1. Introduction to Cancer Genetics
Emma Williams
Genetic Counsellor
NE Thames Regional Genetics Service

2. Cancer Genetic Service
Overview
Cancer Syndromes &
Management options
Genes &
Genetic testing
Genetic Counselling &
Cancer Genetic Service
I’m going to briefly talk about population cancer risks, what Genetic Counselling is and the role of the Cancer Genetics Service, before talking in more detail about genes and genetic testing, common cancer syndromes and briefly ??management options??
Population
cancer risk

3. 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: 6%
Melanoma: %
Ovarian: %
Stomach / Pancreas: 1%
Male breast: %
As I’m sure you’re aware, cancer is becoming increasingly common, so that one in 3 of us will be dx at some point in our lifetime...
This is a list of some of the lifetime risk figures for more common cancer diagnoses
SEER Figures. NCI

4. How Many Cancers are Genetic?
Sporadic (~85%)
Familial (~10%)
It is important to remember that The vast majority of cancers occur sporadically due to non-genetic factors such as lifestyle, environment, hormones and an element of chance, only about 5-10% are due to an inherited predisposition
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
As cancer is common, many patients have a fh of cancer similar to this one… having one or two fm dx with cancer in 60’s or 70’s does not increase risk as is most likely to be sporadic occurrence…. So if a patient has a fh similar to this one, you 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
Genetic counselling is mostly a communication process, which involves helping patients to But it also focuses on the possible psychosocial impact of having a genetic condition as we help patients to make the best possible adjustment to the condition and risk

7. North East Thames Regional Genetics Service
This is just to show you the area covered by NETRGS, covers NE london and the whole of essex with clinics in many local hospitals

8. Referral guidelines
Referral guidelines can be found on our website, along with a fh form that can be printed off for patients to fill in.....

9. Do Genes Affect Cancer Risk?
The purpose of the Cancer Genetics Clinic is to work out whether a fh of cancer is likely to be due to an inherited predisposition, or due to non genetic risk factors.

10. 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

11. 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
Here are some of the main inherited cancer syndromes, the two most common are HBOC and colon cancer syndromes such as LS, FAP and MAP – rarer egs INCIDENCE FIGURES IF CAN FIND

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
This is sort of family we’d see in CGC. Looking at this pedigree you can see that more family members have been diagnosed with cancer than we would usually expect to see, four individuals dx with cancer in their 30’s and 40’s which is relatively young. Several generations affected, on same side of the family –we can see a pattern of how the gene has been passed down through the family. Cases of both breast and ovarian cancer, which we know can be genetically related. While not illustrated here, it’s also more unusual for individuals to be dx with more than one primary cancer.
In genetics clinic we’re trying to determine likelihood that fh of cancer sporadic or inherited… looking for More fms affected than would expect to see by chance, proband and her mother dx in 30’s which is younger age than would expect to see, several generations affected, and cancergs that we know can be genetically related occuring in the same family – here br and ov. Also, having 2 separate primary cancers

13. Most Cancer Susceptibility Genes Are Dominant With Incomplete Penetrance
Normal
Susceptible Carrier
Carrier, affected Ca
Sporadic Ca
Most inherited cancers are passed down in a dominant pattern, which means you only need one altered copy of the gene to have increased risk of cancer
Both men and women can carry the altered copy
It is not possible for a gene to “skip a generation”, although it may appear to, but this is because not everyone with the alteration will develop cancer – this in incomplete penetrance All offspring are at 50:50 or 50% risk of inheriting altered copy of gene
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

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)
Only offered to HR families, unless as part of a research study
Often cannot identify a mutation in a family, if this happens it doesn’t rule out the possibility of an inherited predisposition, just means we haven’t been able to identify specific one.

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
Accounts for 4-5% breast cancer cases
40-70% lifetime risk breast cancer
10-45% lifetime risk ovarian cancer
Increased risk prostate cancer in male carriers
Genetic testing possible for some families
Surgery and surveillance options for affected individuals
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
Most hereditary cases of br/ov cancer are due to mtn in BRCA1/2
Essentially when new cells are ‘made’ TS genes work like a' spell check’ on your computer locating and helping to correct mistakes made. So when one of the TS genes is not functioning the person is at increased risk of developing a cancer.

17. BRCA1 -Associated Cancers: Lifetime Risk
Breast cancer 56%-87%
(often early age at onset)
Second primary breast cancer 64%
Ovarian cancer 16%-44%
Women who carry a gene mutation/misprint in BRCA1 are at increased risk of developing more then one separate breast cancer as well as ovarian cancer
Increased risk of other cancers, eg about double population risk for prostate cancer in men 17

18. BRCA2-Associated Cancers: Lifetime Risk
breast cancer
(50%-80%)
male breast cancer
(7%)
contralateral breast (50%)
prostate (~30%)
ovarian cancer
(15-27%)
Women carrying a BRCA2 gene mutation/misprint are again at risk for more then one breast cancer as well as ovarian cancer
Men carrying a BRCA2 mutation are at increased risk of breast cancer as well as an increased risk of prostate cancer
Other cancers:
pancreatic
malignant melanoma 18

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
Prophylactic bilateral mastectomy
May reduce breast CA risk up to 90%
Prophylactic bilateral oophorectomy
May reduce risk for ovarian CA by 50-90% studies need validation
May reduce risk for breast CA by 50% - studies also need validation
Last point – such as PARP inhibitors/platinum treatment…. 19

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

21. Colorectal Cancer only 7% of sporadic cases occur <55
~75% of cases of CRC are sporadic
only 7% of sporadic cases occur <55
~15-20% are “familial” / multifactorial – genetic testing not generally available for low penetrance genes associated with increased risk of CRC
~5-8% are hereditary (defined cancer susceptibility syndromes caused by single genes)
Feuer EJ: DEVCAN: National CA Inst. 1999

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 yrs
60-70% right-sided/proximal CRC tumors
Polyps may be present, multiple primaries common. Can overlap with AFAP
Typical age of onset is 40-50, range from yrs
Preponderance of right-sided/proximal tumors – 60%
Polyps may be present (usually few to < 100), multiple primaries common. Can overlap AFAP so consider this diagnosis if >20 colon polyps detected.

23. HNPCC Lifetime cancer risks: Colorectal 80% Endometrial 20-60%
Gastric %
Ovarian %
Biliary tract %
Urinary tract %
Small bowel %
Brain/CNS %
Cancer Risk with HNPCC:
CRC - 80% lifetime,
40% for 2nd primary
Higher risk of CRC for men than women

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
Autosomal dominant condition caused by mutations in one of a number of mismatch repair genes
MSH2, MLH1, MSH6, PMS1, or PMS2, others
Sequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCC
Microsatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCC
Genetic testing should be done on an affected family member, only after genetic counseling and informed decision-making

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
Test Method Mutations Detected Mutation Detection Rate  1 Test Availability Sequence analysisAPC sequence alterationUp to 90%Clinical
Mutation scanning
~80-90%
Protein truncation testing (PTT)
Premature truncation of APC protein
~80%
Duplication/deletion analysis
Duplication/deletion of one or more exons
~8-12%  2

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 = years
Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas
30% of individuals with 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
MSI-H tumor, Signet ring type differentiation, Crohn’s-like lymphocytic reaction, Medullary growth pattern

29. Genetics and Uncertainty
Cancer genetics is not relevant for most people
Cancer genetics is not a crystal ball
Not crystal ball as Genetic testing for increased susceptibility to cancer is still in its infancy
It allows us to identify individuals who may be at higher risk of developing certain types of cancer
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 Tel: 0207 905 2625 Fax: 0207 813 8141 Emma Williams
Registered Genetic Counsellor
NE Thames Regional Genetics Service
Great Ormond Street Hospital
Great Ormond Street
London, WC1N 3JH
Tel:
Fax:

33. Paternal grandmother diagnosed with ovarian cancer age at 63
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 33

34. Case 1: Pedigree Russian Jewish Polish Jewish Key -Ov Ca -Br CA Dx 63
82 yrs 58 60
Dx 42
64yrs
Key
-Ov Ca 41
Ruth 35 38
-Br CA 34

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 36

37. Case 2: Pedigree
Dx 61
Died 64
Dx 48 73 65 3 39
30s
DX 53 49 2 2 37

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 38

39. Case 3 YES Colon and uterine cancers 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 French, Irish, Scottish German, English 63 yr 88 yr Dx 50 61 yr
CRC
Dx 48
4 polyps
50 yrs.
Key:
38 yr
35 yr
Endometrial CA
Dx 38
Colorectal CA
Adenomatous polyps
Lynch syndrome
10 yr
8 yr

41. Case 5 YES Is he Jewish? He has a BRCA mutation!
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 Both Breast and ovarian screening
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. Alison has no other risk factors for breast cancer
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 44

45. Case 8: Pedigree British German/Dutch Key: -Breast CA Dx 79 d.81 Dx 58
65 yr
Dx 65
71 yr
Key:
-Breast CA
Alison
40 yr
15 yr 45

46. Patient is in “Moderate” risk category
Case 8: Assessment
Patient is in “Moderate” risk category
Refer to breast clinic for breast cancer screening from 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 46