Presentation on theme: "HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES"— Presentation transcript:
1 HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES Prof. Richard PestellProf. Jan LubinskiProf. T.Rajkumar
2 QUESTIONS TO BE DISCUSSED What is cancer genetic counseling?Issues related to setting up a Hereditary cancer programme in a developing country?Socio-economic issues in India and in the West.Financial implications in testing.Guidelines in gene testingWhat could be the take home message.
3 Assessing the Genetic Risks of Cancer If the family history reveals one or more of the following features, then a further assessment is warranted:cancer in two or more close relativesmultiple primary tumors in the same individualbilateral cancer in paired organsan earlier-than-usual onset of cancera specific constellation of tumors that comprise a known cancer syndromeIf one of these features are found in the individual's own or family history, familial or hereditary factors should be considered and further evaluated.
4 Cancer Risk Counseling In contrast to "traditional" genetic counseling, which often focuses on reproductive risks, those seeking cancer risk counseling are usually at an increased risk of developing cancer themselves.Therefore, much of the discussion and focus of cancer risk counseling concerns the individual's personal risk of developing a disease.
5 Cancer Risk Counseling Thus, those who provide cancer risk counseling should:emphasize prevention of cancer,convey recommendations for surveillance,discuss life-style modifications that may reduce the risk of developing cancer, andprovide an assessment of risk to the individual and other family members.Gene testing – implications of a positive, negative or uninformative test result
6 Assessing the Genetic Risks of Cancer The two major decision points in the assessment of cancer risk are:Is the risk of cancer higher or lower than in the general population?Is the risk higher or lower than that perceived by the patient?
7 Assessing the Genetic Risks of Cancer The family history questionnaire provides the initial information to answer the first question—individuals with negative family histories and minimal family concerns should be counseled as such, putting their concerns in the context of the general population risk. Cancer screening and prevention information are probably all that is needed.
8 Assessing the Risks of Hereditary Cancer Syndromes Although the specific genes involved in several hereditary cancer syndromes have been discovered, the initial identification of families with these syndromes is based on clinical and family history criteria.Hereditary cancer syndromes follow Mendelian inheritance patterns...usually autosomal dominant with reduced penetrance and variable expressivity.
9 PENETRANCE AND EXPRESSIVITY The parent transmitting the gene did not show the trait, even though he or she carried the allele; this is known as incomplete penetrance, that is, the inconsistent phenotypic expression of a gene even though the gene is present.The parent of the affected individual expressed the gene but in ways that were not readily recognized; this is known as variable expressivity.
10 MATERIALS Hereditary breast and ovarian cancer study Total number of cases studied – 80Hereditary Breast Cancer Families - 26Hereditary Breast and Ovarian Cancer Families - 15Hereditary Ovarian Cancer Families - 3Breast and Ovarian Cancer cases - 3Early onset Breast Cancer cases - 29Early onset Ovarian Cancer cases - 3Hereditary Prostate and Breast Cancer families -1
11 CRITERIA FOR GENETIC TESTING HBOC STUDYEarly onset of breast cancer ( at or less than 35 years of age).Two cases of breast cancer diagnosed under the age of 50 years.Three cases of breast cancer diagnosed under 60 years of age.
12 CRITERIA FOR GENETIC TESTING Four or more cases of breast cancer diagnosed at any age.Presence of breast and ovarian cancer in the family or in the same individual.Male breast cancer with a relative (of either sex) with breast cancer.
13 DHPLC Reverse phase ion exchange chromatography DHPLC analysis – All fragments analyzed at a basal temperature of 50°C plus two or more higher partial denaturing temperatures.The DHPLC system’s performance was validated with pUC18 HaeIII digest once every 200 runs.
14 DHPLC pUC18 HaeIII digest dHPLC Unit 80 434 102 174 298 267 257 458 587dHPLC Unit
15 METHODS - SEQUENCINGCycle sequencing was done with both forward and reverse primers in separate reaction and run in ABI 310 Genetic Analyzer.The sequences were analyzed in Sequence Analysis vFor the samples that showed mutation, DNA from fresh aliquot of lymphocytes was used to sequence again to confirm the results.
16 RESULTS HEREDITARY BREAST AND OVARIAN CANCER STUDY No: of women with breast/ovarian cancer studied - 80No: of controls studiedNo: of disease causing mutation detected /80 (15%)No: of variants of unknown significance detected - 1/80 (1.2%)No: of samples wherein polymorphisms detected - 77/80 (96%)No: of samples with no polymorphisms in BRCA1 - 20/80 (25%)No: of samples with no polymorphisms in BRCA2 - 10/80 (12.5%)
29 RESULTS ON MUTATION ANALYSIS BRCA1 and BRCA2 analysis was done for 80 casesNumber of HBOC cases that showed pathogenic mutation8/45 (17.8%)Number of HOC cases that showed pathogenic mutation1/3 (33.3%)Number of early onset breast cancers that showed pathogenic mutation3/29 (10.3%)Number of early onset ovarian cancers that showed pathogenic mutation0/3 (0%)
30 Common Polymorphisms Detected in BRCA1 in the exonic region Percentage11K - c.3311T>C; p.L771L42/80 (52.5%)11N - c.2612C>T; p.P871L38/80 (47.5%)11S - c.3113A>G; p.E1038G20/80 (25%)11TU - c.3548A>G; p.K1183R12/80 (15%)16 - c.4954A>G; p.M1652I4/80 (5%)16 - c.4839G>A; p.S1613G
31 Common Polymorphisms Detected in BRCA2 in the exonic region Percentage10B - c.1114C>A; p.H372N35/80 (43.8%)11B - c.4258G>T; p.D1420Y2/80 (2.5%)11C - c.4779A>C; p.E1593D1/80 (1.25%)11F - c.2538A>C; p.S846S11H - c.2892A>T; p.K964N11I - c.2971A>G; p.N991D5/80 (6.25%)11K - c.3807T>C; p.V1269V4/80 (5%)
32 Common Polymorphisms Detected in BRCA1 in the intronic region Percentagec T>C5/80 (6.25%)c T>C1/80 (1.25%)c del T22/80 (27.5%)c G>Ac A>Gc A>Gc G>A5/80 (8.1%)
33 Common Polymorphisms Detected in BRCA2 in the intronic region Percentagec.1-26G>A4/80 (5%)c delTTAA32/80 (40%)c T>C40/80 (50%)c T>C39/80 (48.8%)
34 QUESTIONS TO BE DISCUSSED What is cancer genetic counseling?Issues related to setting up a Hereditary cancer programme in a developing country?Socio-economic issues in India and in the West.Financial implications in testing.Guidelines in gene testingWhat could be the take home message.