Cancer, CRC Flashcards
What are known risk factors for colorectal cancer?
Aging
- risk due to accumulation of somatic mutations Personal history of colorectal cancer or adenomas
High-fat, low-fiber diet (impact on risk is under debate)
Inflammatory bowel disease (IBD)
-Ulcerative colitis or Crohn’s disease
-no increased risk with irritable bowel syndrome (IBS)
Family history of colorectal cancer
Diagnosis of a hereditary colon cancer syndrome
What percentage of colon cancers are sporadic,
familial, or hereditary?
Colon Cancer
Sporadic = 65-85%
Family clusters = 10-30%
- vulnerability to polyps or colon cancer
- reduced penetrance
- may be the result of interactions between many genes or interactions between genes and environment
Hereditary = ~6%
- caused by mutations in a single gene
- highly penetrant
Identify the syndromes that account for a hereditary
susceptibility to colon cancer.(~6%)
HNPCC = ~5%
FAP = 1%
Rare colorectal cancer syndromes = <0.1%
Describe the association between the APC mutation I1307K and familial colorectal cancer in the Ashkenazi Jewish.
APC I1307K and Ashkenazi Jewish Individuals
Founder mutation in Ashkenazi Jewish I1307K is a missense mutation creating a hypermutable area in APC
-associated with increased lifetime risk for CRC
-indistinguishable phenotype from sporadic CRC
-not associated with risk for FAP or AFAP
Level of risk is controversial
-risk for cancer may be similar to having a first degree relative with colon cancer
Utility of testing is questionable – positive result will not change clinical management
Identify the cancers associated with Lynch Syndrome
and the approximate lifetime risk for each cancer in
mutation positive individuals.
Lynch Syndrome Associated Cancers + Lifetime Risk
Colorectal cancer: 70% Endometrial cancer: 43%-60% Biliary tract cancer: 18% Stomach cancer: 5-13% Urinary tract cancer: 10% Ovarian cancer: 9%
What is the general U.S. population lifetime risk of developing colorectal cancer? What factors or conditions increase an individual’s risk for cancer, and to what level?
General U.S. population lifetime risk of colorectal cancer = 5-6%
Increased Lifetime Risk of Colorectal Cancer (CRC)
Personal history of CRC = 15-20%
Inflammatory bowel disease = 15-40%
-extent of disease affects CRC risk
Lynch syndrome (MMR mutation-positive) = 70-80% Familial adenomatous polyposis = >95%
Identify the cancers associated with FAP and the
approximate lifetime risk for each cancer in
APC mutation positive individuals.
FAP Associated Cancers + Lifetime Risk
Untreated polyposis leading to CRC: 100% Small bowel: duodenum or periampulla: 4-12% Small bowel: distal to duodenum: Rare Pancreatic adenocarcinoma: ~2% Papillary thyroid carcinoma: 1-2% Hepatoblastoma: 1.6% CNS, usually medulloblastoma: <1% Bile duct adenocarcinoma: Low, but increased
Identify the extracolonic features that may
be present in individuals with FAP.
Extracolonic Features
- Small bowel polyps
-duodenal adenomatous polyps (50-90%)
-periampullary adenomatous polyps (>50%), may obstruct pancreatic duct - Gastric polyps
-fundic gland hamartomatous polyps (50%)
-gastric antrum adenomatous polyps - Desmoid tumors (10%)
4, Osteomas, most commonly on skull and mandible - Dental abnormalities – unerupted, congenital absence, supernumerary
- Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
- Benign cutaneous lesions – epidermoid cysts and fibromas
- Adrenal masses (~7-13%) most w/o endocrinopathy or hypertension
Compare and contrast the classic and attenuated
phenotypes of FAP
Classic FAP Average age, 39y (when FAP untreated) 100 to 1,000s of polyps throughout colon Extracolonic features:Present APC mutations: Throughout the gene
Attenuated FAP
Average age, 50-55y
Usually >20 but <100 polyps (tend to be more proximal)
Extracolonic features: Present, but CHRPE and desmoid tumors are rare
APC mutations: Located at 5’ and 3’ ends
Describe the genotype-phenotype correlation of
Lynch syndrome and mutations in MSH6 or PMS2.
MSH6 mutation:
- ~30% less risk for colon cancer (less prominent)
- Predominance of endometrial cancer
PMS2 heterozygotes: Low penetrance PMS2 homozygotes: -Very early onset colorectal cancer -Very early onset duodenal cancer -Leukemia -Lymphoma -Childhood brain tumors -Café au lait spots
Familial Adenomatous Polyposis (FAP)
Inheritance: Autosomal dominant
Gene: APC (25% de novo rate)
Major features:
●100+ adenomatous colon polyps (classic)
oAverage age of onset for first polyps 16 years
●10-99 adenomatous colon polyps (attenuated)
oCan present with later age of onset
Associated tumors:
●Nearly 100% lifetime risk for colon cancer if untreated
●Small bowel
●Pancreatic
●Thyroid – papillary
●CNS
●Liver (rarely hepatoblasotma in children)
●Bile duct
●Stomach
●Small bowel polyps
FAP: Treatment
●For some individuals with attenuated FAP, polyp burden is low enough for colonoscopy surveillance
●For most individuals, colectomy is necessary as polyp burden is too high
●Endoscopic surveillance for small bowel polyps
Gardner Syndrome
●FAP with additional features
●Osteomas
●Soft tissue tumors
oDesmoid, epidermoid, fibromas
Turcot syndrome
FAP with CNS tumors, specifically medulloblastoma
Hereditary Non-Polyposis Colon Cancer (HNPCC/Lynch Syndrome)
Inheritance: Autosomal Dominant
Genes: MLH1, PMS2, MSH2, MSH6, EPCAM
Associated tumors:
●Colorectal
oMost are located on the right-side (ascending) colon
●Ovarian
●Uterine
●Stomach
●Gallbladder
●Urinary tract (ureter and renal pelvis)
●Brain
●Small bowel
