Introduction to Cancer Genetics
Emma Williams
Genetic Counsellor
NE Thames Regional Genetics
Service
Overview
Cancer Syndromes &
Management options
Genes &
Genetic testing
Genetic Counselling &
Cancer Genetic Service
Population
cancer risk
What are the cancer risks for the general
population?
• 1 in 3 people will develop cancer at some
point in their lives
–
–
–
–
–
–
–
–
Prostate:
Female Breast:
Lung:
Colorectal cancer:
Melanoma:
Ovarian:
Stomach / Pancreas:
Male breast:
17%
12-13%
6-8%
6%
1-2%
1.5%
1%
0.1%
SEER Figures. NCI 2001-2003
How Many Cancers are Genetic?
Sporadic (~85%)
Familial
(~10%)
Hereditary (~5%)
Sporadic Cancer
• Many patients may
have a similar FHx
• Age of diagnosis
typically later in life
• Usually not inherited
• Can be reassuring
Aims of Genetic Counselling
Help patients to…
• Understand the information about
the genetic condition
• Appreciate inheritance patterns and
risk of recurrence
• Understand available options
• Make informed choices appropriate
to their personal and family situation
• Make the best possible adjustment
to the condition and risk
North East Thames Regional Genetics Service
Genetic Clinics in NE Thames
Cancer Genetics Clinics
General Genetics Clinics
Referral guidelines
http://www.ich.ucl.ac.uk/gosh/clinicalservices/Clinical_genetics/Custom%20Menu_01
Do Genes Affect Cancer Risk?
Risk Assessment Tools
•
•
•
•
•
Referral guidelines / NICE guidelines
Family History form
Comprehensive 3 generation pedigree
Confirmation of cancer pathology
Pedigree assessment
– Manchester score
– BOADICEA (Breast and Ovarian Analysis of Disease Incidence
and Carrier Estimation Algorithm)
– Amsterdam I/II Criteria
– Bethesda Criteria
Genetic Cancers
•
•
•
•
•
•
•
•
•
•
•
•
•
Breast and ovarian
Colon cancers
Cowden syndrome
Gastric cancer
Gorlin Syndrome
Li-Fraumeni
Multiple endocrine neoplasia (MEN)
Neurofibromatosis
Peutz-Jeghers syndrome
Phaeochromocytoma
Retinoblastoma
von Hippel-Lindau disease
Wilm’s tumour
Hereditary Cancer
 Several affected family
members
 Earlier than average age
of onset
 Multiple generations are
affected on one side of
the family
 A particular pattern of
cancers noted
 Individuals with more
than one primary tumour
site

5-10% of Cancer Cases
Most Cancer Susceptibility Genes Are Dominant
With Incomplete Penetrance
Normal
Susceptible Carrier
Carrier, affected
Ca
Sporadic Ca
• You only need one altered copy of the gene to have an
increased risk of cancer
• Gender is irrelevant
• It is not possible to “skip” generations
• Penetrance can be incomplete
• All offspring are at 50:50 risk
Genetic Testing
• Genetic testing is usually carried out on DNA from a blood sample
• Technically difficult to locate the mutation in a cancer gene for a
particular family
– Can take up to three months
• Usually need to first test a living relative who has already developed
cancer
• Is only offered to high risk families (>20% chance of mutation)
• Often cannot locate a mutation in a family (only identified in about
20% of families)
Genetic Testing cont…
• Genetic testing is NOT usually possible if there are no living affected
relatives
– Exception is populations with founder mutations eg Ashkenazi Jewish
population
• Once a mutation is found, testing can be offered to other at-risk
family members
• Individuals who DO NOT carry the family mutation ARE NOT at
increased risk of developing the cancers, but are still at population
risk
• Individuals who DO carry the family mutation ARE at increased risk
of developing cancer but there is still uncertainty. . .
However, testing enables us to identify
individuals who may be at higher risk of
developing certain types of cancer
Hereditary Breast and Ovarian Cancer
Other
genes
BRCA1
BRCA2
5-10%
Sporadic
Hereditary
• Most cases caused by a mutation in
BRCA1 or BRCA2 gene
• BRCA1 / 2 are tumour suppressor genes,
which are involved in the repair of DNA
• Accounts for about 5% of breast cancer
cases and about 12% of ovarian cancer
cases
BRCA1 -Associated Cancers: Lifetime Risk
Breast cancer 56%-87%
(often early age at onset)
Second primary breast cancer 64%
Ovarian cancer 16%-44%
Increased risk of other cancers, eg about double
population risk for prostate cancer in men
BRCA2-Associated Cancers: Lifetime Risk
breast cancer
(50%-80%)
male breast cancer
(7%)
contralateral breast
(50%)
ovarian cancer
(15-27%)
prostate
(~30%)
Other cancers:
pancreatic
malignant melanoma
Options for BRCA1/2 Carriers
• Cancer Screening
– Additional breast screening by mammography / MRI
– Ovarian screening through UKFOCSS research trial
• Prophylactic bilateral mastectomy
– ~90% reduction in breast CA risk
• Prophylactic bilateral salpingo-oophorectomy
– ~up to 96-98% reduction in ovarian CA risk
– ~50% reduction in breast CA risk (age dependant)
• ? Chemoprevention in the future
• ? Tailoring of treatment for carriers in the future
When to refer
• 2 first or second degree relatives with breast
cancer < 50 yr
• 3 first or second degree relatives with breast
cancer <60yr
• 4 relatives with breast cancer at any age
• 1 ovarian cancer at any age + 1 breast cancer <
50yr
• 1 ovarian cancer + 2 breast cancer both < 60y
• 2 ovarian cancer any age
• Patients who are thought to be of Ashkenazi
Jewish heritage with at least one first degree
relative with breast cancer <50 years or ovarian
cancer any age
• NB bilateral breast primaries equivalent to 2
relatives
Colorectal Cancer
Sporadic
(~60%)
Familial
(~30%)
Rare
FAP (~1%)
Syndromes
(~4%) MAP (~1%)
HNPCC
(3-5%)
HNPCC or Lynch syndrome
Hereditary non-polyposis colorectal cancer (HNPCC)
•
3-5% of all colorectal cancer cases
•
Autosomal dominant – multiple generations affected
•
High penetrance
•
Typical age of CA onset is 40-50 yrs
•
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
Caused by mutations or deletions in mismatch repair (MMR)
genes
MMR genes are like spell checkers in our DNA.
 MSH2, MLH1, MSH6, PMS2
 90% of detectable mutations in MSH2 and MLH1
 7-10% of detectable mutations in MSH6
Options for individuals
with HNPCC
• 1-2 yearly colonoscopy
• Ovarian and endometrial screening (not proven to be
effective)
• ? renal/upper GI screening effective
(if have history of gastric/renal cancers)
• Surgery
– Prophylactic bowel surgery not often chosen
– Total abdominal hysterectomy and salphingo
oophorectomy for females
Familial adenomatous polyposis
(FAP)
• 1 in 10,000 incidence
• 100’s to 1000’s of colonic
adenomas by teens
• 7% risk of CRC by 21 yrs; 93% by
50 yrs
• 20-25% no history in parents
• Extra-colonic features
• Screening
– 1 – 2 yearly flexible sigmoidoscopy
from age 10 – 12
– Upper GI endoscopy 1 –3 yearly
from age 25
MAP syndrome/MYH gene
• MYH associated 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 >10-15 polyps
(and APC gene testing negative)
When to refer
•
•
•
•
Patient or 1 first degree relative affected with
–
Colorectal cancer <50yrs
–
2 or more colorectal primary cancers any age
–
Colorectal cancer and a related cancer* any age.
2 first degree relatives affected with colorectal cancer or related cancer* at
any age
3 relatives affected with colorectal cancer or related cancer* at any age, one
of which must be a first degree relative.
History of Polyposis (e.g. Familial adenomatous Polyposis)
–
*related cancers- endometrial, ovarian, small bowel, ureter, renal pelvis and stomach
Genetics and Uncertainty
• Cancer genetics is not relevant for most people
• Cancer genetics is not a crystal ball
But cancer genetics can have a great impact on those
families most at risk of familial cancer
What Can You Do?
• Recognise patterns of cancers in families
– Young onset
– Lots of one or two particular types of cancer
– Jewish?
• If not sure ask
– Don’t be afraid to contact genetics for advice
• Take a blood sample for DNA banking
DNA Banking
• DNA banking provides families with the chance to
pursue genetic testing at a later point in time.
– where there is currently no genetic test available.
DNA banking will allow the family to take advantage
of future advances in genetic testing technology.
– A family member diagnosed with cancer who is
terminally ill and there is no time for traditional a
genetic assessment and/or testing. The family can
then focus their attention on their loved one and
defer the process of genetic counselling and testing
to a time when they are ready.
Contact Details
Emma Williams
Registered Genetic Counsellor
NE Thames Regional Genetics Service
Great Ormond Street Hospital
Great Ormond Street
London, WC1N 3JH
email:
emma.williams@gosh.nhs.uk
Tel: 0207 905 2625
Fax: 0207 813 8141
Case 1: Ruth
Ruth, a 35 year old Ashkenazi Jewish woman,
comes because she is anxious about her family
history of cancer. You inquire about family health
history and find out the following information:
– Paternal family history is as follows:
• Paternal grandmother diagnosed
with ovarian cancer age at 63
• Paternal aunt diagnosed with breast
cancer age 42
Ruth has no other risk factors or pertinent family
history
Case 1: Pedigree
Polish Jewish
Russian Jewish
Dx 63
82 yrs
Dx 42
60
58
Key
64yrs
41
Ruth
35
38
-Ov Ca
-Br CA
Case 1: Assessment
• Patient is in “Moderate risk” category
• However ethnicity is important as she is of
Ashkenazi Jewish descent
• Refer to genetics clinic
• Moderate risk screening for breast cancer
arranged
• Genetic testing for 3 common ‘Jewish
Mutations’
Case 2: Ann
• Ann has come along because her sister has
ovarian cancer, sadly the cancer has spread. Her
family history is a follows:
• Sister diagnosed with ovarian CA at 53 yrs.
• Mother diagnosed with ovarian CA at 61 yrs and
has sadly died.
• Maternal aunt diagnosed with breast cancer at 48
yrs.
Ann has no other risk factors for breast cancer. She
feels that with her family history, cancer is
inevitable
Case 2: Pedigree
Dx 61
Dx 48
Died 64
73
39
DX 53
2
49
65
3
30s
2
Case 2: Assessment
• Patient is in “High” risk category
• Refer to genetics clinic promptly
• High risk screening breast and ovarian
cancer
• Genetic testing offered
Case 3
•
•
•
Helen has primary
ovarian cancer
Would this family
need seeing by
genetics?
What other cancer
could she be at risk
for?
YES
Colon and uterine
cancers
Case 4
French, Irish, Scottish
German, English
88 yr
Dx 50
61 yr
CRC
Dx 48
63 yr
4 polyps
50 yrs.
Key:
38 yr
35 yr
Endometrial CA
Dx 38
Colorectal CA
Adenomatous polyps
Lynch syndrome
10 yr
8 yr
Case 5
•
•
Would you refer this
gentleman to genetics?
What else would you ask
about the family?
YES
Is he Jewish?
He has a BRCA mutation!
Case 6
•
•
Which side of the family
are you worried about?
What surveillance does
she need?
Both
Breast and ovarian
screening
She actually had two
BRCA mutations!
Case 7: 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
Reassure
Case 8: Alison
Alison is a 40 year old Caucasian (non-Jewish) patient who asks
you for information about the “breast cancer gene test”. She states
she wants this test.
You ask about her family history:
– Mother with breast cancer - age 58
– Maternal aunt with breast cancer – age 65
– Paternal grandmother with breast cancer – age 79
Alison has no other risk factors for breast cancer
She feels that with her family history, breast cancer is inevitable
Case 8: Pedigree
British
German/Dutch
Dx 79
d.81
Dx 58
65 yr
Dx 65
71 yr
Key:
Alison
40 yr
15 yr
-Breast CA
Case 8: Assessment
• Patient is in “Moderate” risk category
• Refer to breast clinic for breast cancer
screening from 40-50 years then NBSP
• Counselling issues:
– Unlikely to be due to a BRCA1 or BRCA2
mutation
– Screening and preventive strategies
– Psychosocial – perceived risk, fears
– Support resources