ICL 18.2: Molecular Biology of Colon Cancer and Colon Cancer Screening and Anal Cancer and HPV Flashcards
what are the 5 most common types of polyps?
- inflammatory
- hyperplastic
- adenomatous
- villus or tubulovilous adenoma
- serrated adenoma
how common, what’s the cancer risk and treatment for inflammatory polyps?
typically found in people with inflammatory bowel disease like Crohn’s and ulcerative colitis
low cancer risk; growths are generally benign
removed during colonoscopy
how common, what’s the cancer risk and treatment for hyperplastic polyps?
usually small and located at the end of the colon and rectum
low cancer risk
removed during colonoscopy
how common, what’s the cancer risk and treatment for adenomatous polyps?
most common type of polyp! about 70% of polyps found in the colon are this type
most do not develop into cancer although larger polyps pose higher threat
remove during colonoscopy; regular follow-ups needed to screen for and remove new polyps
how common, what’s the cancer risk and treatment for vilous polyps?
they’re 15% of polyps
most do not develop into cancer but larger polyps pose a higher threat
can be flat and tougher to remove; smaller villus adenoma are removed during colonoscopy; larger polyps may require surgery
how common, what’s the cancer risk and treatment for serrated adenoma polyps?
10-15% of polyps
cause 20-30% of colon cancers
hard to detect during colonoscopy
sessile vs. pedunculate polyps?
sessile are flat and against the colon wall
pedunculate means they have a stalk and are easy to take off
what is colorectal cancer?
any cancer affecting anywhere from the cecum to the colon and rectum
anal canal and appendix are not considered in the definition and are treated as separate entities
what is the most common colon cancer?
adenocarcinoma is the most common cancer in the GI tract and also specifically the colon!
it’s the second most common cause of cancer related deaths in north america
what are the risk factors for colorectal carcinoma?
75% of people have no predisposing risk factors so get a scope at 45
15% have a family history
4-10% have hereditary nonpolyposis colorectal cancer
1% familial adenomatous polyposis
1% inflammatory bowel disease
what are high risk factors for colon cancer?
- familial adenomatous polyposis
- hereditary non-polyposis colon cancer
- family history of colorectal carcinoma
- previous colorectal cancer, ovarian, endometrial, breast cancer
- 45+ years old
- IBS (UC > CD)
- poor diet (red meat, decreased fiber, increased fat)
- smoking
what causes colorectal cancer?
progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma
most are in the sigmoid and rectum but can be anywhere
takes 10 years to progress
which gremline variants are associated with possible risk of colon cancer?
- familial adenomatous polyposis (FAP)
- Gardner syndrome
- Turcot syndrome
- attenuated adenomatous polyposis
- heriditary nonpolyposis colorectal cancer aka Lynch syndrome
- MAP
what is the clinical presentation of familial adenomatous polyposis?
- multiple adenomas
- colorectal carcinomas
- duodenal polyps and carcinomas
- gastric fundus polyps
- congenital hypertrophy of retinal epithelium
100% risk of colon cancer so they all get their colon taken out after puberty
APC gene defect
what is Gradner syndrome?
same as familial adenomatous polyposis but additional demoed tumors and mandibular osteomas = extra teeth!
APC gene defect
what is Trucot syndrome
polyposis and CRC with brain tumors like medulloblastomas or glioblastomas
APC or MLHI gene defects
what is attenuated adenomatous polyposis?
less than 100 polyps although marked aviation in polyp numbers
seen in mutation carriers within a single family
APC mutation
what is Lynch syndrome?
colorectal cancer with modest polyposis
high risk of endometrial cancer, some risk of ovarian, gastric, urothelial, hepatobiliary and brain cancers
multiple gastrointestinal polyps
AR but start screening at 21 with colonoscopy every 2 years
MSH2, MLHI, MSH6 and PMS2 gene defects**
what is MAP?
MUTYH-assocaited polyposis
10-100 polyps
AD so scope at 20 years or 10 years before youngest family member
which syndromes have hamartomatous polyps?
- Peutz-Jeghers syndrome
- Cowden disease
- juvenile polyposis syndrome
what is Peutz-Jeghers syndrome?
- hamartomatous polyps throughout the gastrointestinal (GI) tract
- mucocutaneous pigmentation
- estimated 9- to 13-fold increased risk of GI and non-GI cancers
- multiple hamartomas involving breast, thyroid, skin, brain, and GI tract
- increased risk of breast, uterus, thyroid, and some GI cancers
STKI I mutation
what is Cowden disease?
multiple hamartomas in youth, predominantly in colon and stomach
variable increase in colorectal and stomach cancer risk
facial changes (large heads and skin tags)
PTEN mutation which controls cell growth and the mutation results in uncontrolled growth
what is juvenile polyposis syndrome?
polyps anywhere in the GI tracts from the stomach to the rectum
they vary in size
it’s called juvenile due to the microscopic appearance
diagnose in the 20s
BMPRIA and SMAD4 mutations
what is the risk of cancer with familial adenomatous polyposis?
risk of colorectal cancer is 100%!!!!!
unscreened and untreated patients will have symptoms at 33 and dead by 42
polyps appear around 16
what is the biggest cause of death in familial adenomatous polyposis patients?
duodenal carcinoma and demoed tumors count for 50% of deaths in FAP patients who have undergone curative proctocolectomy = whole colon and recutm are removed
what is the gene mutation associated with FAP?
APC gene = adenomatous polyposis coli gene
chromosome 5Q
AD
each FAP pedigree has a characteristic mutation along APC gene
how do you screen for FAP?
flexible sigmoidoscopy or colonoscopy
every 1-2 years beginning at puberty!!
do a genetic analysis too
how do you treat FAP?
remove all mucosa at risk by doing a total proctocolectomy or end ileostomy
how do you screen people for familial colorectal cancer?
colonoscopy at 40 or 10 years earlier than the age at diagnosis of the youngest relative with colorectal cancer
when do you screen for lynch syndrome?
21 years old every 1-3 years colposcopy
how do you treat Lynch syndrome?
take out the whole colon because they have a 50% risk of getting cancer in another part of the colon
if they have rectal cancer too then do a total proctocolectomy and remove both the colon and tumor
what are the causes of sporadic vs. hereditary colon cancer?
colorectal cancers that are sporadic are usually due to chromosomal instability or CpG island methylation pathway
hereditary colorectal cancer is due to chromosomal instability or MSI pathway
what is the MSI pathway?
a common cause of hereditary colorectal cancers
MSI = micro satellite instability pathway
micro satellites = simple repetitive DNA sequences scattered throughout the genome that are composed of 1 or more repetitive base pair units and may be repeated up to 100 times
given their repetitive nature, they are liable for errors that occur during DNA replication
errors result in insertion/deletion loops
MMR genes play a critical role in identification and correction of these errors
what is a proto-oncogene?
they produce proteins products that normally enhance cell divine or inhibit normal cell death
mutated forms of these genes are called oncogenes
what are tumor suppressor genes?
genes that make proteins that normally prevent cell division or cause cell death
what is the mechanism of the genetic changes that cause colorectal cancer?
the mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis
CRC is a paradigm for multi-step carcinogenesis with morphologic genomic association in this adenoma-carcinoma sequence
proto-oncogenees = K-RAS
tumor supressor genes = APC, DCC
what is the 4 step sequential pathway in the colon cancer pathway?
Step 1 : APC inactivation causes adenoma development
Step 2 : KRAS mutations promote adenomatous growth
Step 3 : Genetic alterations of chromosome 18q allowed progression with biallelic loss
Step 4 : p53 inactivation triggers the final transition to carcinoma
what is the CIN pathway?
CIN = chromosomal instability pathway
how can you prevent colorectal cancers?
- increase fiber in diet
- decrease animal fat and red meat
- decrease smoking and EtOH
- increase exercise and decrease BMI
- secondary prevention with screening
we don’t really know how to prevent it…
how do screen for colorectal cancer?
- flexible sigmoidoscopy
- stool testing
- colonoscopy
- digital rectal exam
- fecal occult blood test
- virtual colonoscopy
- air contrast varium enema
- carcinogenic embryonic antigen (CEA) = monitors for recurrence; doesn’t diagnose
what are the symptoms of colon cancer?
- change in bowel habits
2 anemia/fatigue
- obstruction
usually symptoms aren’t till later
what are the symptoms of rectal cancer?
- rectal bleeding
- tenesmus
- obstruction
usually symptoms aren’t till later
how does colon cancer spread?
lymphatic spread so it goes to the liver
how does rectal cancer spread?
rectum drains through IVC so mets go to the lungs
what is T for colon cancer?
depth of the tumor
