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Genetics and Primary Care
Familial Cancer Risk Assessment
Colorectal Cancer
Case 1:Joan
• 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
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
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
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
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 >60 years
with no other family history of CRC
Characteristics of “Familial” CRC
• “Clustering” of colon cancer cases in the family (> 50 at
diagnosis) without clear dominant pattern, or
• One close relative with CRC <60 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 2003:124:544-560
Characteristics of Hereditary CRC
• Multiple relatives with colorectal cancer
– One or more diagnosed at an early age (<50)
• 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
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)
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
20’s.
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
HNPCC
• Lifetime cancer risks:
– Colorectal
–
–
–
–
–
–
–
Endometrial
Gastric
Ovarian
Biliary tract
Urinary tract
Small bowel
Brain/CNS
80%
20-60%
13-19%
9-12%
2%
4%
1-4%
1-3%
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
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
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 HNPCCrelated cancer, with at least one cancer diagnosed <50
years of age
• Always test an affected family member first!
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
Criteria for MSI/IHC screening
Revised Bethesda Criteria, 2004
• CRC or endometrial CA <50 yrs
• 2 HNPCC cancers in same person
• CRC with “MSI-H histology” diagnosed <60 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 <50 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
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
FAP
• 1 in 10,000 incidence
• 100’s to 1000’s 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
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
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 20’s
– Option of subtotal colectomy
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
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
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 >15 polyps (and APC
gene testing negative)
Peutz-Jeghers syndrome
• <1% 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 < 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
Familial Juvenile Polyposis
• <1% 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 30’s
– Increased risk gastric, GI, pancreatic CA
• ~50% of cases have mutations in
either the MADH4 or BMPR1A genes
What can YOU do?
CRC Risk Screening: Steps to take
1. Take a thorough cancer family history
2. Does family history meet hereditary criteria?
–
If yes, refer to genetics
3. Classify based on family history: average,
moderate or high risk.
–
Create surveillance plan based on risk level
CRC Risk Screening: Steps to take
1. Take a thorough cancer family history
2. Does family history meet hereditary criteria?
–
If yes, refer to genetics
3. Classify based on family history: average,
moderate or high risk.
–
Create surveillance plan based on risk level
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
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
CRC Risk Screening: Steps to take
1. Take a thorough cancer family history
2. Does family history meet ‘potentially
hereditary’ criteria?
–
If yes, refer to genetics
3. Classify based on family history: average,
moderate or high risk.
–
Create surveillance plan based on risk level
Consider Genetics Referral for:
• Two or more family members with CRC* at least one <50
• Three or more family members w/CRC*; any age
• Patient with colon cancer before 40 yrs
• Endometrial cancer and family history of CRC <50
• Persons with more than one primary CRC <50 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 <50 yrs.
*Same side of family
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
CRC Risk Screening: Steps to take
1. Take a thorough cancer family history
2. Does family history meet hereditary criteria?
–
If yes, refer to genetics
3. Classify based on family history: average,
moderate or high risk.
–
Create surveillance plan based on risk level
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
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 <50
3-4 fold
One 2nd or 3rd degree relative w/CRC
Two 2nd degree relatives w/CRC
~1.5-fold
2-3 fold
Goal: Classification
Assessment
Risk Classification
Average
Family Hx
Intervention
Standard prevention
recommendations
Moderate
(“Familial”)
Personalized prevention
recommendations
High/Genetic
Referral for genetic evaluation
with personalized prevention
recommendations
CRC Risk Management
Average Risk
Age to Begin
50 yrs
1.
No family history CRC OR
2.
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
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 < 60
- Colonoscopy every 5 yrs
2. One 1st degree relative with CRC >60 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: 2003;124:544-560
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
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
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
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 atrisk relatives
• Results disclosure
American Society of Clinical Oncology, March, 2003
Case 1:Joan
• 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
Pedigree: Case 1
French, Irish, Scottish
German, English
88 yr
Dx 50
61 yr
CRC
Dx 48
63 yr
4 polyps
50 yrs.
Key:
38 yr
Endometrial CA
Dx 38
Colorectal CA
Adenomatous polyps
10 yr
8 yr
35 yr
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
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
Case 2: Pedigree
Italian
CRC 79
d.82
Irish
84
56
German
d. 58
MI
BrCa 85 yrs
d.87
55
Colon Ca
54 yrs
58
60
Cerv.Ca Cerv.Ca
30 yr
32 yr
Key:
34 yrs
30 yrs
CRC
Breast CA
Cervical CA
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)
– Ted’s lifetime risk of colorectal CA is increased 2 to 3 fold due to
one affected first degree relative (>50)
– Moderate/familial risk: Screening by colonoscopy starting at age
40, or 10 yrs earlier than earliest case in family, is reasonable
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)
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
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.healthoregon.org/genetics
• Genetics tutorials on www.modimes.org
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