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HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES

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Presentation on theme: "HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES"— Presentation transcript:

1 HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES
Prof. Richard Pestell Prof. Jan Lubinski Prof. 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 testing What 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 relatives multiple primary tumors in the same individual bilateral cancer in paired organs an earlier-than-usual onset of cancer a specific constellation of tumors that comprise a known cancer syndrome If 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, and provide 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 – 80 Hereditary Breast Cancer Families - 26 Hereditary Breast and Ovarian Cancer Families - 15 Hereditary Ovarian Cancer Families - 3 Breast and Ovarian Cancer cases - 3 Early onset Breast Cancer cases - 29 Early onset Ovarian Cancer cases - 3 Hereditary Prostate and Breast Cancer families -1

11 CRITERIA FOR GENETIC TESTING
HBOC STUDY Early 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
587 dHPLC Unit

15 METHODS - SEQUENCING Cycle 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 v For 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 - 80 No: of controls studied No: 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%)

17 CASE -1 Novel mutation 60C 50C Frame shift mutation
B1 E12 - c.4158_4162delCTCTC; p.Ser1369Ser fsX2 50 2 3 62 28 6 Breast 44 Frame shift mutation Novel mutation

18 CASE-II 54C 50C Frame shift mutation
Throat 45 41 Uterus 43 36 35 39 Breast 2 B2 E11O - c.6214_6218delCTTAA; p.Ser2072Ser fsX4 54C 50C Frame shift mutation

19 CASE-III 59C 50C Nonsense mutation B1E13 - c.4327C>T; p.R1443X 3
64 Breast 2 48 40 43 41 35 51 3 B1E13 - c.4327C>T; p.R1443X Nonsense mutation

20 CASE-IV Novel mutation 57C 50C Frame shift mutation
B1 E11C - c.1148_1149delAT; p.Asn383Arg fsX6 50C 57C 2 39 Breast 38 50 60 49 Frame shift mutation Novel mutation

21 CASE-V 50°C 53°C Frame shift mutation 3
B2 E11D - c.5130_5133delTGTA; p.Tyr1693X 30 50 27 Breast 2 3 Frame shift mutation

22 CASE-VI Novel mutation 56°C 50°C Nonsense mutation 2
B1 E14 -c.4399C>T; p.Gln1467X 75 Ovary 74 53 Liver 60 Throat 45 Breast 39 Uterine 38 47 2 44 Nonsense mutation Novel mutation

23 CASE-VII Novel mutation 56°C 50°C Frame shift mutation
61 Ovary 72 2 28 43 39 B1 E17 - c.5024_5025insT; p. Thr1675Thr fsX4 Frame shift mutation Novel mutation

24 CASE-VIII Novel mutation 59°C 50°C Frame shift mutation
B1EX16- c.4705_4706insTGGAATC; p.Ilefsx5 57 Ovary 56 Breast 45 2 NOS 48 3 Frame shift mutation Novel mutation

25 CASE-IX, X, XI, XII 33 Breast 2 60 NOS 58 59 Ovary 48 44 4 39

26 CASE-IX, X, XI, XII 50 58 Breast 33 3 2 NOS 60 Ovary 42 39

27 CASE-IX, X, XI, XII 55°C 50°C Frame shift mutation
B1 EX2- c.68_69delAG p. Glu23Val fsX16 Frame shift mutation

28 CASE-XIII- UNKNOWN SIGNIFICANCE
B1 E11G – c.1511G>A; p. R504H Breast 30 76 46 4 2 50C 57C Missense mutation Novel mutation

29 RESULTS ON MUTATION ANALYSIS
BRCA1 and BRCA2 analysis was done for 80 cases Number of HBOC cases that showed pathogenic mutation 8/45 (17.8%) Number of HOC cases that showed pathogenic mutation 1/3 (33.3%) Number of early onset breast cancers that showed pathogenic mutation 3/29 (10.3%) Number of early onset ovarian cancers that showed pathogenic mutation 0/3 (0%)

30 Common Polymorphisms Detected in BRCA1 in the exonic region
Percentage 11K - c.3311T>C; p.L771L 42/80 (52.5%) 11N - c.2612C>T; p.P871L 38/80 (47.5%) 11S - c.3113A>G; p.E1038G 20/80 (25%) 11TU - c.3548A>G; p.K1183R 12/80 (15%) 16 - c.4954A>G; p.M1652I 4/80 (5%) 16 - c.4839G>A; p.S1613G

31 Common Polymorphisms Detected in BRCA2 in the exonic region
Percentage 10B - c.1114C>A; p.H372N 35/80 (43.8%) 11B - c.4258G>T; p.D1420Y 2/80 (2.5%) 11C - c.4779A>C; p.E1593D 1/80 (1.25%) 11F - c.2538A>C; p.S846S 11H - c.2892A>T; p.K964N 11I - c.2971A>G; p.N991D 5/80 (6.25%) 11K - c.3807T>C; p.V1269V 4/80 (5%)

32 Common Polymorphisms Detected in BRCA1 in the intronic region
Percentage c T>C 5/80 (6.25%) c T>C 1/80 (1.25%) c del T 22/80 (27.5%) c G>A c A>G c A>G c G>A 5/80 (8.1%)

33 Common Polymorphisms Detected in BRCA2 in the intronic region
Percentage c.1-26G>A 4/80 (5%) c delTTAA 32/80 (40%) c T>C 40/80 (50%) c T>C 39/80 (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 testing What could be the take home message.


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