Presentation on theme: "Introduction to Cancer Genetics"— Presentation transcript:
1 Introduction to Cancer Genetics Emma WilliamsGenetic CounsellorNE Thames Regional Genetics Service
2 Cancer Genetic Service OverviewCancer Syndromes &Management optionsGenes &Genetic testingGenetic Counselling &Cancer Genetic ServiceI’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??Populationcancer risk
3 What are the cancer risks for the general population? 1 in 3 people will develop cancer at some point in their livesProstate: %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 diagnosesSEER 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 predispositionHereditary (~5%)
5 Sporadic Cancer Many patients may have a similar FHx Age of diagnosis typically later in lifeUsually not inheritedCan be reassuringAs 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 conditionAppreciate inheritance patterns and risk of recurrenceUnderstand available optionsMake informed choices appropriate to their personal and family situationMake the best possible adjustment to the condition and riskGenetic 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 guidelinesReferral 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 formComprehensive 3 generation pedigreeConfirmation of cancer pathologyPedigree assessmentManchester scoreBOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)Amsterdam I/II CriteriaBethesda Criteria
11 Genetic Cancers Breast and ovarian Colon cancers Cowden syndrome Gastric cancerGorlin SyndromeLi-FraumeniMultiple endocrine neoplasia (MEN)NeurofibromatosisPeutz-Jeghers syndromePhaeochromocytomaRetinoblastomavon Hippel-Lindau diseaseWilm’s tumourHere 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 onsetMultiple generations are affected on one side of the familyA particular pattern of cancers notedIndividuals with more than one primary tumour site5-10% of Cancer CasesThis 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 NormalSusceptible CarrierCarrier, affected CaSporadic CaMost 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 cancerBoth men and women can carry the altered copyIt 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 geneYou only need one altered copy of the gene to have an increased risk of cancerGender is irrelevantIt is not possible to “skip” generationsPenetrance can be incompleteAll offspring are at 50:50 risk
14 Genetic TestingGenetic testing is usually carried out on DNA from a blood sampleTechnically difficult to locate the mutation in a cancer gene for a particular familyCan take up to three monthsUsually need to first test a living relative who has already developed cancerIs 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 studyOften 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 relativesException is populations with founder mutations eg Ashkenazi Jewish populationOnce a mutation is found, testing can be offered to other at-risk family membersIndividuals who DO NOT carry the family mutation ARE NOT at increased risk of developing the cancers, but are still at population riskIndividuals 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 cases40-70% lifetime risk breast cancer10-45% lifetime risk ovarian cancerIncreased risk prostate cancer in male carriersGenetic testing possible for some familiesSurgery and surveillance options for affected individualsHereditary Breast and Ovarian CancerOther genesBRCA1BRCA25-10%SporadicHereditaryMost cases caused by a mutation in BRCA1 or BRCA2 geneBRCA1 / 2 are tumour suppressor genes, which are involved in the repair of DNAAccounts for about 5% of breast cancer cases and about 12% of ovarian cancer casesMost hereditary cases of br/ov cancer are due to mtn in BRCA1/2Essentially 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 cancerIncreased risk of other cancers, eg about double population risk for prostate cancer in men17
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 cancerMen carrying a BRCA2 mutation are at increased risk of breast cancer as well as an increased risk of prostate cancerOther cancers:pancreaticmalignant melanoma18
19 Options for BRCA1/2 Carriers Cancer ScreeningAdditional breast screening by mammography / MRIOvarian screening through UKFOCSS research trialProphylactic bilateral mastectomy~90% reduction in breast CA riskProphylactic 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 futureProphylactic bilateral mastectomyMay reduce breast CA risk up to 90%Prophylactic bilateral oophorectomyMay reduce risk for ovarian CA by 50-90% studies need validationMay reduce risk for breast CA by 50% - studies also need validationLast point – such as PARP inhibitors/platinum treatment….19
20 When to refer2 first or second degree relatives with breast cancer < 50 yr3 first or second degree relatives with breast cancer <60yr4 relatives with breast cancer at any age1 ovarian cancer at any age + 1 breast cancer < 50yr1 ovarian cancer + 2 breast cancer both < 60y2 ovarian cancer any agePatients 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 ageNB bilateral breast primaries equivalent to 2 relatives
21 Colorectal Cancer only 7% of sporadic cases occur <55 ~75% of cases of CRC are sporadiconly 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 casesAutosomal dominant – multiple generations affectedHigh penetranceTypical age of CA onset is yrs60-70% right-sided/proximal CRC tumorsPolyps may be present, multiple primaries common. Can overlap with AFAPTypical age of onset is 40-50, range from yrsPreponderance 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 primaryHigher 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, PMS290% of detectable mutations in MSH2 and MLH17-10% of detectable mutations in MSH6Autosomal dominant condition caused by mutations in one of a number of mismatch repair genesMSH2, MLH1, MSH6, PMS1, or PMS2, othersSequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCCMicrosatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCCGenetic 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 colonoscopyOvarian and endometrial screening (not proven to be effective)? renal/upper GI screening effective(if have history of gastric/renal cancers)SurgeryProphylactic bowel surgery not often chosenTotal abdominal hysterectomy and salphingo oophorectomy for females
26 Familial adenomatous polyposis (FAP) 1 in 10,000 incidence100’s to 1000’s of colonic adenomas by teens7% risk of CRC by 21 yrs; 93% by 50 yrs20-25% no history in parentsExtra-colonic featuresScreening1 – 2 yearly flexible sigmoidoscopy from age 10 – 12Upper GI endoscopy 1 –3 yearly from age 25Test Method Mutations Detected Mutation Detection Rate 1 Test Availability Sequence analysisAPC sequence alterationUp to 90%ClinicalMutation scanning~80-90%Protein truncation testing (PTT)Premature truncation of APC protein~80%Duplication/deletion analysisDuplication/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 geneMedian number of polyps = 55Mean age of polyp diagnosis = yearsPolyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas30% of individuals with polyps have homozygous mutations in the MYH geneGenetic 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 <50yrs2 or more colorectal primary cancers any ageColorectal 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 stomachMSI-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 peopleCancer genetics is not a crystal ballNot crystal ball as Genetic testing for increased susceptibility to cancer is still in its infancyIt allows us to identify individuals who may be at higher risk of developing certain types of cancerBut 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 onsetLots of one or two particular types of cancerJewish?If not sure askDon’t be afraid to contact genetics for adviceTake a blood sample for DNA banking
31 DNA BankingDNA 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 CounsellorNE Thames Regional Genetics ServiceGreat Ormond Street HospitalGreat Ormond StreetLondon, WC1N 3JHTel:Fax:
33 Paternal grandmother diagnosed with ovarian cancer age at 63 Case 1: RuthRuth, 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 63Paternal aunt diagnosed with breast cancer age 42Ruth has no other risk factors or pertinent family history33
34 Case 1: Pedigree Russian Jewish Polish Jewish Key -Ov Ca -Br CA Dx 63 82 yrs5860Dx 4264yrsKey-Ov Ca41Ruth3538-Br CA34
35 Case 1: Assessment Patient is in “Moderate risk” category However ethnicity is important as she is of Ashkenazi Jewish descentRefer to genetics clinicModerate risk screening for breast cancer arrangedGenetic testing for 3 common ‘Jewish Mutations’
36 Case 2: AnnAnn 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 inevitable36
37 Case 2: PedigreeDx 61Died 64Dx 48736533930sDX 53492237
38 Case 2: Assessment Patient is in “High” risk category Refer to genetics clinic promptlyHigh risk screening breast and ovarian cancerGenetic testing offered38
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?YESColon and uterine cancers
40 Case 4 French, Irish, Scottish German, English 63 yr 88 yr Dx 50 61 yr CRCDx 484 polyps50 yrs.Key:38 yr35 yrEndometrial CADx 38Colorectal CAAdenomatous polypsLynch syndrome10 yr8 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?YESIs 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?BothBreast and ovarian screeningShe actually had two BRCA mutations!
43 Case 7: TedTed 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 & 34Maternal grandmother: breast cancer age 85Reassure
44 Alison has no other risk factors for breast cancer Case 8: AlisonAlison 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 58Maternal aunt with breast cancer – age 65Paternal grandmother with breast cancer – age 79Alison has no other risk factors for breast cancerShe feels that with her family history, breast cancer is inevitable44
45 Case 8: Pedigree British German/Dutch Key: -Breast CA Dx 79 d.81 Dx 58 65 yrDx 6571 yrKey:-Breast CAAlison40 yr15 yr45
46 Patient is in “Moderate” risk category Case 8: AssessmentPatient is in “Moderate” risk categoryRefer to breast clinic for breast cancer screening from years then NBSPCounselling issues:Unlikely to be due to a BRCA1 or BRCA2 mutationScreening and preventive strategiesPsychosocial – perceived risk, fearsSupport resources46