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Introduction to Cancer Genetics

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Presentation on theme: "Introduction to Cancer Genetics"— Presentation transcript:

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

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