Download Clinical Genetics Risk Assessment, Screening and Testing for

Clinical Genetics:
Risk Assessment, Screening
and Genetic Testing for
Inherited Susceptibility for
Cancer
Mollie L. Hutton, MS, CGC
Certified Genetic Counselor
Clinical Genetics Service, RPCI
[email protected]
Genetics is everywhere…

Health care & medical
literature
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Mainstream media
TV, newspapers,
magazines
 Direct to consumer
marketing of gene tests
Careers: bioinformatics,
agriculture, business,
forensics, military
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
Guidelines & standards of
practice developed
General Principles
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Causes of cancer
Inheritance Patterns
Importance of diagnosing a genetic disorder
Cancer genetic risk assessment
Inherited Cancer Syndromes
5%-10%
Hereditary
20% - 25%
Multifactorial
70% Sporadic

All cancer is genetic, not all cancer is inherited
Cancer Associated Genes:
Inheritance Patterns
Normal
“Unaffected” Carrier
+
Carrier, affected
Sporadic
+

Gene mutation inherited in autosomal dominant manner (e.g.,
BRCA1), but expression may be at
AD level (e.g, oncogene) or
AR level (e.g, tumor suppressor gene)
 Individuals may inherit altered gene, but not have
phenotype (ie, reduced penetrance)
Importance of diagnosing a
genetic disorder

Impacts
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Medical management
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Screening/surveillance
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For individual and family
Possible risk for another diagnosis
Options for prevention
Participation in research
 Family planning
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Genetic Counseling
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Clinical consultation involves:
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Genetic risk assessment (cancer & non-cancer)
individual & family hx
 review of med records
 physical exam
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Genetic counseling:
■ inheritance pattern
■ risk models
■ medical management options
■ genetic testing
■ ethical/legal/psychosocial issues
■ support decision/facilitate adjustment

Work in conjunction with other clinic/s, or separate
Risk Assessment

Obtain at least a 3 generation family
history (if possible)
Maternal & Paternal family history
are equal in importance
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Confirm diagnoses (if possible)

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Medical records, death certificates, etc.
Consider
Environmental exposures
 Ethnicity/racial background
 Constellation of cancers
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Personal and Family History
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Early age onset
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Multiple primary cancers
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Bilateral cancers
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Rare cancers
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Cancer with no identifiable
risk factor
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Positive family hx of same
cancers
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Family hx of
cancers/conditions that
occur together in syndromes
Pancreas
d. 62
Prostate, 68
dx 62y
Breast, dx 45
d. 89
86
Breast, dx 52
Ovary, dx 59
d. 60
71
36
R Breast, dx 32
L Breast, dx 36
Breast,
dx 59
Importance of Family History

Before genetic testing was available,
family history was used to identify
“high risk” families


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Still used in cases where
mutation not identified
Clinical diagnostic criteria applied to
HOWEVER, family history is not fool proof:
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De novo mutations
 Ex. FAP
Reduced penetrance
 Ex. BRCA in small family or family with few females
Examples of Cancer Syndromes
~70% Sporadic
Hereditary breast and ovarian ca BRCA1, BRCA2
Li-Fraumeni syndrome
p53
Cowden syndrome
PTEN
Peutz-Jeghers syndrome
STK11
Hereditary nonpolyposis
MLH1, MSH2, MSH6,
colorectal ca
Familial adenomatous polyposis
PMS2
APC
Multiple endocrine neoplasia 2
Multiple endocrine neoplasia 1
RET
MEN1
Hereditary Diffuse Gastric Cancer CDH1
Multifactorial
5%–10%
Hereditary
Breast Cancer: Associated with
Different Genetic Syndromes
Syndrome

HBOC
Associated Cancers/Traits
Chr./Gene
breast (both female & male), ovarian,
17q21.1/
BRCA1
13q12-13/
BRCA2
prostate, pancreas, melanoma

Li-Fraumeni breast, sarcomas, brain tumors,
leukemia, adrenocortical cancer
breast, thyroid & endometrial ca,
macrocephaly, structural thyroid
probs, lipomas, hamartomas
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Cowden

Peutz Jegher breast & pancreas ca, GI polyps, sex
cord tumors
17p13/ p53
10q22-23/
PTEN
19p13.3/
STK11
Ex. changes in tstg
technology & criteria
Hereditary Breast Cancer:
Cowden Syndrome
Associated w/ mutations in PTEN
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Characteristics
 Cancers: breast; thyroid (follicular);
endometrial
 fibrocystic breast disease and uterine
fibroids
 macrocephaly
 mucocutaneous lesions
 lipomas / fibromas
 trichilemmomas
Penetrance (lifetime risk)
 breast cancer: 25-50% for women
 thyroid cancer: ~10%
 endometrial cancer: 5-10%
Clinical diagnostic criteria established to
make diagnosis
www.infocompu.com/.../images/s_cowden1.jpg
www.uveitis.org/images/Image1.jpg
Common Cancer Syndromes
~70% Sporadic
Hereditary breast and ovarian ca
Li-Fraumeni syndrome
Cowden syndrome
BRCA1, BRCA2
P53
PTEN
Peutz-Jeghers syndrome
STK11
Familial adenomatous polyposis APC
Hereditary nonpolyposis
colorectal ca
MLH1, MSH2, MSH6, PMS2
Multiple endocrine neoplasia 2
Multiple endocrine neoplasia 1
RET
MEN1
Hereditary Diffuse Gastric Cancer CDH1
Multifactorial
5%–10%
Hereditary
Familial Adenomatous Polyposis:
FAP
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mutation in APC gene (a tumor suppressor)
autosomal dominant, nearly 100% penetrant
30% new mutation rate
patients develop 100s – 1000s of colon polyps,
some of which become malignant

Also risk for desmoids,
CHRPEs, hepatoblastoma
attenuated form (AFAP)
with typically <100 polyps
 genotype/phenotype correlation
exists

dro.hs.columbia.edu/vr6/beartracksa.jpg
Hereditary Non-Polyposis Colorectal
Cancer: HNPCC
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80% lifetime risk for colorectal cancer
early age of onset (45y average)
excess of proximal (right-sided) tumors
multiple primary colorectal tumors
polyps progress to tumors 100-1000x more rapidly
than do sporadic colon polyps
presence of extracolonic tumors:
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uterine (60%)
ovarian (12%)
gastric (13%)
renal pelvis (3%)
Clinical Criteria:
Amsterdam Criteria
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3 affected family members
in which two are first degree relatives of the
third
in two generations
and one of them had colon cancer at <50 years
of age
Common Cancer Syndromes
~70% Sporadic
Hereditary breast and ovarian ca
Li-Fraumeni syndrome
Cowden syndrome
BRCA1, BRCA2
P53
PTEN
Peutz-Jeghers syndrome
STK11
Hereditary nonpolyposis
MLH1, MSH2, MSH6,
colorectal ca
Familial adenomatous polyposis
PMS2
APC
Multiple endocrine neoplasia 1
Multiple endocrine neoplasia 2
MEN1
RET
Hereditary Diffuse Gastric Cancer CDH1
Familial
5%–10%
Hereditary
Multiple Endocrine Neoplasia Type 1
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MEN1
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Pituitary tumors
Parathyroid tumors
Endocrine tumors of the
gastro-entero-pancreatic
tract
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gastrinoma, insulinoma,
glucagonoma
90% symptomatic by
mid-20s
10% new mutation rate
endocrine.niddk.nih.gov/pubs/men1/images/men.gif
Multiple Endocrine Neoplasia Type 2
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MEN2A
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Medullary thyroid cancer -- occur in ~95% of cases
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Pheochromocytoma -- occur in ~50% of cases
Parathyroid disease -- occur in ~20-30% of cases
MEN2B
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Medullary thyroid cancer -- occur in 100% of cases
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Average onset by age 15-20
Average onset in early-childhood
Pheochromocytoma – occur in ~50% of cases
Mucosal neuromas
Marfanoid body habitus
FMTC
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Medullary thyroid cancer -- occur in 100% of cases
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Average onset in middle-adulthood
Common Cancer Syndromes
~70% Sporadic
Hereditary breast and ovarian ca
Li-Fraumeni syndrome
Cowden syndrome
BRCA1, BRCA2
P53
PTEN
Peutz-Jeghers syndrome
STK11
Hereditary nonpolyposis
MLH1, MSH2, MSH6,
colorectal ca
Familial adenomatous polyposis
PMS2
APC
Multiple endocrine neoplasia 1
Multiple endocrine neoplasia 2
MEN1
RET
Hereditary Diffuse Gastric Cancer CDH1
Familial
5%–10%
Hereditary
Hereditary Diffuse Gastric Cancer
(HDGC)

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CDH1 gene – only gene known to be associated
w/ HDGC; however accounts for only 1/3 of
hereditary diffuse gastric cancers
CDH1 mutations confer:
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Increased risk for diffuse gastric cancer
67% lifetime risk for men
 83% lifetime risk for women

Increased risk for lobular breast cancer (39% lifetime
risk)
 Majority of cancers diagnosed before age 40
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Differential Diagnosis:
Cancer Syndromes

brain
ovary
H
H prostate B
P
O
C
C
sarcoma
Li
Fr
au
m
en
i
renal
colon
breast
Tu
rc
ot
H
N
P
C
C
polyps
F
A
P P
J
Benign
tumors
eye
M
E
N
endometrial
thyroid
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Overlap in
cancer
syndromes
Must consider all
possibilities – then
determine most
likely
Also take into
consideration
benefit of
identifying one
syndrome over
another as it relates
to medical
management
options
Common Genetics Terms
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Genotype
Phenotype
Expression
Pleiotrophy
Penetrance
Phenocopy
Genotype vs. Phenotype
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Same genotype (genetic makeup) different phenotype (observed features)
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Pleiotropy (single gene influences multiple phenotypic traits)
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Ex. MLH1 assoc. w/ colon ca, endometrial ca, ovarian ca, ureter ca, etc.
Expression (different degrees of presentation)

Ex. APC – classic vs. attenuated
 Same phenotype different genotype
Ex. Breast cancer assoc. w/ mutations in BRCA, PTEN, p53
Genotype vs. Phenotype

Phenocopy = Normal genotype with
disease phenotype
VS
Penetrance = Mutant genotype with no
disease phenotype
Thus, susceptibility (rather than predisposition)
Majority of hereditary cancer syndromes are NOT
100% penetrant
Genetic Testing
Why?
 Explanation for cancer
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Clarify personal cancer risks
Determine appropriate screening/management
Preventive options
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Treatment options following dx
Chemopreventive, surgical
Identification of at-risk family members
Potentially rule out inherited risk
Genetic Screening & Testing:
Important Considerations
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Who to test?
Clinical vs Research testing
Type/Method
Biochemical – protein product
 Cytogenetic – all/part of chromosome
 Molecular – gene/DNA/RNA
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Results: sensitivity, specificity
Result interpretation: +,-,VUS
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negative vs true negative
Genetic Screening & Testing
(continued)
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IMPORTANTLY – can test for lots of things,
but cannot interpret many things

If cannot clarify cancer risk based on presence of
mutation and/or cannot screen for or manage
increased cancer risk, is genetic testing justified?

Ex. PALB2
Pros and cons of testing
PROS:
 identifies those at high risk and those not at high
risk
 option of increased surveillance/prophylactic
surgery
 relief from anxiety
 appreciate risk to children
 opportunity to be proactive in making medical
and lifestyle choices
Pros and cons of testing
CONS:
 negative results may be meaningless or falsely
reassuring
 often no proven interventions
 increases anxiety
 psychological burden – fear, guilt, etc.
 impact on family dynamics
 cost & availability
Common misunderstandings
regarding genetic testing
Testing not covered by insurance
 Risk for discrimination

 Extension
 HIPAA
 GINA
of Civil Rights Act
Genetic Testing of Minors:
Issues

When is it appropriate?
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Not for adult onset disorders
(Fryer, Arch Dis Child, „00)
Parental choice vs child‟s choice: consent vs
assent
Potential harms
stigmatization
 negative effect on family & interpersonal relationships;
different view of child
 self-concept; psych risks (Grosfeld, Pt Educ/Coun, „97)
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“shall only be tested when ...for ...purpose of
better medical care” (WHO document, 1998)
Other applications of genetics
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DNA Banking
Pharmacogenetics
DNA Banking

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Allows an individuals DNA to be saved for
future genetic testing
Important in situations where genetic testing is
not currently available due to limitations in
knowledge/technology or when a patient is
terminally ill and there is no time for traditional
genetic evaluation
Pharmacogenetics & CRC
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Patients with colon cancer may be treated with a
chemotherapy agent called irinotecan
Some UGT1A1 gene polymorphisms predispose to
irinotecan toxicity
Genotyping can identify those at high risk for toxicity and
who may be better treated with a different agent