Sigmoidoscopy

Question 14

What is the recommended timeline for colorectal screenings?

Answer 14

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

Question 15

What are the kinds of polyposis syndromes?

Answer 15

adenomas (FAP, MAP)
hamartomas (Peutz-Jeghers, Juvenile Polyposis, PTEN syndromes like Cowden’s and BRRS)
Serrated (serrated polyposis syndrome)
Mixed (HMPS)

Question 16

What is Familial Adenomatous Polyposis?

Answer 16

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

Question 17

How does FAP present?

Answer 17

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)

Question 18

What is attenuated FAP?

Answer 18

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)

Question 19

Describe the AJ mutation for FAP.

Answer 19

I1307K
DO NOT get polyps BUT get CRC
2x higher than GP risk

Question 20

Describe the pathophysiology of APC mutations.

Answer 20

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

Question 21

What is MUTYH-Associated Polyposis (MAP)?

Answer 21

AR
MUTYH gene (biallelic inactivation)
most common mutations are G382D and Y165C
monoallelic inactivation: CRC>adenomas

Question 22

How does MAP present?

Answer 22

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

Question 23

What is the mechanism of MYH polyposis?

Answer 23

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

Question 24

Contrast Lynch syndrome and FAP.

Answer 24

FAP: tumor initiation is fast, but tumor progression is normal
Lynch: tumor initiation is normal, but tumor progression is accelerated

Question 25

What is Lynch syndrome?

Answer 25

AD
3-5% of all CRCs
80% lifetime risk of CRC
germline mutation in a DNA mismatch repair gene (MSH2, MLH1, PMS1, PMS2, MSH6, and EPCAM

Question 26

What are the clinical features of Lynch syndrome?

Answer 26

colonic neoplasms- few adenomas, proximal location, multiple simultaneous colon cancers (12-15%), typical histology (signet ring cell; mucinous)
extra-intestinal cancers- endometrium (second most common), GU tract, small bowel, brain (glioblastoma), stomach, ovary, pancreas

Question 27

What is the Amsterdam Criteria?

Answer 27

Lynch Syndrome
3+ HNPCC-associated cancers (two of whom are first-degree relatives)
2+ generations
1 person affected by age 50
MLH1-PMS2 pairing

Question 28

Describe MSI testing in CRC.

Answer 28

microsatellite instability
performed on tissue (not blood)
95% of LS tumors are MSI(+)
10-15% of sporadic CRC are MSI(+)

Question 29

How is Lynch Syndrome diagnosed?

Answer 29

diagnose the cancer by IHC testing (pathologists take antibodies for MLH1/MSH2/MSH6/PMS2)
MLH1 is very prone to methylation and is shut off in many tumors (may be sporadic)
Do BRAF testing (+ means sporadic cancer)

Question 30

What is the effect of MSI status on survival?

Answer 30

MSI(+) tumors have a better 5 year survival
HOWEVER on treatment with 5-FU, this survival benefit is lost (need immunotherapy or checkpoint inhibitors
5-FU treatment improves survival for MSI (-) tumors (conventional chemorx)

Question 31

What screening is recommended in patients with Lynch syndrome?

Answer 31

colorectum cancer- colonoscopy beginning at 20-25 years (or 10 years younger than youngest cancer in teh family) every 1-2 years
uterus/ovaries- pelvic exam, TVUS, CA125 beginning at 30-35 every 1-2 years
stomach (if at least one family member is affected with this type)- EGD starting at 30-35 every 1-2 years
GU (if at least one family member is affected with this type)- uterine cytology, sonogram starting at 30-35 years every 1-2 years

Question 32

What are the most key points about Lynch syndrome?

Answer 32

1 in 280 to 300 people (at least as common as BRCA)
risk fo cRC adn GYN cancers vary somewhat depending on what MMR gene is mutated
polyps progress more rapidly to cancer (need for colonoscopy every 1-2 years)
metachronous CRC is much more common than in sporadic CRC, even without treatment beyond surgery
if CRC is diagnosed, ti may change the type of surgery that is planned
MSI(+) CRC cancers are highly responsive to immunotherapy (checkpoint inhibitors), and poorly responsive to conventional chemorx

Question 33

What is Peutz Jegher Syndrome?

Answer 33

AD
STK11/LKB1
50% have no FHx
mucocutaneous pigmentation
GI and Non-GI cancers
GI tract polyps (hamartomas; smooth muscle bands)
polyps start traveling downstream towards the colon; can get stuck in the intestine; loss of a healthy small bowel due to a polyp

Question 34

What is Juvenile Polyposis Syndrome?

Answer 34

AD
SMAD4 (20%) or BMPR1A (20%) or Eng (rare)
phenotype may mimic IBD pseudopolyps (need to biopsy flat mucosa between polyps)

Question 35

What are the diagnostic criteria for JPS?

Answer 35

any one of the following:
5+ juvenile polyps of colorectum
juvenile polyps throughout GI tract
any number of juvenile polyps in the GI tract with a family history of JPS