Colon Cancer

Question 1

public health impact of colon cancer

Answer 1

*#2 leading cause of cancer death
*10% of all cancer deaths
*5% lifetime risk
*highest incidence in North America, Australia, and Western and Northern Europe

Question 2

risk factors of colon cancer in the US

Answer 2

*age (90% of cases after age 50; rare before age 40)
*family history (up to 25% of cases)
*inflammatory bowel disease

Question 3

germline mutations

Answer 3

occur in sperm or ovum, and will be present in all cells of the progeny

Question 4

somatic mutations

Answer 4

occur in cells of a tissue or organ

Question 5

oncogene

Answer 5

*mutations of normal cellular genes, called proto-oncogenes, that promote cell growth
*oncogenes can drive uncontrolled cellular proliferation

Question 6

tumor suppressor genes

Answer 6

normal cellular genes that inhibit cell growth

Question 7

mismatch repair genes (MMR)

Answer 7

these correct nucleotide base mispairings that occur during DNA replication

Question 8

microsatellite instability

Answer 8

repeated errors of short sequences of nucleotide bases within the genome

Question 9

3 important genetic changes implicated in colon cancer

Answer 9

1. K-ras
2. APC gene
3. TP53 gene

Question 10

K-ras & colon cancer

Answer 10

*most frequent mutation of the ras oncogene in colorectal cancer
*this mutation effectively leaves the growth switch ON

Question 11

adenomatous polyposis coli (APC) gene & colon cancer

Answer 11

*the most important tumor suppressor gene in colorectal cancer
*mutation of this gene leaves cell growth unchecked

Question 12

TP53 gene & colon cancer

Answer 12

*“the guardian of the genome” produces a DNA-binding protein that activates transcription of growth inhibitory genes
*mutation of this tumor suppressor gene can result in uncontrolled cell division

Question 13

sporadic colon cancers

Answer 13

*result from stepwise occurrence of multiple somatic mutations
*APC - MMR - K-ras - p53

Question 14

colon cancer pathogenesis: adenoma -> carcinoma sequence

Answer 14

we think that it takes 10 years to develop from normal colon to cancer:
normal colonic mucosa -> small polyp (adenoma) -> large polyp (adenoma) -> high grade dysplasia / early cancer -> cancer (invasive adenocarcinoma)

Question 15

familial colon cancer syndromes

Answer 15

*familial adenomatous polyposis (FAP)
*hereditary nonpolyposis colorectal cancer
*MUTYH-associated polyposis
*Peutz-Jeghers Syndrome

Question 16

familial adenomatous polyposis (FAP) - overview

Answer 16

*autosomal dominant
*germline mutation of the APC gene
*clinical manifestations:
-more than 100 colorectal polyps (“carpets of polyps”)
-average age of colon cancer dx age 39
*100% will have colon cancer by age 45 w/o tx
-duodenal ampullary carcinoma

Question 17

FAP variants

Answer 17

1. Gardner’s syndrome:
   -associated with extra-GI tumors (osteomas, cutaneous tumors, desmoid tumors)
2. Turcot’s syndrome:
   -associated with brain tumors (medulloblastoma, glioblastoma)

Question 18

familial adenomatous polyposis (FAP) - dx and tx

Answer 18

*identified endoscopically
*tx = total proctocolectomy (removal of colon & rectum)
*timing depends on size and histology of polyps

Question 19

hereditary nonpolyposis colorectal cancer

Answer 19

*aka HNPCC or Lynch Syndrome
*autosomal dominant
*germline mutations in DNA mismatch repair (MMR) genes
*60% lifetime risk of colon cancer
*predominance for the right side of the colon
*synchronous and metachronous cancers are common
*extra-colonic tumors:
-uterus, ovary, stomach, bile ducts, ureters

Question 20

MUTYH-associated polyposis

Answer 20

*autosomal recessive
*biallelic germline mutation of the MUTYH gene (base excision repair gene)
*clinical manifestations:
-multiple colorectal adenomas and sessile serrated polyps

Question 21

Peutz-Jeghers syndrome

Answer 21

*autosomal dominant
*characterized by multiple pigmented (brown) spots on the lips and buccal mucosa
*associated with HAMARTOMAS (small bowel, colon, stomach)
*typically present in 3rd decade with:
-intussusception, obstruction, bleeding
*15-fold increased risk of cancer at ANY SITE

Question 22

clinical presentation of colorectal cancer

Answer 22

*varies but some symptoms include:
-abdominal pain, rectal bleeding, change in bowel habit, weakness, etc
*R colon lesions tend to present with BLOOD LOSS
*left colon lesions tend to present with pain and altered BM
*patients presenting with pain have a worse prognosis

Question 23

tests for the diagnosis of colon cancer

Answer 23

**colonoscopy - best test to dx
-best sensitivity and specificity
-allows biopsy of any lesions found
-detects any synchronous cancers and removal of any synchronous benign polyps

Question 24

clinical staging of colon cancer

Answer 24

*tumor size/spread, lymph node involvement, metastasis
*commonly look for metastasis to liver

Question 25

treatments of colon cancer

Answer 25

*endoscopic polypectomy
*surgical resection
*chemotherapy (FOLFOX)

Question 26

methods of screening for colon cancer

Answer 26

average-risk screening for colon cancer begins age 45-50

*fecal immunochemical testing (FIT) - every 1 year
*FIT-DNA - every 3 years
*flexible sigmoidoscopy - every 5 years
*CT colonography - every 5 years
*colonoscopy - every 10 years

Question 27

screening in patients at increased risk for colon cancer: 1st degree relative with CRC age < 60

Answer 27

*interval = 5 years
*details = start at age 40, or tens years younger than the index patient, whichever comes first

Question 28

screening in patients at increased risk for colon cancer: personal history of colon adenoma

Answer 28

*interval = 3-7 years
*details = use 3 year interval if > 1 cm, more than 2 polyps, villous, or high grade dysplasia

Question 29

screening in patients at increased risk for colon cancer: personal history of colon cancer

Answer 29

*interval = 1, 3, and 5 year interval
*then, every 5 years thereafter; looking for missed lesions and metachronous lesions

Question 30

screening in patients at increased risk for colon cancer: personal history of ulcerative colitis

Answer 30

*interval = 1 year
*start after 8-10 years of pancolitis