Colon Cancer Flashcards
public health impact of colon cancer
*#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
risk factors of colon cancer in the US
*age (90% of cases after age 50; rare before age 40)
*family history (up to 25% of cases)
*inflammatory bowel disease
germline mutations
occur in sperm or ovum, and will be present in all cells of the progeny
somatic mutations
occur in cells of a tissue or organ
oncogene
*mutations of normal cellular genes, called proto-oncogenes, that promote cell growth
*oncogenes can drive uncontrolled cellular proliferation
tumor suppressor genes
normal cellular genes that inhibit cell growth
mismatch repair genes (MMR)
these correct nucleotide base mispairings that occur during DNA replication
microsatellite instability
repeated errors of short sequences of nucleotide bases within the genome
3 important genetic changes implicated in colon cancer
- K-ras
- APC gene
- TP53 gene
K-ras & colon cancer
*most frequent mutation of the ras oncogene in colorectal cancer
*this mutation effectively leaves the growth switch ON
adenomatous polyposis coli (APC) gene & colon cancer
*the most important tumor suppressor gene in colorectal cancer
*mutation of this gene leaves cell growth unchecked
TP53 gene & colon cancer
*“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
sporadic colon cancers
*result from stepwise occurrence of multiple somatic mutations
*APC - MMR - K-ras - p53
colon cancer pathogenesis: adenoma -> carcinoma sequence
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)
familial colon cancer syndromes
- familial adenomatous polyposis (FAP) - related to APC gene mutations
- hereditary nonpolyposis colorectal cancer (Lynch syndrome) - related to DNA mismatch repair gene mutations
- MUTYH-associated polyposis
- Peutz-Jeghers Syndrome
familial adenomatous polyposis (FAP) - overview
*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
FAP variants
- Gardner’s syndrome:
-associated with extra-GI tumors (osteomas, cutaneous tumors, desmoid tumors) - Turcot’s syndrome:
-associated with brain tumors (medulloblastoma, glioblastoma)
familial adenomatous polyposis (FAP) - dx and tx
*identified endoscopically
*tx = total proctocolectomy (removal of colon & rectum)
*timing depends on size and histology of polyps
hereditary nonpolyposis colorectal cancer
*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 (endometrial), ovary, stomach, bile ducts, ureters
MUTYH-associated polyposis
*autosomal recessive
*biallelic germline mutation of the MUTYH gene (base excision repair gene)
*clinical manifestations:
-multiple colorectal adenomas and sessile serrated polyps
Peutz-Jeghers syndrome
*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
clinical presentation of colorectal cancer
*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
tests for the diagnosis of colon cancer
**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
clinical staging of colon cancer
*tumor size/spread, lymph node involvement, metastasis
*commonly look for metastasis to liver
treatments of colon cancer
*endoscopic polypectomy
*surgical resection
*chemotherapy (FOLFOX)
methods of screening for colon cancer
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
screening in patients at increased risk for colon cancer: 1st degree relative with CRC age < 60
*interval = 5 years
*details = start at age 40, or tens years younger than the index patient, whichever comes first
screening in patients at increased risk for colon cancer: personal history of colon adenoma
*interval = 3-7 years
*details = use 3 year interval if > 1 cm, more than 2 polyps, villous, or high grade dysplasia
screening in patients at increased risk for colon cancer: personal history of colon cancer
*interval = 1, 3, and 5 year interval
*then, every 5 years thereafter; looking for missed lesions and metachronous lesions
screening in patients at increased risk for colon cancer: personal history of ulcerative colitis
*interval = 1 year
*start after 8-10 years of pancolitis
