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Genetics & Colorectal Cancer. Lisen Axell, MS, CGC University of Colorado Cancer Center. Overview. Cancer risk assessments Family history of Colon cancer/ adenomatous (precancerous) polyps Screening guidelines 3. Inherited Colon Cancer Lynch syndrome (HNPCC) Amsterdam criteria/Bethesda

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genetics colorectal cancer

Genetics & Colorectal Cancer

Lisen Axell, MS, CGC

University of Colorado Cancer Center

overview
Overview
  • Cancer risk assessments
  • Family history of Colon cancer/ adenomatous (precancerous) polyps
    • Screening guidelines

3. Inherited Colon Cancer

    • Lynch syndrome (HNPCC)
    • Amsterdam criteria/Bethesda
    • Screening guidelines
    • Inheritance

4. Genetic discrimination protection

genes and cancer
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.
cancer risk assessment
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

identifying the important family history
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
classification who needs what
Classification: Who Needs What?

Standard screening

recommendations

Average

(Sporadic)

Personalized screening recommendations

Moderate

(“Familial”)

FamilyHx

genetic evaluation/testing

with personalized screening and risk reduction recommendations

High/Genetic

sporadic cancer1

Dx 73

Dx 78

43

“Sporadic” Cancer
  • 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
familial cancer1

Dx 70

Dx 59

43

Dx 60

“Familial” Cancer
  • 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
family history and crc risk
Family History and CRC Risk

Relative Risk

Family History

inherited cancer
Inherited Cancer

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

Dx 55

Colon cancer

uterine cancer

Dx 65

Dx 35

43

Dx 45

Colon dx 50

Uterine dx 55

colorectal cancer
Colorectal Cancer

Sporadic

(average risk) (65%–85%)

Family

history(10%–30%)

Rare syndromes (<0.1%)

Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)

Familial adenomatous polyposis (FAP) (1%)

amsterdam criteria
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
slide19

Amsterdam II Criteria

  • 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

hnpcc results from failure of mismatch repair mmr genes

T C G A C

A G C T G

T

C

A

T

C

A G C T G

T

T C T A C

C

A

T

C

A G AT G

A G C T G

HNPCC Results From Failure of Mismatch Repair (MMR) Genes

Normal DNA repair

Base pair mismatch

Defective DNA repair (MMR+)

slide21

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.

  • 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.

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

Clinical Features of Lynch syndrome
cancer risks in hnpcc
Cancer Risks in HNPCC

100

80

% with cancer

Colorectal 78%

60

Endometrial 40-60%

40

Stomach 13%

20

Ovarian 12%

Urinary tract 10%

Biliary tract 2%

0

0

20

40

60

80

Age (years)

management of hnpcc
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
inherited genetic abnormality
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
slide26

Carrier

Not carrier

Not carrier

Carrier

Carrier parent has a 50% or 1 in 2 chance to pass on the mutation with each pregnancy

benefits and limitations of genetic testing
Benefits

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

Benefits and Limitations of Genetic Testing
slide28

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
    • positive result
    • true negative result
genetic discrimination in health insurance is illegal
“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

“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,

gina genetic information non discrimination act
GINA (Genetic Information Non-discrimination Act)
  • Enacted May 2009. 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
whom do we test
Whom Do We Test?
  • Informed patients
  • Reasonable likelihood of positive test
  • Youngest affected individual
  • ?Minors
  • ?Prenatal