Genetics and Primary Care

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Genetics and Primary Care

• Familial Cancer Risk Assessment
• Colorectal Cancer

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Case 1Joan

• Joan, age 38, was recently diagnosed with
  endometrial cancer. Family history reveals
• Paternal grandmother endometrial cancer, age 50
• Paternal uncle colon cancer, age 48
• Father colonoscopy at age 50 four adenomatous
  polyps removed
• No other significant history
• Both sides of the family are Northern European
  Caucasian

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Case 2 Ted

• Ted is 30 and wants a colonoscopy because his
  mother was just diagnosed with colon cancer after
  routine screening at age 54. Family history
  reveals
• Paternal grandfather died of CRC at age 79
• No hx of endometrial, ovarian, small bowel or
  ureter/kidney cancer on either side of family
• Two maternal aunts cervical cancer at ages 30
  34
• Maternal grandmother breast cancer age 85

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Outline

• Hereditary colorectal cancer syndromes
• Cancer family history a primary tool
• Evaluating your patients for familial CRC risk
• Genetic counseling and testing for hereditary
  colorectal cancer
• How, when, where to refer patients for genetic
  services

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Colorectal Cancer

• 5-8 of all cases of CRC are hereditary
• 15-20 are familial / multifactorial
• 75 of cases are sporadic
• Feuer EJ DEVCAN National CA Inst. 1999

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Characteristics of Average Risk

• No well-defined threshold between sporadic and
  familial CRC at this time
• Probably safe to include individuals with
• No personal risk factors or family history of CRC
• One 2nd or 3rd degree relative with CRC gt60 years
  with no other family history of CRC

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Characteristics of Familial CRC

• Clustering of colon cancer cases in the family
  (gt 50 at diagnosis) without clear dominant
  pattern, or
• One close relative with CRC lt60 yrs and family
  history does not meet criteria for known
  hereditary CRC syndromes
• Likely to be multiple low pentrant genes plus
  environmental factors at play
• Family members warrant earlier CRC screening
• Starting at 40 years or 5-10 yrs earlier than age
  of diagnosis of the youngest affected relative

Winawer et al., Gastroenterology 2003124544-560
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Characteristics of Hereditary CRC

• Multiple relatives with colorectal cancer
• One or more diagnosed at an early age (lt50)
• Sequential generations affected
• Except in autosomal recessive syndromes
• Other cancers in the family known to be
  associated with CRC (uterine, ovarian, GI)
• Multiple primary tumors or polyps

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Hereditary CRC syndromes

• Hereditary Non-Polyposis Colorectal Cancer
  (HNPCC)
• Variants Muir-Torre, Turcot
• Familial Adenomatous Polyposis (FAP)
• Variants Gardner, Turcot
• Attenuated FAP
• APC mutation in Ashkenazi Jews
• Others
• Multiple adenomatous polyposis syndrome/MYH gene
  (MAP)
• Peutz-Jeghers syndrome (PJS)
• Familial Juvenile Polyposis (FJP)

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In Your Practice Colon Cancer

• In the typical primary care practice, 2 to 8
  patients (1/200 to 1/800) are from high risk
  families, with a condition called Hereditary
  Non-Polyposis Colon Cancer (HNPCC). These
  patients have a high lifetime risk of colorectal
  and other cancers with risk starting in their
  20s.

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HNPCC AKA Lynch syndrome

• 2-3 of all colorectal cancer cases
• Autosomal dominant high penetrance
• Typical age of CA onset is 40-50 yrs
• Multiple affected generations
• 60-70 right-sided/proximal CRC tumors
• Polyps may be present, multiple primaries common.
  Can overlap with AFAP

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HNPCC

• Lifetime cancer risks
• Colorectal 80
• Endometrial 20-60
• Gastric 13-19
• Ovarian 9-12
• Biliary tract 2
• Urinary tract 4
• Small bowel 1-4
• Brain/CNS 1-3

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HNPCC Clinical Diagnostic Criteria

• Amsterdam II Criteria (3-2-1 rule)
• 3 or more relatives with an HNPCC-related
  cancer, one of whom is a 1st degree relative of
  the other two
• 2 or more successive generations affected
• 1 or more cancers diagnosed before age 50

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HNPCC

• Caused by mutations or deletions in mismatch
  repair (MMR) genes
• MSH2, MLH1, MSH6, (PMS2)
• 90 of detectable mutations in MSH2 and MLH1
• 50 of families meeting Amsterdam II Criteria
  have detectable mutations
• Testing/screening options
• Direct genetic testing of MMR genes (in select
  families)
• Initial screening of the tumor tissue by MSI/IHC

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Proceed Directly To Genetic Testing After
genetic counseling and informed consent!

• IF
• Family history fulfills Amsterdam II criteria or
• Patient has two HNPCC related cancers or
• Patient has CRC and a 1st degree relative with
  HNPCC-related cancer, with at least one cancer
  diagnosed lt50 years of age
• Always test an affected family member first!

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MSI/IHC screening

• Microsatellite Instability (MSI) on tumor tissue
• can be used to screen for HNPCC in select cases
• Immunohistochemistry (IHC) on tumor tissue
• can be used to detect the presence or absence of
  the mismatch repair proteins (MSH2, MLH1, etc.)
• Screen positive individuals can be offered
  cancer genetic counseling/assessment and targeted
  genetic testing

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Criteria for MSI/IHC screening

• Revised Bethesda Criteria, 2004
• CRC or endometrial CA lt50 yrs
• 2 HNPCC cancers in same person
• CRC with MSI-H histology diagnosed lt60 yrs
• Infiltrating lymphocytes, Crohns-like lymphocytic
  reaction, mucinous/signet ring differentiation,
  medullary growth pattern
• CRC and one or more 1st degree relative with an
  HNPCC-related cancer, one diagnosed lt50 yrs
• CRC and two or more 1st or 2nd degree relatives
  with HNPCC-related cancers, any age

Umar A et al J Natl Cancer Inst, 2004
96(4)261-268
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HNPCC Surveillance

• Gene carriers or at-risk relatives
• CRC colonoscopy age 20-25, repeat 1-2 yrs
• Women gyn exam, endometrial aspiration, TV U/S,
  CA-125 (?) age 25-35, repeat 1-2 yrs
• If one HNPCC family member affected w/the
  following
• Stomach CA EGD age 3-35, repeat 1-2 yrs
• Urinary tract CA urine cytology age 30-35,
  repeat 1-2 yrs

NCCN practice guidelines in oncology v.1.2003
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FAP

• 1 in 10,000 incidence
• 100s to 1000s of colonic adenomas by teens
• Cancer risk colon, gastric, duodenum
  (periampulla), small bowel, pancreas, papillary
  thyroid, childhood hepatoblastoma
• 7 risk of CRC by 21 yrs 93 by 50 yrs
• Autosomal dominant APC gene mutations
• Variants Gardner, Turcot

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FAP surveillance

• Colon
• Annual sigmoidoscopy, age 10-12 yrs
• Prophylactic colectomy following polyp detection
  w/continued surveillance of rectum, ileal pouch
• Duodenal/gastric
• EGD age 25, repeat 1-3 yrs
• Thyroid
• Annual PE, age 10
• Hepatoblastoma
• Annual screen by abd U/S AFP from birth to 5
  yrs.

Gastroenterology 2001 121 195. AGA Statement
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Attenuated FAP

• 20 to 100 polyps, usually more proximal
• Onset later than FAP, average AOO 50
• Lifetime risk of CRC 80
• Extracolonic tumors occur at same rate as FAP
• Variant of FAP, mutations in same APC gene
• Surveillance
• annual colonoscopy starting late teens or early
  20s
• Option of subtotal colectomy

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Genetic Testing FAP/AFAP

• Test an affected family member first!
• After genetic counseling and informed consent
• APC gene testing can confirm a suspected
  diagnosis
• Family members of a person with a known APC
  mutation can have mutation-specific testing
• Genetic testing for children at risk for FAP can
  be considered before beginning colon screening

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APC gene mutation in Ashkenazi Jews

• Missense mutation (I1307K) associated with
  increased risk of CRC and adenomas in Ashkenazi
  Jews (AJ)
• Found in 6 of the general AJ population
• 12 of AJs with CRC
• 29 of AJs with CRC and a positive family history
  
• Lifetime risk of CRC in mutation carrier is
  10-20
• Screening colonscopy every 2-5 yrs starting at
  35 yrs

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MAP syndrome/MYH gene

• Multiple adenomatous polyposis (MAP) syndrome
• Autosomal recessive mutations in the MYH gene
• Median number of polyps 55
• Mean age of polyp diagnosis 30-50 years
• Polyps mainly small, mildly dysplastic tubular
  adenomas. Some tubulovillous, hyperplastic,
  serrated adenomas, microadenomas
• 30 of individuals with 15-100 polyps have
  homozygous mutations in the MYH gene
• Genetic testing should be offered if gt15 polyps
  (and APC gene testing negative)

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Peutz-Jeghers syndrome

• lt1 of all CRC cases
• Hamartomatous polyps of GI tract as early as 1st
  decade
• Mucocutaneous hyperpigmentation
• lips, mouth, buccal mucosa, fingers
• Usually seen in children lt 5 yrs
• Cancer risk
• colon, small intestine, stomach, pancreas,
  breast, ovaries, uterus, testes, lungs, kidneys
• Mutations in STK11 gene
• found in 70 of familial cases and 30-70 of
  sporadic cases

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Familial Juvenile Polyposis

• lt1 of all CRC cases
• Autosomal dominant
• 5 or more juvenile polyps in colon or GI tract
• Appear in 1st or 2nd decade
• 50 lifetime risk of CRC AOO in 30s
• Increased risk gastric, GI, pancreatic CA
• 50 of cases have mutations in either the MADH4
  or BMPR1A genes

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What can YOU do?
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CRC Risk Screening Steps to take

• Take a thorough cancer family history
• Does family history meet hereditary criteria?
• If yes, refer to genetics
• Classify based on family history average,
  moderate or high risk.
• Create surveillance plan based on risk level

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CRC Risk Screening Steps to take

• Take a thorough cancer family history
• Does family history meet hereditary criteria?
• If yes, refer to genetics
• Classify based on family history average,
  moderate or high risk.
• Create surveillance plan based on risk level

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Family Health History

• The family tree has become the most important
  genetic test of all. The more you know, the more
  tools you have to practice preventive medicine
• Donna Russo, Certified Genetic Counselor, NY
  Presbyterian-Columbia Hospital

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Family History Details to Record

• Type of primary cancer(s) in each relative
• Age of disease onset in each relative
• Cancer status in 1st and 2nd degree relatives
• Cancer status in both sides of the family
• Other medical findings

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CRC Risk Screening Steps to take

• Take a thorough cancer family history
• Does family history meet potentially hereditary
  criteria?
• If yes, refer to genetics
• Classify based on family history average,
  moderate or high risk.
• Create surveillance plan based on risk level

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Consider Genetics Referral for

• Two or more family members with CRC at least one
  lt50
• Three or more family members w/CRC any age
• Patient with colon cancer before 40 yrs
• Endometrial cancer and family history of CRC lt50
• Persons with more than one primary CRC lt50 yrs or
  with both endometrial CA and CRC
• Family or personal history of CRC and one or more
  1st degree relative with an HNPCC-related cancer,
  one diagnosed lt50 yrs.
• Same side of family

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Consider Genetics Referral for

• MSI and/or IHC tumor results suspicious for HNPCC
• Autosomal dominant pattern of cancers in the
  family
• Persons with 15 or more adenomatous colorectal
  polyps
• Persons with multiple hamartomatous or juvenile
  GI polyps
• Persons with a family history of a known
  hereditary cancer syndrome

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CRC Risk Screening Steps to take

• Take a thorough cancer family history
• Does family history meet hereditary criteria?
• If yes, refer to genetics
• Classify based on family history average,
  moderate or high risk.
• Create surveillance plan based on risk level

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Empiric Risk of CRC

• Risk for CRC based on family history increases
  with
• Closer degree of relationship and of affected
  members
• Younger age of onset
• Presence of extracolonic tumors, multiple
  primaries

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Family History Empiric Risks

• Lifetime Risk CRC
• General population in US 2 to 6
• One 1st degree relative w/CRC 2-3 fold
• Two 1st degree relatives w/CRC 3-4 fold
• 1st degree relative w/CRC lt50 3-4 fold
• One 2nd or 3rd degree relative w/CRC 1.5-fold
• Two 2nd degree relatives w/CRC 2-3 fold

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Goal Classification
Assessment
Intervention
Risk Classification
Standard prevention recommendations
Average
Personalized prevention recommendations
Moderate (Familial)
Family Hx
Referral for genetic evaluation with personalized
prevention recommendations
High/Genetic
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CRC Risk Management

• Age to Begin Average Risk 50 yrs
• No family history CRC OR
• One 2nd or 3rd degree relative with CRC
• - FOBT annually Flex sig every 5 yrs OR
• - Colonoscopy every 10 yrs OR
• - DCBE every 5 yrs

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CRC Risk Management

• Moderate/Family history Age to begin
• 1. Two 1st degree relatives with CRC any age 40
  years
• or one 1st degree relative with CRC lt 60
• - Colonoscopy every 5 yrs
• 2. One 1st degree relative with CRC gt60 or 40
  years
• two 2nd degree relatives with CRC any age
• - Average risk screening
• Or 5-10 yrs earlier than earliest case in family

Gastroenterology 2003124544-560
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CRC Risk Management

• Age to Begin
• HNPCC or suspected HNPCC 20-25 yrs
• 1. Colonoscopy every 1-2 yrs
• 2. Genetic counseling consider genetic
  testing
• FAP or suspected FAP 10-12 yrs
• 1. Flex sig or colonoscopy every1-2 yrs
• 2. Genetic counseling consider genetic
  testing

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Cancer Genetic Counseling

• Full pedigree analysis and risk assessment
• Discussion of
• Personal cancer risks based on family history
• Genetic testing options and risk of mutation
• Advantages, risks and limitations of genetic
  testing
• Personalized, risk-based screening and prevention
  options
• Support resources

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Cancer Genetic Testing Elements of Informed
Consent

• Information on specific test(s) being considered
• Implications of positive, negative, uninformative
  results
• Options for risk assessment and management
  without genetic testing
• Risk of passing a mutation to offspring
• Technical accuracy of test
• Fees involved in testing and counseling
• Option of DNA banking

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Cancer Genetic Testing Informed Consent (cont.)

• Psychological implications of test results
• Risks of insurance/employment discrimination
• Confidentiality issues
• Options for and limitations of medical
  surveillance and strategies for prevention
  following testing
• Importance of and guidance on sharing results
  with at-risk relatives
• Results disclosure
• American Society of Clinical Oncology, March, 2003

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Case 1Joan

• Joan, age 38, was recently diagnosed with
  endometrial cancer. Family history reveals
• Paternal grandmother endometrial cancer, age 50
• Paternal uncle colon cancer, age 48
• Father colonoscopy at age 50 four adenomatous
  polyps removed
• No other significant history
• Both sides of the family are Northern European
  Caucasian

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Pedigree Case 1
French, Irish, Scottish
German, English
88 yr
Dx 50
63 yr
61 yr
4 polyps 50 yrs.
CRC Dx 48
Key
38 yr
35 yr
Endometrial CA
Dx 38
Colorectal CA
Adenomatous polyps
8 yr
10 yr
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Case 1 Assessment

• Joan meets Amsterdam II Criteria and is at risk
  for HNPCC
• Refer to genetics for cancer genetic counseling
  and discussion of genetic testing for HNPCC
• Testing options
• Direct gene testing of MLH1 and MSH2 OR
• MSI/IHC screening of tumor tissue with gene
  sequencing if MSI positive

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Case 2 Ted

• Ted is 30 and wants a colonoscopy because his
  mother was just diagnosed with colon cancer after
  routine screening at age 54. Family history
  reveals
• Paternal grandfather died of CRC at age 79.
• No hx of endometrial, ovarian, small bowel or
  ureter/kidney cancer on either side of family.
• Two maternal aunts cervical cancer at ages 30
  34
• Maternal grandmother breast cancer age 85

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Case 2 Pedigree
Italian
Irish
German
BrCa 85 yrs d.87
d. 58 MI
CRC 79 d.82
84
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58
60
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Colon Ca 54 yrs
Cerv.Ca 30 yr
Cerv.Ca 32 yr
Key
CRC
30 yrs
34 yrs
Breast CA
Cervical CA
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Case 2 Ted

• Verify Diagnoses! Obtain and review pathology
  reports on all reported cancers, whenever
  possible
• If diagnoses are correct Ted has no family
  history indicative of a known colon cancer
  syndrome (HNPCC, FAP, other)
• Teds lifetime risk of colorectal CA is increased
  2 to 3 fold due to one affected first degree
  relative (gt50)
• Moderate/familial risk Screening by colonoscopy
  starting at age 40, or 10 yrs earlier than
  earliest case in family, is reasonable

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Oregon Genetics Providers

• Portland
• Oregon Health Science University
• Legacy Health Care
• Northwest Perinatal Services
• Kaiser-Permanente
• Eugene
• Center for Genetics Maternal Fetal Medicine
• Bend
• Genetic Counseling of Central Oregon (cancer only)

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Referral for Genetic Services

• Consult Genetic Services Contact List
• Phone consultations available
• OHSU Genetics Consult Line 503-494-5516
• Refer patients by phone, fax, mail, or patient
  self-referral
• Indications for Referral in resource packet
• Preconception/Prenatal
• Pediatric
• Adolescent/Adult

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Resource Materials

• Patient pamphlets
• Do You Have Cancer in Your Family?
• Genetic Testing A Fact Sheet
• Web-based cancer genetics resource list
• Hereditary Colon Cancer Association
• www.hereditarycc.org
• Resource materials at www.oregongenetics.org
• Genetics tutorials on www.modimes.org