1. Genetics & Colorectal Cancer
Lisen Axell, MS, CGC
University of Colorado Cancer Center

2. Overview Cancer risk assessments
Family history of Colon cancer/ adenomatous (precancerous) polyps
Screening guidelines
3. Inherited Colon Cancer
Lynch syndrome (HNPCC)
Amsterdam criteria/Bethesda
Inheritance
4. Genetic discrimination protection

3. Genes and Cancer All cancers are caused by gene mutations
The mutations can be either acquired or inherited.
Personal and family history are the indicators of when it may be inherited.

4. Cancer Risk Assessment
Likelihood of developing cancer based on family history
Likelihood of a inherited cancer syndrome
Likelihood of a detectable mutation
Medical management recommendations based on family history/mutation status
Recommendations for at risk family members
Discussion of genetic testing and if patient wants to pursue testing 4

5. Identifying the IMPORTANT family history
BOTH SIDES OF THE FAMILY
At least 3 generations
Establish age at diagnosis
Clarify the exact diagnosis (pathology reports can be invaluable)
Determine the number of family members without cancer

6. Cancer risk based on family history6

7. Classification: Who Needs What?
Standard screening
recommendations
Average
(Sporadic)
Personalized screening recommendations
Moderate
(“Familial”)
Family Hx
genetic evaluation/testing
with personalized screening and risk reduction recommendations
High/Genetic 7

8. “Sporadic” Cancer

9. “Sporadic” Cancer Later ages of onset >60
Dx 73
Dx 78 43
Later ages of onset >60
No clear pattern on one side of family
Unilateral cancer
No inherited gene that is the cause of the cancer
Family members have a small if any increase in cancer risk

10. “Familial” Cancer

11. “Familial” Cancer Clustering of cancer but no clear pattern
Dx 60
Dx 59 43
Dx 70
Clustering of cancer but no clear pattern
Typically later in life
May be due to:
inherited unknown genes (less penetrant)
or environment
or a combination of the two
At risk family members may have a small to moderate increased risk for cancer based on family history

12. Family History and CRC Risk
Relative Risk
Family History

14. All cancer is genetic but only a small portion is inherited

15. Inherited Breast Cancer

16. Inherited Cancer Cancer in young individuals (less than age 50)
Dx 55
Colon cancer
uterine cancer
Dx 35
Dx 65 43
Dx 45
Colon dx 50
Uterine dx 55
Cancer in young individuals (less than age 50)
Many generations affected with the same type of cancer on the same side of the family
Two primary cancers or two related cancers in same individual
Related cancers in family

17. Colorectal Cancer Sporadic (average risk) (65%–85%) Family
history (10%–30%)
About 1600 new cases of colon cancer are diagnosed each year in Colorado.
The majority of colon cancers, 65% to 85%, occur in people with no known cause (i.e., they are considered sporadic).
10% to 30% of cases of colorectal cancer occur in people who have a family member who has had a polyp or colorectal cancer.
A small percentage of colorectal cancers occur as part of an inherited syndrome. Approximately 5% are associated with hereditary nonpolyposis colorectal cancers (HNPCC) and 1% are associated with familial adenomatous polyposis (FAP).
Less than 0.1% are rare colorectal cancer syndromes.
Rare syndromes (<0.1%)
Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)
Familial adenomatous polyposis (FAP) (1%)

18. Amsterdam Criteria 3 first-degree relatives with CRC
2 or more generations
1 CRC by age 50
Other cancers, especially endometrial may be substituted for colon cancer in making the diagnosis
>50% of families who meet criteria will have gene mutation
<8% of those who don’t will have mutation
The hallmark for diagnosing HNPCC is still clinical criteria. The most stringent of these clinical criteria is the Amsterdam Criteria which is the rule. These criteria were then modified to include the other types of cancer that we see in HNPCC namesly
The big one is endometrial cancer
ovarian cancer
stomach cancer
renal pelvis cancer
hepatobilliary
The clinical criteria is still the main way to diagnose these families because even of families that meet these most stringent criteria only about 60-70% will actually be found to have a mutation. This doesn’t mean that the other families don’t have HNPCC but more likely that current technonoloyt can’t detect them yet or that there are other genes out there that we haven’t discovered yet.

19. Amsterdam II Criteria Dx <50 Dx <50 HNPCC related cancers:
colorectal cancer
endometrial cancer
ovarian cancer
gastric cancer
hepatobiliary
small bowel
transitional cell ca of
renal pelvis or ureter
Dx <50
Dx <50

20. HNPCC Results From Failure of Mismatch Repair (MMR) Genes
Normal DNA repair
T C G A C
A G C T G
Base pair mismatch T C A
A G C T G T C A
A G C T G
A G A T G
T C T A C
Defective DNA repair (MMR+)

21. Bethesda Criteria (modified)
do MSI and IHC screening first, if positive go to sequencing
HNPCC related cancers:
colorectal cancer
endometrial cancer
ovarian cancer
gastric cancer
hepatobiliary
small bowel
transitional cell ca of
renal pelvis or ureter 1.
CRC Dx <50
Two HNPCC related cancers:
(incl synchronous /metachronous colorectal ca) 2. 3.
Ind. with CRC and 1st degree with
Lynch related cancer dx<50
Dx <50 4.
These criteria were recently modified and the A MA came out with a piece with new recommendations for genetic testing.
If an individual fulfills these first two Bethesda or the Amsterdam crieteria the current recommendation is to go directly to sequescing for th genes known to be involved in HNPCC. This recommendation is based on the likelihood to find a mutation.
Even if you do not find a mutation you may follow these individuals as if the HNPCC
Ind. with CRC with two or more 1st degree or 2nd degree relatives with Lynch related tumor regardless of age
Ind. With CRC W/ infiltrating lymphocytes, Crohn’s like lymphocytic
reaction, mucionous/signet-ring or medullary features on pathology dx<60 5.

22. Clinical Features of Lynch syndrome
Autosomal dominant
Average age of CRC- 44 yrs
Only few adenomas
Proximal location
Multiple- 20% synchronous 50% metachronous
Mucinous, signet-ring, solid/cribiform, lymphocytic infiltration
HNPCC- Hereditary non polyposis colorectal cancer
This is the syndrome that you will be most likely to see because it is the most common and it is also the one that doesn’t have such distinguishing features on an individual basis so the gathering of correct family history becomes very important.
This is also autosomal dominant. These individuals do develop adenomas but they don’t tend to have very many.
One of the distinguishing features is that these tumors tend to be
right sided,
they tend to have MSI
and can be mucinous, signet-ring, solid/cribiform and have lymphocytic infiltration.

23. Cancer Risks in HNPCC 100 % with cancer 80 60 40 20 20 40 60 80
Colorectal 78% 60
Endometrial 40-60% 40
Stomach 13%
There is a substantial risk for cancer with HNPCC a lifetime risk of cancer. The types of cancer that we see with HNPCC are Colorectal, endometrial, stomach ovairan urinary tract and billiary. These cancers also occur at young ages 20
Ovarian 12%
Urinary tract 10%
Biliary tract 2% 20 40 60 80
Age (years)

24. Management of HNPCC
Genetic testing (MSI and IHC, then mutation testing), start with index case
Colonoscopy, age 25 years, or 10 years younger than earliest diagnosis, repeat every 1-2 years
Appropriately timed colectomy
Other tumor screening
Endometrial, ovarian, gastric, biliary, small bowel, urinary tract

25. Inherited genetic abnormality
Individuals are born with an abnormal gene passed on by a parent and one normal gene from the other parent
This mutation is present in all cells though it only increases risk of some types of cancer
A blood test can often detect presence of mutation in families at very high risk

26. Carrier
Not carrier
Not carrier
Carrier
Carrier parent has a 50% or 1 in 2 chance to pass on the mutation with each pregnancy

27. Benefits and Limitations of Genetic Testing
Cancer prevention and early detection
Information for the health care of family members. If mutation in family can determine who is at increased risk and who is a true negative and at general population risk
Results can alleviate uncertainty and anxiety
Limitations
A negative result is not informative unless there is a known mutation in the family
Some genetic variants are of unknown clinical significance
Slide 18
Benefits and Limitations of Genetic Testing for HNPCC
Genetic testing for HNPCC can have important benefits for members of high-risk families who choose to be tested. Those who are found to carry deleterious mutations can take steps to reduce their cancer risk, especially through earlier and more intensive surveillance or consideration of prophylactic surgery. Individuals with HNPCC-related colorectal cancer can undergo surgical management designed to address the increased risk of a second cancer.
In families in whom a deleterious mutation has been found, those who are mutation-negative can be spared the need for more intensive surveillance and intervention. However, these individuals remain at risk for sporadic colorectal cancer and should be encouraged to adhere to age-appropriate general population screening guidelines.
Before consenting to genetic analysis, patients should also consider the limitations of testing. Currently, genetic testing cannot detect unusual mutations responsible for HNPCC, such as those occurring in MMR genes other than MLH1 and MSH2. Therefore, a negative result in an individual who does not have a family member with a documented mutation must be interpreted cautiously. The test may also detect a variant of uncertain significance whose effect on cancer risk has not yet been established. In such situations, testing other family members for the specific variant to determine if it is associated with cancer may provide clarification of the significance. Such follow-up testing is provided without charge by Myriad Genetic Laboratories.
Reference
Syngal S. Hereditary nonpolyposis colorectal cancer: A call for attention. Journal of Clinical Oncology 2000;18:

28. Possible tests results and implications
If no known mutation in family
positive result
indeterminate negative result
variant of uncertain significance
If known mutation in family
true negative result

29. “Genetic Discrimination” in Health Insurance is Illegal
Health Insurance Portability and Accountability Act (HIPAA)
Prohibits group health insurance plans from discriminating on the basis of genetic information.
Most states have enacted additional protections
Family members do not have to disclose whether a relative has undergone genetic testing
Slide 19
“Genetic Discrimination” in Health Insurance is Illegal
Some individuals have expressed concern that identification of hereditary risk of cancer could have adverse consequences on their access to affordable health insurance. The Health Insurance Portability and Accountability Act of 1996 made it illegal in the United States for group health plans to consider genetic information a “pre-existing” condition” or to use it to deny or limit coverage. A majority of states have also passed laws that prevent genetic discrimination in health insurance as well as in employment. Moreover, a family member does not have to disclose to their insurers whether a relative has undergone genetic testing (unless in some circumstances where the family member’s policy also covers the relative who was tested).
Genetic testing for hereditary cancer risk has been available for several years, and there are few if any reported cases of genetic discrimination following testing for mutations in MLH1 and MSH2 or other cancer susceptibility genes. Summarizing a recent study that found little evidence of health insurers either asking for or using genetic predisposition test results in their underwriting decisions, a commentary in the Journal of the American Medical Association noted that “the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely unsubstantiated.”
Increasing numbers of individuals are requesting and obtaining coverage for the cost of genetic testing from their insurance carrier. Individuals seeking information and assistance regarding their own insurance coverage for HNPCC testing can call the Myriad Reimbursement Assistance Program (“MRAP”) at
References
Stephenson J. Genetic test information fears unfounded. JAMA 1999;282:
Hall MA, Rich SS. Laws restricting health insurers' use of genetic information: impact on genetic discrimination. American Journal of Human Genetics 2000;66:
“Like so-called urban legends that are built on rumor rather than fact, the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely unsubstantiated.”- JAMA 1999;282:2197-8,

30. GINA (Genetic Information Non-discrimination Act)
Enacted May Federal protections against discrimination based on genetic information
Genetic information is defined as predictive genetic tests, family members’ genetic tests and family history information
Applies to group and individual health insurance as well as employment practices
Does not cover life, disability, long term care and other forms of insurance

31. Whom Do We Test? Informed patients
Reasonable likelihood of positive test
Youngest affected individual
?Minors
?Prenatal