Genetics: Colorectal Cancer

How is Lynch syndrome different from FAP?

1. pts develop only a few adenomas, usually on right side of colon.

What may create familial coloractal cancer?

1. single-gene mutations 2. multiple gene mutations 3. or combined effect of gene mutations and environmental risk factors

Of patients with classic FAP what percentage of people have a mutation in the APC gene and which percent have mutation in MYH gene?

15% APC 25% MYH

1. Familial Colorectal Cancer makes up _______% to ________% of colorectal cancers

15% to 30%

Tests that mainly find cancer:

=stool-based tests. Find cancer in the stool 1. Fecal occult blood test (FOBT*) 2. Fecal immunochemical test (FIT*) 3. Stool DNA test (sDNA*) -If test results are positive, colonosopy* should be done

What is used for HNPCC (Lynch syndrome) dx?

Amsterdam criteria II

Explain why it fits with the multi-step model of tumor progression.

Because APC loss by itself is not sufficient enough for cancer progression. It is an early step, but other steps are necessary

If the genetic testing documents an HNPCC gene mutation, when and how often should affected relatives be screened with colonoscopy?

Beginning at age 25 and every 1-2 years

What should be considered significant when taking family history of coloractal cancer?

Fam history with one or more members with frank colorectal cancer or premalignant polyps

What effects the number of polpys formed and the type of extracolonic features seen?

Location of the mutation on chromosome 5

What patterns are considered familial?

Patterns within a family that exist without the identification of a specific mutation are considered familial*

What is Bethesda Criteria used for?

Used to identify individuals who should receive genetic testing for HNPCC (lynch syndrome) -more sensitive than Amsterdam II criteria in detecting individuals and families at risk for Lynch Syndrome

When does colorectal cancer occur?

When cells that line the colon or rectum become abnormal and grow out of control

Those who inherit a mutated adenomatous polyposis coli (APC) gene have avery high likelihood of developing ________________, though onset is variable.

adenomas

Many patients with colorectal cancer do not experience sx until the disease is___________.

advanced

How should tumors be verified under the Amsterdam II criteria?

by pathologic examination

Majority of colon cancers are _________________.

sporadic

What type of gene is APC?

tumor suppressor gene

What is the Amsterdam II criteria?

-3 or more relatives with Lynch associated cancer (colorectal, edomentiral, small intestine, ureter, renal pelvis) -2 or more successive generations affected, 1 is first degree of other two -1 or more relatives diagnosed before age 50 -Familial Adenomatous Polyposis has been ruled out

Genetics of FAP: What gene is mutated? What happens?

-APC tumor suppressor gene is mutated -Premature stop codons shorten the APC gene product*, which disrupts its roll in regulation of cell adhesion and apoptosis

HNPCC

-Also termed Lynch* Syndrome* -Fewer polyps than FAP -Other tumors common in this syndrome

What is the varriant form of FAP? Why is it different?

-Attenuated* FAP -Different because there are fewer polyps, has later onset, though they still have same 100% lifetime risk of developing colon cancer

What are Polyps? What happens if they become untreated?

-Benign adenomatous* growths protruding from the mucous membrane of the colon and rectum -if left untreated, they may evolve into cancer

Signs and sx associated with Coloractal Cancer

-Blood in stool -weight loss -diarrhea -constipation for long period -cramps in abdomen -change in bowel habits -unexplained anemia -decrease in size of stool -feeling of ab distention -vomiting and lack of energy

Genetics of HNPCC: What genes are defected? What are they normally involved in?

-Defect in one of several genes= MLH1, MSH2, MSH6, and PMS2 -Normally these genes are involved in DNA mismatch repair -loss of function increases the mutation rate 1000X

FAP

-Gene that is mutated is APC (adenomatous polyposis coli) -Adenomas* that start as polyps may form, will continue to form a lot of them, which can progress to malignancy

What causes the polyp formation? How many polyps can form in that tissue?

-Loss of second copy of APC gene -several hundred

FAP can ALSO be caused by mutation in which gene? How is it inherited?

-MYH gene -Inherited in an autosomal recessive fashion

While the majority of colon cancers are sporadic and occur randomly, it is still important to:

-Recognize familial or hereditary patterns early in pts using screening and management guidelines for patient and relatives. -important to take a good family history to access risk

Genetic counseling and testing methods for FAP

-offered to pts with diagnosed FAP and at-risk relatives -offered to pts with 20 or more adenomas -MYH testing would be considered when pts have negative APC results, and suspected attenuated* FAP -children of pts with FAP should do genetic screening at age 10

Lynch syndrome occurs at ____________age than sporatic colorectal cancer. Other cancers that may arise in these families include:

-younger age other cancers: 1.uterine 2. ovarian 3. stomach 4. urinary tract 5. small bowel 6. bile ducts

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Lynch Syndrome)

1. Autosomal Dominant 2. 3-5% of all colorectal cancers

What are the Bethesda Criterias?

1. Colorector cancer in patient under 50 years old 2. Synchronous, metachronous colorectal cancer or other Lynch-related tumors (any age) 3. Colorectal cancer with microsatellite instability histology in pts younger than 50 4. Colorectal cancer or Lynch related tumor in 1 or more 1st degree relatives. 1 below age of 50 5. Colorectal cancer/ Lynch tumor diagnosed in 2 or more first or second degree relatives (any age)

Familial Adenomatous Polyposis (FAP) is autosomal ________________, with a __________% chance of passing condition to children.

1. Dominant 2. 50%

What are the two types of Hereditary colorectal cancer that are caused by mutations in two different genes?

1. Familial Adenomatous Polyposis Coli (FAP)= ABC gene 2. Hereditary Non-Polyposis Colon Cancer (HNPCC)

Screening tests to find polyps and cancer by directly seeing them:

1. Flexible sigmoidoscopy (every 5 years*) 2. Colonoscopy (10 years) 3. Double-contrast barium enema (every 5 years*) 4. CT colonography (virtual colonoscopy, every 5 years*)

Screening for FAP

1. annual colonoscopy in those where genetic testing can't be done, beginning at age 12 -if diagnosed, most pts undergo complete-proctocolectomy* or colorectomy* by age 20 -If attenuated FAP is suspected, it is important that family members are screening with colonoscopy rather than flexible sigmoidoscopy

Families who have HNPCC should be evaluated first by a genetic counselor and give __________________before testing is performed. Genetic screening should be considered for pts meeting any of the revised __________________criteria

1. informed consent 2. Bethesda