3. What are the cancer risks for the general
population?
• 1 in 3 people will develop cancer at some
point in their lives
– Prostate: 17%
– Female Breast: 12-13%
– Lung: 6-8%
– Colorectal cancer: 6%
– Melanoma: 1-2%
– Ovarian: 1.5%
– Stomach / Pancreas: 1%
– Male breast: 0.1%
SEER Figures. NCI 2001-2003
4. How Many Cancers are Genetic?
Sporadic (~85%)
Familial
(~10%)
Hereditary (~5%)
5. Sporadic Cancer
• Many patients may
have a similar FHx
• Age of diagnosis
typically later in life
• Usually not inherited
• Can be reassuring
6. 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
7. North East Thames Regional Genetics Service
Genetic Clinics in NE Thames
Cancer Genetics Clinics General Genetics Clinics
12. 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
13. Most Cancer Susceptibility Genes Are Dominant
With Incomplete Penetrance
• 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
Normal
Carrier, affected
Ca
Sporadic Ca
Susceptible Carrier
14. 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)
15. 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
16. Hereditary Breast and Ovarian Cancer
• 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
BRCA2
5-10%
Other
genes
Sporadic
Hereditary
17. BRCA1 -Associated Cancers: Lifetime Risk
Increased risk of other cancers, eg about double
population risk for prostate cancer in men
Breast cancer 56%-87%
(often early age at onset)
Second primary breast cancer 64%
Ovarian cancer 16%-44%
18. BRCA2-Associated Cancers: Lifetime Risk
Other cancers:
pancreatic
malignant melanoma
breast cancer
(50%-80%)
ovarian cancer
(15-27%)
male breast cancer
(7%)
contralateral breast
(50%)
prostate
(~30%)
19. 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
20. 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
22. 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
24. 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
25. 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
26. 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
27. 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)
28. 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
29. 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
30. 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
31. 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.
32. 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
33. 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
34. Case 1: Pedigree
Key
-Ov Ca
-Br CA
Dx 63
82 yrs
Ruth
35
Russian Jewish Polish Jewish
41 38
60
58
Dx 42
64yrs
35. 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’
36. 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
38. Case 2: Assessment
• Patient is in “High” risk category
• Refer to genetics clinic promptly
• High risk screening breast and ovarian
cancer
• Genetic testing offered
39. 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
40. Case 4
Key:
Endometrial CA
Colorectal CA
Adenomatous polyps
Dx 38
Dx 50
88 yr
63 yr
4 polyps
50 yrs.
CRC
Dx 48
61 yr
38 yr
10 yr 8 yr
35 yr
French, Irish, Scottish German, English
Lynch syndrome
41. 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!
42. 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!
43. 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
44. 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
45. Case 8: Pedigree
Dx 58
65 yr
Dx 65
71 yr
Dx 79
d.81
German/Dutch
British
Key:
-Breast CA
Alison
40 yr
15 yr
46. 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
