Genetics & Colorectal Cancer

Lisen Axell, MS, CGCUniversity of Colorado Cancer Center

Overview

1. Cancer risk assessments 2. 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

• 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

• 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

• 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

Cancer risk based on family history

Sporadic70%

Familial25%

Hereditary5%

Family Hx

Personalized screening recommendations

genetic evaluation/testingwith personalized screening and risk reduction recommendations

Standard screeningrecommendations

Average(Sporadic)

Moderate(“Familial”)

High/Genetic

Classification: Who Needs What?

“Sporadic” Cancer

Sporadic70%

Familial25%

Hereditary5%

Dx 73

Dx 78

43

“Sporadic” Cancer

• Later ages of onset >60Later ages of onset >60• No clear pattern on one side of familyNo clear pattern on one side of family• Unilateral cancerUnilateral cancer• No inherited geneNo inherited gene that is the cause of the cancer that is the cause of the cancer• Family members have a small if any increase in cancer riskFamily members have a small if any increase in cancer risk

Sporadic70%

Familial25%

Hereditary5%

“Familial” Cancer

Dx 60

Dx 59

43

Dx 70

• Clustering of cancer but no clear patternClustering of cancer but no clear pattern• Typically later in lifeTypically later in life• May be due to: May be due to:

– inherited unknown genes (less penetrant) inherited unknown genes (less penetrant) – or environment or environment – or a combination of the twoor a combination of the two

• At risk family members may have a small to moderate increased At risk family members may have a small to moderate increased risk for cancer based on family historyrisk for cancer based on family history

“Familial” Cancer

Family History and CRC Risk

0

1

2

3

4

5

6

7

8

9

10

1 FDR 2 FDR >2 FDR

Rel

ativ

e R

isk

Family History

All cancer is genetic but only a small portion is inherited

Inherited Breast Cancer

Sporadic70%

Familial25%

Hereditary5%

Colon dx 50Uterine dx 55

Colon canceruterine cancer

Dx 35

43 Dx 45

Dx 55

Dx 65

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

Colorectal Cancer

Sporadic Sporadic (average risk) (65%–(average risk) (65%–85%)85%)

FamilyFamilyhistoryhistory(10%–30%)(10%–30%)

Hereditary nonpolyposis Hereditary nonpolyposis colorectal cancer colorectal cancer

(HNPCC) (5%)(HNPCC) (5%)Familial adenomatous Familial adenomatous polyposis (FAP) (1%)polyposis (FAP) (1%)

Rare Rare syndromes syndromes

(<0.1%)(<0.1%)

Amsterdam Criteria

3 first-degree relatives with CRC3 first-degree relatives with CRC 2 or more generations2 or more generations 1 CRC by age 501 CRC by age 50 Other cancers, especially endometrial Other cancers, especially endometrial

may be substituted for colon cancer in may be substituted for colon cancer in making the diagnosismaking the diagnosis

>50% of families who meet criteria will >50% of families who meet criteria will have gene mutationhave gene mutation

<8% of those who don’t will have <8% of those who don’t will have mutationmutation

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

HNPCC Results From Failure of Mismatch Repair (MMR)

Genes

Base pair Base pair mismatchmismatch

Normal Normal DNA DNA

repairrepair

Defective DNA Defective DNA repair (MMR+)repair (MMR+)

TT CCTT AA CC

A G C T GA G C T G

T C G A CT C G A C

A G C T GA G C T G

TT CCTT AA CC

A G C T GA G C T G A G A G AA T GT G

T C T C TT A C A C

III:1Two HNPCC related cancers:(incl synchronous/metachronous colorectal ca)II:1colorectal caDx <50I:1I:2colorectal ca and/or HNPCCrelated ca and/or colorectaladenoma (adenoma dx<40)III:2

Two HNPCC related cancers:(incl synchronous /metachronous colorectal ca)

•Ind. with CRC with two or more 1st degree or 2nd degree relatives with Lynch related tumor regardless of age

Dx <50

•Ind. with CRC and 1st degree with Lynch related cancer dx<50

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

CRC Dx <50

Ind. With CRC W/ infiltrating lymphocytes, Crohn’s like lymphocytic reaction, mucionous/signet-ring or medullary features on pathology dx<60

1.

2.

3.

4.

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

Cancer Risks in HNPCC

% with

cancer

100

80

60

40

20

020 40 60 800

Age (years)

Colorectal 78%Colorectal 78%

Endometrial 40-60%Endometrial 40-60%

Stomach 13%Stomach 13%

Biliary tract 2%Biliary tract 2%Urinary tract 10%Urinary tract 10%

Ovarian 12%Ovarian 12%

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

• 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

Carrier CarrierNot carrier Not 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

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

• 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, Like so-called urban legends that are built on rumor rather than fact, the perception of insurance company bias against patients who the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely undergo predictive genetic testing seems to be largely unsubstantiated.”- unsubstantiated.”- JAMAJAMA 1999;282:2197-8, 1999;282:2197-8,

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?

• Informed patients

• Reasonable likelihood of positive test

• Youngest affected individual

• ?Minors

• ?Prenatal