family first: what you need to know about family history, genetic testing, and colorectal cancer

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Family First: What you need to know about genetic testing,

family history& colorectal cancer

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Speaker

Heather Hampel, MS, CGCOhio State University

Comprehensive Cancer CenterTwitter: @hhampel1

Family First: What you need to know about genetic testing, family history & colorectal cancer

Heather Hampel, MS, CGCProfessor, Division of Human Genetics November 5, 2011

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Most cancers are not inherited

5-10% hereditary10-15% familial

75-85% sporadic

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Who is at high risk for cancer?History is the key…

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Family History

An important first step in risk assessment for genetic diseases and other hereditary health conditions

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Genetic Family History – My Family Health Portrait

• “The family tree has become the most important genetic test of all…”

• To help focus attention on the importance of family health history, U.S. Surgeon General in cooperation with other agencies within the U.S. Department of Health and Human Services (HHS) has launched a national public health campaign, called the U.S. Surgeon General's Family History Initiative, to encourage all American families to learn more about

their family health history. http://www.hhs.gov/familyhistory/

http://www.hhs.gov/familyhistory/

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My Family Health Portrait• Americans know that family history is

important to health. A recent survey found that 96 percent of Americans believe that knowing their family history is important. Yet, the same survey found that only one-third of Americans have ever tried to gather and write down their family's health history. http://www.hhs.gov/familyhistory/

http://www.hhs.gov/familyhistory

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My Family Health Portrait• Because family health history is such a

powerful screening tool, the Surgeon General has created a new computerized tool to help make it fun and easy for anyone to create a sophisticated portrait of their family's health. http://www.hhs.gov/familyhistory/

http://www.hhs.gov/familyhistory/

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National Family History Day• Thanksgiving is an annual National

Family History Day. Thanksgiving is the traditional start of the holiday season for most Americans.

• Whenever families gather, the Surgeon General encourages them to talk about, and to write down, the health problems that seem to run in their family. Learning about their family's health history may help ensure a longer future together.

• http://www.hhs.gov/familyhistory/

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Family history is a risk factor for diseases throughout all stages of

life

infantschildren

adolescents

adults older adults

birth defectsblood

disorders

Alzheimer’s disease

osteoporosis

cancerheart

disease

diabetesdepressio

n

asthma

autism

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Taking a Family History

Obtain at least a three-generation pedigree

Ask about all individuals in the family and record: Age at any diagnosis, age at and

cause of death Any corrective surgeries Associated congenital abnormalities

Record ethnicity and religious background Some cancer syndromes are more common

in individuals from certain ethnic groups

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Three-Generation Pedigree

Colon cancerdx 4062

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German/Polish English/Irish

Endometrial Cancerdx 49d. 72

d. 80

67 5565 Diabetes, dx 45 59

52

30

d. 70 d. 85

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Family History Questionnaires

Name

Davis, John

Jones, Mary

Date of Birth

2/1/40

4/9/42

Age at dx/ Type of Cancer

CRC dx 48

Endometrial dx 52

Date of

Death

4/3/87

N/A

Hospital

U. Minn.

Franklin Medical center

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Information to Obtain About Affected Relatives

Current age Age at and date of diagnosis/death Type and number of colon polyps Type and location of cancer Primary cancer location vs. metastatic

cancer site Hospital where treated Environmental exposures (eg, sun)

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Information to Obtain About Unaffected Relatives

Current age

Health status and history of significant illnesses

Presence of other physical findings associated with syndromes

If deceased, cause of and age at death

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“Female” cancer

Ask about the presenting features Detected by Pap smear – likely cervical cancer Diagnosed due to heavy bleeding – likely

uterine/endometrial cancer Bloated (looked 6 months pregnant) – likely ovarian

cancer

Ask about the treatment Hysterectomy but ovaries left behind – probably not

ovarian cancer No chemotherapy – probably NOT ovarian cancer LEEP procedure or colposcopy – probably cervical

dysplasia or cancer

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Unknown type of cancer

Request copies of medical records (pathology reports are the key) from the hospital where the relative was treated If a family member makes the request, there will be a

charge for the records If you physician or genetic counselor makes the

request, there will not be a charge for the records

Request death certificates Can be obtained from the state department of health

relatively inexpensively Can be obtained at www,vitalchek.com from any state

– arrive quickly, slightly more expensive

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High Risk Clues: Cancer in 2 or more close relatives

(on same side of family)

Multiple generations affected

Early age at diagnosis

Multiple rare cancers (sebaceous skin cancer)

Multiple primary tumors (colon and uterus; more than one colon cancer)

Multiple colon polyps (>10) Patients with certain pathology findings

Abnormal IHC or MSI+ testing

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CAUTION

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Family History can be unreliable

Many people do not know the details of their family history. Specific sites of tumors unknown Ages of onset unknown

Historical information needs to be verified in order to accurately assess risk.

Family size is getting smaller – can “hide” susceptibility

Increased use of effective screening/prevention options (i.e. colonoscopy) can prevent cancers that would have occurred otherwise

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Initial pedigree After review of records

Stomach Ca

Prostateproblems

Bone Cad. 48

Breast Cadx 45d. 48

Ovarian Cadx 43, d. 49

Prostate Cadx 50

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Histories are dynamic

With the passage of time, additional diagnoses may have been made.

These changes in diagnosis may affect the likelihood of a hereditary cancer syndrome.

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Initial History 2 years later

Colon Ca, 50Colon Ca, 50

Endometrial Ca, 44

Colon polyps, 48

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Flowchart for Hereditary Colon Cancer Differential Diagnosis

Presence of >10 polyps

Type of polyps

Lynch syndromeFamilial Colorectal Cancer

syndrome type XMUTYH-Associated Polyposis

Peutz-Jeghers syndromeJuvenile Polyposis

Serrated Polyposis syndrome

Familial Adenomatous Polyposis Attenuated FAP

MUTYH-Associated Polyposis

NoYes

AdenomatousHamartomatous

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Hereditary Cancer Syndromes: Lynch Syndrome & FAP

MLH1

PMS2

MSH2 MSH6 APC

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Sporadic Inherited

• Later age at onset (60s or 70s)• Little or no family history of cancer• Single or unilateral tumors

• Early age at onset (<50)• Multiple generations with

cancer• Clustering of certain

cancers (i.e. breast/ovarian)

Normal gene

Somatic mutation

Somatic mutation

Germline mutation

Somatic mutation

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Autosomal Dominant Inheritance

Carrier Parent Non-carrier Parent

Aa aa

Aa Aa aa aa

Carrier Carrier Non-carrier Non-carrier

1/2 1/2

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Lynch Syndrome

Early but variable age at CRC diagnosis (~45 years)

Tumor site in proximal colon predominates

Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

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Amsterdam II criteria

• 3 or more relatives with verified HNPCC-associated cancer in family

• Two or more generations• One case a first-degree relative of the

other two• One CRC dx <50• FAP excluded

Vasen HFA et al. Gastroenterology. 116:1453, 1999

Does not include ovarian, gastric, brain,

biliary tract or pancreatic cancer

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Bethesda Guidelines

Individual with CRC dx <50 Individual with synchronous or metachronous

CRC, or other HNPCC-associated tumors regardless of age

Individual with CRC with MSI-H histology dx <60 Individual with CRC with >1 FDR with an

HNPCC-associated tumor, with one cancer dx <50

Individual with CRC with >2 FDRs or SDRs with an HNPCC-associated tumor, regardless of age

Umar A, et al. JNCI. 2004;96(4):261-268.

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Lynch Syndrome Cancer Risks (to 70)

Cancer Lynch syndrome General Public

Colon cancer 56-85% 5%

Endometrial cancer 35-60% 2%

Gastric cancer 13% 1%

Ovarian cancer 12% 1.5%

Small bowel, bladder, ureter, renal pelvis, brain

<4% each <1% each

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Lynch syndrome Surveillance Options

Lindor N et al. JAMA 2006;296:1507-17. & Vasen HFA et al. J Med Genet 2007;44:353-62.

Intervention Recommendation

Colonoscopy Every 1-2 y beginning at age 20-25 (MLH1 & MSH2), or 30 (MSH6 & PMS2)

Endometrial sampling Every 1 y beginning at age 30-35

Transvaginal U/S Every 1 y beginning at age 30-35

Urinalysis with cytology Every 1-2 y beginning at age 30-35

History & Exam w/ review of systems

Every 1 y beginning at age 21

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Case 1

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Case 2

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Clinical Features of FAP

Estimated penetrance for adenomas >90%

Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)

CHRPE may be present

Untreated polyposis leads to 100% risk of cancer

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Attenuated FAP

Later onset (CRC ~age 50) Few colonic adenomas Not associated with CHRPE UGI lesions Associated with mutations at

5' and 3' ends of APC gene

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MUTYH-Associated Polyposis (MAP) Recessive inheritance – carrier frequency high Biallelic MYH mutations are found in:

96/1457 (6.6%) patients with >100 adenomas 233/3253 (7%) patients with 20-99 adenomas 37/970 (4%) patients with 10-19 adenomas 19/1147 (2%) patients with <10 adenomas

Y165C & G382D common in W.E. Caucasians E466X in Eastern Indian families

Grover S et al. JAMA 2012;308:485-92.

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MUTYH-Associated Polyposis (MAP)

MYH mutations in CRC dx <50 8/1116 (0.7%) + 12/1238 (1%) + 4/64 (6.3%) +

Heterozygote risk 14/259 heterozygotes had adenomas vs 2/107

controls 2/50 obligate carrier parents had CRC – Expected If there is a cancer risk for heterozygotes – LOW

Wang L et al. Gastroenterology 2004;127:9-16; Croitoru S et al. J Natl Cancer Inst 2004;96:1631-4.Balaguer et al. Clin Gastroenterol Hepatol 2007;5:379-87

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MAP Management

Colonoscopy every 2-3 y begin at 25-30 if negative for polyps

Once polyps are found, colonoscopy and polypectomy every 1-2 y

Subtotal colectomy or proctocolectomy depending on adenoma density and distribution

Consider UGI endoscopy and side viewing duodenoscopy begin at 30-35 and repeat depending on findings

Annual physical examination

NCCN Guidelines for Colorectal Cancer Screening 2.2014

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Who to test for FAP & MAP? APC testing criteria

Personal history of >10 adenomas Personal history of a desmoid tumor Known APC mutation in family

MUTYH testing criteria Personal history of >10 adenomas Individual meeting SPS criteria with some adenomas Known MUTYH mutations in family

Start testing with affected relative if possible If affected relative is deceased, can test at-risk

relative but negative result is uninformative Can test minors because cancer screening starts in

childhood

NCCN Guidelines for Colorectal Cancer Screening 2.2014

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Moderate Risk Families

1-2 cases of a cancer in the family Do not need referral for genetic counseling Do need increased cancer surveillance Generally the first degree relatives of a person with a

cancer are about twice as likely to develop that same cancer than someone without that family history

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Familial Colorectal Cancer Risks

Taylor, DP, Gastroenterology 2010;138:877-886.

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Familial Colorectal Cancer Screening Recommendations FDR diagnosed <50 or 2 FDR dx at any age

Colonoscopy every 3-5 years beginning at age 40 (or 10 years before earliest dx of CRC

FDR diagnosed >50 Colonoscopy every 5 years beginning at age 50 (or 10

years before earliest dx of CRC SDR diagnosed <50

Colonoscopy beginning at age 50 repeat depending on findings

FDR with advanced adenoma(s) Colonoscopy beginning at age 50 or age of onset repeat

depending on findings Otherwise follow Average Risk recommendations

Colonoscopy every 10 years beginning at age 50

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Family Healthlink

Interactive web tool that estimates risk by reviewing patterns of cancer and heart disease and related conditions in a family

10-15 min depending on the size of the family No pedigree to view; no updating Personalized risk assessment (pdf) to share with

healthcare providers

https://familyhealthlink.osumc.edu

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Genetic Counseling

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Genetic Counseling:Purpose

Appreciate the way heredity contributes to cancer

Understand an individual’s risk of developing cancer

Understand the options for dealing with an increased risk for cancer

Choose a course of action for managing cancer risk that seems personally appropriate (genetic testing, screening or long-term follow up)

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Genetic Counseling:What happens

Collection of personal and family history 3 generation pedigree

Education and risk assessment Options for genetic testing and medical

management Discussion of risks, benefits and limitations Screening/Chemoprevention/Prophylaxis

Follow-up Provide psychosocial support Family members

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Genetic Testing:Purpose

If the exact gene mutation can be identified in a family, it can: Diagnose the family with a specific cancer syndrome Determine for which cancers the family is at risk Determine a cancer surveillance & prevention plan Allow at-risk family members to be tested

inexpensively and reliably Relatives who inherit the mutation need to follow the

increased cancer surveillance & prevention plan Relatives who do NOT inherit the mutation can follow

the American Cancer Society guidelines for cancer screening in the general population 50 colonoscopies versus 3 colonoscopies

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Genetic Testing:What happens

Testing is most accurate when you begin by testing a family member who has had cancer (or polyps) If they test positive, the family has a diagnosis and a

known mutation for follow-up testing If they test negative, the family history may or may not

still be hereditary but there is no known mutation for follow-up testing

Many sites will start Lynch syndrome testing with a screening test on the colon or endometrial tumor Stored in a wax block at the hospital where you had

surgery

Genetic Testing is done using either a blood sample or a saliva/mouthwash sample

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Genetic Testing:What happens

Costs: Tumor screening tests $500-$1500 Genetic testing $1500/gene or $1500-4500/all genes Known mutation testing $200 - $500

Results: Can take anywhere from 2-12 weeks May be given by telephone or in the setting of post-

test genetic counseling depending on center

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Genetic Testing:Informed Consent Benefits

Know reason for cancers in family Ability to determine who is and who is not at risk Ability to be screened appropriately

Limitations Variants of Uncertain Significance Genes that have not been discovered yet

Risks Bruise from blood draw Psychological risks (guilt from passing gene onto

children, adjustment to testing positive, survival guilt when testing negative)

Insurance discrimination

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GINA

Prevents health insurers from denying coverage, adjusting premiums, or otherwise discriminating on the basis of genetic information. Group and self-insured policies

Insurers may not request that an individual undergo a genetic test.

Employers cannot use genetic information to make hiring, firing, compensation, or promotion decisions.

Sharply limits a health insurer's or employer's right to request, require, or purchase someone's genetic information.

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Refer to an cancer genetic counselor near you Find a Local Counselor from the NSGC

http://nsgc.org/p/cm/ld/fid=164 Find a Local Cancer Genetics expert from the NCI

http://www.cancer.gov/cancertopics/genetics/directory

Refer to a national telecounseling service Informed DNA at http://www.InformedDNA.com 1-800-975-4819

How to find a genetic counselor near you

Heather Hampel

http://nsgc.org/p/cm/ld/fid=164

http://www.cancer.gov/cancertopics/genetics/directory

http://www.informeddna.com/

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Resources

Heather Hampel 614-293-7240 [email protected]

Family HealthLink https://familyhealthlink.osumc

.edu Free, on-line tool that

assesses family history of cancer and cardiovascular disease

mailto:[email protected]

https://familyhealthlink.osumc.edu/

https://familyhealthlink.osumc.edu/

family first: what you need to know about family history, genetic testing, and colorectal cancer

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