Transcript Document

Cancer Genetics for Primary
Care
Sara Levene
Registered Genetic Counsellor
Proportion of cancer that is inherited
Inherited susceptibility to cancer:
‘genetic’
Single genes
Family history of cancer:
‘familial’
?multi-factorial origins
Population risk:
Breast cancer 1:10
Ovarian cancer 1:100
Colorectal cancer 1:25 - 35
No family
history of
Cancer: ‘sporadic’
?multi-factorial origins
To make a long story short:
All cancer is genetic
Cancer is rarely inherited
Sporadic cancer
2 normal genes
1 normal gene
1 mutated gene
hormones
viruses chemicals
radiation
2 mutated genes
cancer
Spontaneous mutations
Inherited cancer
1 normal gene
1 mutated gene
hormones
viruses chemicals
radiation
2 mutated genes
Spontaneous mutations
cancer
Inherited Mutations and Cancer
• Inherited mutations relating to cancer do not
cause cancer
• Mutations are often found in genes that are
‘tumour suppressors’
• Mutations mean that protection from cancer
is lost or reduced
• Mutations lead to increased susceptibility to
certain types of cancer
Autosomal dominant inheritance
mother
child
father
child
Each child has 50:50 chance of inheriting the altered gene.
Genetic testing
Cancer Genes
Mendelian Inheritance (AD)
• In the last 10 years several genes relating to
specific cancer syndromes have been
identified
• There are more cancer genes waiting to be
‘discovered’
• It is difficult to locate the exact mutation in
a cancer gene for a particular family
Cancer Genes
Multi-factorial Inheritance
• More recently the search for other AD genes
has led to the discovery of some ‘lower risk’
genes eg. CHEK2
– found in ~2% cases ca br
– est doubles risk of ca br
• ? Liability/threshold model with several
similar genes (+ env factors)
• This research is not yet applicable to clinical
practice
Genetic Testing
• Technically difficult
• Can only be offered to high risk families
• Can only search small number of high risk
dominant genes
• Can take more than a year to search for the
mutation in a family
• Often cannot locate the mutation for a
family (?unknown genes)
Searching for the faulty gene
cgattgagg
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cgattgagg
cgattgagg
cgattgagg
gatccattgga
gatccattgga
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ctataccagtc
ctataccagtc
ctataccagtc
atcgtacgta
atcgtacgta
atcgtacgta a
gtcatcgatgtt
gtcatcgatgtt
gtcatcgatgtt
gatccattgga
gatccattgga
gatccattgga
ttaacggtag
ttaacggtag
ttaacggtag
cgattgagg
cgattgagg
cgattgagg
gtcatcgatgtt
gtcatcgatgtt
gtcatcgatgtt
ctataccagtc
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atcgtacgta
atcgtacgta
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cgattgagg
cgattgagg
cgattgagg
gatccattgga
gatccattgga
gatccattgga
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ctataccagtc
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ttaacggtag
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gatccattgga
gatccattgga
gatccattgga
ctataccagtc
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gtcatcgatgtt
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Genetic Testing
• First test in family always done on person who
has had the cancer (mutation search test)
• If no living affected relatives available – cannot
offer genetic test for family
• If a mutation is found predictive testing can be
offered to at-risk relatives:
– If relative doesn’t carry familial mutation they are not
at increased risk of cancer (still at population risk)
– If a person does carry the familial mutation they are at
increased risk of developing cancer
Family History of Breast Cancer
High Risk
Cancer risks associated with
BRCA1 and BRCA2
Breast and ovarian cancer
Other cancers
• Breast cancer risk ~80%
• Ovarian cancer risk ~45%
• Increased risk of second
primary for women who
have already had breast
cancer
•
•
•
•
Prostate cancer
Male breast cancer
Pancreatic cancer
Colorectal cancer
• Stomach cancer
Recent NICE Guidelines on
Familial Breast Cancer
• Women at or near population risk are
cared for in primary care.
• Women at moderate risk are cared for
in secondary care.
• Women at high risk are cared for in
tertiary care.
Breast cancer case study 1
Ca breast, diag 70y
Died 85y
68y
Brain tumour, died 67y
? Prev breast cancer in
40s?
Breast cancer case study 1
Ca breast, diag 70y
Died 85y
68y
Brain tumour, died 67y
No record of prev ca br
Can this patient
now be reassured?
Population risk
Screening and management
• National breast screening from 50y
• Breast awareness
• Reassure patient:
– For most women, increasing age is the greatest risk
factor.
– The great majority of women with a family history of
breast cancer do not fall into a high-risk category and
do not develop breast cancer.
Breast cancer case study 2
Ca breast, diag 54y
Patient is requesting
screening and is considering
prophylactic mastectomies.
What is her level of risk?
Ca breast, diag 52y
20y
What is appropriate
management of her risk?
Patient is also interested in
genetic testing. Can this be
offered?
Moderate risk
Referral to secondary care
Female breast cancers
• One 1st degree relative diagnosed
before age 40
• Two 1st degree relatives (or one 1st degree
relative and one 2nd degree relative) diagnosed after
average age 50
Moderate risk
Screening and management
•
•
•
•
Annual breast surveillance from age 40 – 50y
National Breast Screening from 50y.
?Chemoprevention studies
Breast awareness
Breast cancer case study 3
Ca breast
Died 40y
Ca breast
Diag 32y
What can we offer this
family?
Considering
prophylactic
mastecomies
Breast cancer case study 3
Ca breast
Died 40y
Recommend
screening
Ca breast
Diag 32y
Blood taken for
BRCA1/2 testing
Recommend
screening
Breast cancer case study 3
Ca breast
Died 40y
Ca breast
Diag 35y
Ca breast
Diag 32y
BRCA1/2
testing on-going
Breast cancer case study 3
Ca breast
Died 40y
Ca breast
Diag 35y
Ca breast
Diag 32y
BRCA1 mutation
found
Breast cancer case study 3
Ca breast
Died 40y
N
Ca breast
Diag 35y
BRCA1
mutation
carrier
BRCA1
mutation
carrier
Ca breast
Diag 32y
BRCA1 mutation
found
High risk
Referral to secondary care, then tertiary care
• Two 1st degree relatives (OR one 1st degree relative
and one 2nd degree relative) with breast cancer, av
age <50
• Three or more 1st or 2nd degree relatives
with breast cancer at any age
• One 1st degree male relative with breast
cancer at any age
• One 1st degree relative with bilateral breast
cancer where 1st primary diagnosed <50
• One 1st or 2nd degree relative with ovarian
cancer at any age and one 1st or 2nd degree
relative with breast cancer at any age
High risk
Screening and management
• 30-39y: may be eligible for annual
mammograms
• 40-49y: annual mammograms
• >50y: NBSP, plus may be eligible for
additional screening
• Refer to genetics to discuss genetic testing
• ?MRI screening in the future
• ?Prophylactic surgery
• ?Ovarian screening
Breast cancer case study 4
What should we
do for this
family?
Ca ?type
Ca breast, diag 51y
Died 53y
Ca breast, diag 41y
Breast cancer case study 4
Ca ovary, died 48y
Ca breast, diag 51y
Died 53y
Breast & ovarian
screening
Ca breast, diag 41y
Breast cancer case study 4
Ca ovary, died 48y
Ca breast, diag 51y
Died 53y
Breast & ovarian
screening
Ca breast, diag 41y
Blood taken for
BRCA1/2 testing
Breast cancer case study 4
Ca ovary, died 48y
Ca breast, diag 51y
Died 53y
Considering
surgery
Ca breast, diag 41y
BRCA1/2 tested
No mutations found
Other factors to consider:
• Paternal history:
two or more breast cancers on father’s side of family
• Unusual cancers:
Bilateral breast cancer
Male breast cancer
Ovarian cancer
Sarcoma <45y
Glioma or childhood adrenal cortical carcinoma
Complicated patterns of multiple cancers at young age
• Jewish ancestry
Women with Jewish ancestry are around 5–10 times more likely to
carry BRCA1 or BRCA2 mutations than women in non-Jewish
populations.
Family History of Colorectal
Cancer
FAP
HNPCC
Familial Adenomatous
Polyposis
Hereditary Non-Polyposis
Colon Cancer
• 100% affected by 35y
• Hundreds/thousands of
polyps in colon
• Mutation on APC gene
• Accounts for <1% colon
cancers
• Other cancer risks:
duodenal, gastric
• Up to 80% lifetime risk
• Less than 10 polyps
found
• At least 5 genes found
• Accounts for up to 5%
of colon cancers
• Other cancer risks:
endometrial, ovarian,
gastric
Familial Adenomatous Polyposis (FAP)
CRC FH Risk categorisation
Low risk
One FDR with CRC at > 45
(No screening required, bowel awareness)
Low-Moderate risk
Two FDRs with CRC at average age > 60.
Screening: One colonoscopy at 35y-40y and one at 55y
High-Moderate risk
One FDR with CRC <45, or three older FDRs i.e. >50.
Screening: Begins at 45 or 5yrs prior to youngest
diagnosis (not prior to 35). Repeat 5yrly to 75y.
What is High Risk?
• A known polyposis syndrome e.g. FAP
Be sure to ask if there is any history of polyposis in the
family.
• HNPCC (Amsterdam positive families).
– At least 3 of HNPCC related cancers
(CRC, endometrium, ovarian, small bowel, ureter or renal pelvis)
– One should be a FDR of the other two
– At least two successive generations affected
– At least one cancer diagnosed < 50 years
High risk screening/management
HNPCC
• Colonoscopies from 25y, continuing 2 yearly to 75y
• ?Endometrial/ovarian screening annually from 35y
(research)
FAP
• Colonoscopies annually from teens (or younger
depending on family history)
• Prophylactic colectomy offered
• ?Upper GI screening annually (research)
Summary
• Most cancer is not due to dominant, high-risk genes.
• Most patients with a family history of cancer can be
reassured and possibly referred for screening.
• For most patients with a family history of cancer, current
genetic testing is not helpful and is not available.
• Patients with a high risk of cancer due to family history
can have screening, and genetic testing may be available.
• Patients who inherit a mutation in a high risk gene have a
high risk of developing cancer themselves.
Take-home messages
• Young diagnoses of cancer (<45y) may be
significant
• Three or more cases of the same / related types of
cancer, in one family (even if older ages) may be
significant
• Genetic testing may or may not be available /
informative for a given family
• Genetic testing must start with a living affected
relative
• Screening may be available
If you have enquiries about a family history :
Contact your local Clinical Genetics dept:
Clinical Genetics
Great Ormond Street Hospital
London WC1N 3JH
Tel: 0207 905 2138
Clinics held at Barts and The London.