DrTerespolsky

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  • Sue’s family history
  • Mary’s first pedigree
  • Mary’s second pedigree
  • DrTerespolsky

    1. 1. Hereditary Breast & Ovarian Cancer Debbie Terespolsky Clinical Geneticist
    2. 2. Common question <ul><li>“ There is cancer in my family. Am I at increased risk of getting cancer?” </li></ul><ul><ul><li>Pattern of cancer in family </li></ul></ul><ul><ul><li>Type of cancer </li></ul></ul><ul><ul><li>Age at diagnosis of cancer </li></ul></ul><ul><ul><li>Discuss screening </li></ul></ul><ul><ul><li>Referral to genetics if appropriate </li></ul></ul>
    3. 3. Objectives <ul><li>Overview of role of genetics in cancer </li></ul><ul><li>Known hereditary breast/ovarian cancer syndrome genes </li></ul><ul><ul><li>BRCA1/BRCA2 </li></ul></ul><ul><li>Genetics clinic </li></ul>
    4. 4. All cancer is genetic <ul><li>Genetic code controls all cell growth </li></ul><ul><ul><li>Cell cycle </li></ul></ul><ul><ul><li>Several classes of genes </li></ul></ul><ul><ul><ul><li>Promote growth </li></ul></ul></ul><ul><ul><ul><li>Suppress growth </li></ul></ul></ul><ul><ul><ul><li>Repair damaged DNA </li></ul></ul></ul><ul><ul><li>Series of checks and balances to maintain the rate of new cell growth and cell death </li></ul></ul>
    5. 5. Mutations causing cancer <ul><li>Activating gain-of-function mutations of one allele of a proto-oncogene (RET – MEN2) </li></ul><ul><li>Loss of function of both alleles of a tumour-suppressor gene </li></ul><ul><li>Chromosomal translocations that cause misexpression of genes or create chimeric genes (CML) </li></ul>
    6. 6. Tumour suppressor genes <ul><li>BRCA1 and BRCA2 </li></ul><ul><li>Contribute to cancer through loss of function of both alleles of the gene </li></ul><ul><li>Involved in sporadic and hereditary breast cancer </li></ul>
    7. 7. Sporadic cancer At birth 30 – 50 years 50 – 70 years
    8. 8. 2-hit hypothesis At birth 30 – 50 years 50 – 70 years
    9. 9. 2-hit hypothesis <ul><li>Germline mutation exists in all tissues </li></ul><ul><li>Second hit can cause a tumour whenever it occurs in one of the numerous cells of a tissue </li></ul><ul><ul><li>Initial tumour may arise at multiple sites </li></ul></ul>
    10. 10. Tumour suppressor genes <ul><li>Highly heterogeneous </li></ul><ul><ul><li>“ gate-keepers” – directly regulate cell growth (RB1) </li></ul></ul><ul><ul><li>“ caretakers” – repair DNA damage and maintain cell integrity (BRCA1/2) </li></ul></ul>
    11. 11. BRCA1 and BRCA2 <ul><li>Proteins interact with RAD51 protein in cell cycle </li></ul><ul><li>Functions in repair of damaged DNA </li></ul><ul><li>Regulate activities of other genes </li></ul><ul><li>Critical role in embryo development </li></ul>
    12. 12. Breast and ovarian Cancer
    13. 13. Breast cancer <ul><li>Most common cancer amongst Canadian women </li></ul><ul><li>1 in 9 women </li></ul><ul><li>In 2006: </li></ul><ul><ul><li>22,300 women diagnosed </li></ul></ul><ul><ul><li>5,300 women will die </li></ul></ul><ul><ul><li>160 men, 45 will die </li></ul></ul>
    14. 14. Ovarian Cancer <ul><li>1 in 70 women </li></ul><ul><li>2,300 new cases in 2006 </li></ul>
    15. 15. Familial clustering <ul><li>~15% </li></ul><ul><ul><li>Common environment exposures </li></ul></ul><ul><ul><li>Common lifestyle </li></ul></ul><ul><ul><li>Chance </li></ul></ul><ul><ul><li>Hereditary </li></ul></ul>
    16. 16. Hereditary cancer
    17. 17. Hereditary susceptibility to breast cancer 30 - 70 UNDISCOVERED <1 PTEN CHEK2 <1 TP53 10 - 30 BRCA2 20 - 40 BRCA1 % CONTRIBUTION GENE
    18. 18. BRCA1 <ul><li>Discovered 1994 </li></ul><ul><li>Chromosome 17q21 </li></ul><ul><li>> 600 mutations </li></ul><ul><ul><li>Missense </li></ul></ul><ul><ul><li>Nonsense </li></ul></ul><ul><ul><li>Frameshift – insertion/deletion </li></ul></ul>
    19. 19. BRCA1 <ul><li>Increased risk of </li></ul><ul><ul><li>Breast </li></ul></ul><ul><ul><li>Ovarian </li></ul></ul><ul><ul><li>Prostate </li></ul></ul><ul><ul><li>Colorectal </li></ul></ul>
    20. 20. BRCA2 <ul><li>Discovered 1996 </li></ul><ul><li>Chromosome 13q12.3 </li></ul><ul><li>~ 450 mutations </li></ul><ul><ul><li>Insertions </li></ul></ul><ul><ul><li>deletions </li></ul></ul>
    21. 21. BRCA2 <ul><li>Fanconi anaemia </li></ul><ul><li>Increased risk of </li></ul><ul><ul><li>Breast </li></ul></ul><ul><ul><li>Ovarian </li></ul></ul><ul><ul><li>Prostate </li></ul></ul><ul><ul><li>Pancreas </li></ul></ul><ul><li>Mutations in midsection of gene </li></ul><ul><ul><li>Increased ovarian cancer </li></ul></ul><ul><ul><li>Decreased prostate cancer </li></ul></ul>
    22. 22. BRCA1 and BRCA2 <ul><li>Autosomal dominant </li></ul><ul><li>Ethnic specific mutations </li></ul><ul><ul><li>Ashkenazi Jewish </li></ul></ul><ul><ul><ul><li>185 – 2 bp deletion BRCA1 </li></ul></ul></ul><ul><ul><ul><li>5382 – 1 bp insertion BRCA1 </li></ul></ul></ul><ul><ul><ul><li>6174 – 1 bp deletion BRCA2 </li></ul></ul></ul>
    23. 23. BRCA1 and BRCA2 <ul><li>Up to an 85% chance for a woman to develop breast cancer up to age 70 years </li></ul><ul><li>Average age mid-40’s </li></ul><ul><li>For affected patients, the risk of second primary is 40-60% </li></ul><ul><li>Increased risk male breast cancer (6-10%) </li></ul>
    24. 24. BRCA1 <ul><li>16-44% lifetime risk to develop ovarian cancer (serous invasive ca most common); includes fallopian tubes </li></ul><ul><li>Increased risk of prostate cancer (8-16%) and male breast cancer </li></ul><ul><li>Other possible associated cancers </li></ul><ul><ul><li>Pancreas </li></ul></ul><ul><ul><li>Colorectal </li></ul></ul>
    25. 25. BRCA2 <ul><li>Increased risk of ovarian cancer (10-25%) </li></ul><ul><li>Increased risk for prostate (8-16%) and male breast cancer </li></ul><ul><li>Pancreas </li></ul><ul><li>Other </li></ul>
    26. 26. Likelihood of BRCA1 Mutation <ul><li>No family history: 0.13% </li></ul><ul><li>Br ca <40: 6% </li></ul><ul><li>2 br ca <40: 37% </li></ul><ul><li>Br ca <50 & ov ca <50: 46% </li></ul><ul><li>2 ov ca <50: 61% </li></ul><ul><li>2 br ca & 2 ov ca: 91% </li></ul><ul><li>adapted from Cole et al., 1998 </li></ul>
    27. 27. Clinical relevance <ul><li>Importance of ovarian cancer and BRCA1/2 </li></ul><ul><li>Serous ovarian cancer most likely to be due to BRCA1/2 mutation </li></ul>
    28. 28. Clinical characteristics of individuals with BRCA1/2 mutations <ul><li>No br <50; no ov 3.9% </li></ul><ul><li>Br <50 4.4% </li></ul><ul><li>More than 1 Br <50 11% </li></ul><ul><li>Ov any age; no br <50 3.9% </li></ul><ul><li>More than 1 ov; no br 8.5% </li></ul><ul><li>Br <50 and ov any age 16.4% </li></ul><ul><li>Frank et al, 2002 </li></ul>
    29. 29. Clinical characteristics of individuals with BRCA1/2 mutations <ul><li>Proband with br <40: </li></ul><ul><li>No br <50; no ov 13.2% </li></ul><ul><li>Br <50 29.7% </li></ul><ul><li>More than 1 Br <50 50.7% </li></ul><ul><li>Ov any age; no br <50 24.1% </li></ul><ul><li>More than 1 ov; no br 23.5% </li></ul><ul><li>Br <50 and ov any age 56.3% </li></ul><ul><li>Frank et al, 2002 </li></ul>
    30. 30. Clinical characteristics of individuals with BRCA1/2 mutations <ul><li>Importance of ovarian cancer history regardless of age </li></ul><ul><li>Insufficient evidence to merit testing BRCA1/2 based on dx of DCIS </li></ul><ul><li>Importance of both BRCA1 and BRCA2 in male breast cancer </li></ul>
    31. 31. Ductal carcinoma in-situ <ul><li>DCIS is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2 </li></ul><ul><li>Mutation rates similar to those found for invasive breast cancer. </li></ul><ul><li>Screen patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer. </li></ul>
    32. 32. Referral to Genetics <ul><li>Guidelines available </li></ul><ul><li>Detailed family history </li></ul><ul><li>Confirmation of pathology </li></ul><ul><li>Risk assessment </li></ul><ul><li>Surveillance </li></ul><ul><li>Genetic testing </li></ul>
    33. 33. Issues for patients and families <ul><li>Right to know or NOT to know </li></ul><ul><li>Sharing of information </li></ul><ul><li>Privacy </li></ul><ul><li>Reproduction decision making </li></ul><ul><li>Testing of minors </li></ul>
    34. 34. Who is eligible for testing <ul><li>Breast cancer < 35 </li></ul><ul><li>Two breast cancer < 50 </li></ul><ul><li>> 2 breast cancer </li></ul><ul><li>Serous ovarian cancer </li></ul><ul><li>Breast and ovarian </li></ul><ul><li>Bilateral breast cancer – one < 50 </li></ul><ul><li>Male breast cancer </li></ul>
    35. 35. Best testable <ul><li>Affected individual </li></ul><ul><li>If no affected, unaffected with > 10% risk of having BRCA1/2 mutation </li></ul>
    36. 36. Genetic testing <ul><li>Protein truncation testing (PTT) </li></ul><ul><li>Sequencing </li></ul><ul><li>MLPA (multiplex ligation probe amplification) </li></ul><ul><li>DHPLC (denaturing high performance liquid chromatography) </li></ul>
    37. 37. Genetic testing <ul><li>Turn-around-time </li></ul><ul><li>New tests more efficient </li></ul><ul><li>Myriad in USA </li></ul>
    38. 38. Results <ul><li>Mutation detected </li></ul><ul><li>Mutation not detected </li></ul><ul><ul><li>Missed </li></ul></ul><ul><ul><li>Involves another gene </li></ul></ul><ul><ul><li>Individual’s cancer is not hereditary </li></ul></ul><ul><li>True negative result </li></ul><ul><ul><li>Population risk </li></ul></ul>
    39. 39. Management for BRCA carriers <ul><li>Enhanced surveillance </li></ul><ul><ul><li>Mammogram, CBE, </li></ul></ul><ul><ul><li>Transvaginal u/s, CA-125 </li></ul></ul><ul><li>Chemoprevention </li></ul><ul><li>Prophylactic surgery </li></ul><ul><ul><li>Bilateral mastectomy </li></ul></ul><ul><ul><li>BSO/TAH </li></ul></ul>
    40. 40. Risk reduction <ul><li>Bilateral prophylactic mastectomy </li></ul><ul><ul><li>90% decrease in breast ca </li></ul></ul><ul><li>BSO + TAH </li></ul><ul><ul><li>50% decrease in breast ca (<50 yrs) </li></ul></ul><ul><ul><li>>50% decrease in ovarian ca </li></ul></ul>
    41. 41. Cancer Br @ 33,35 Br @68, 69 2 ovarian 3 Br, died at 33
    42. 42. 63 40 Cancer Br @62 2 Br @46 2 Stroke @82 2 Ov Abd MI @76
    43. 43. 63 40 Cancer Br @62 2 Br @51 2 Stroke @82 2 cervical stomach MI @76
    44. 44. 2 2 2 dx34 2 5 3 3 40
    45. 45. 42 40 35 dx57 dx40’s 38 3 65 69 2 65 62
    46. 46. Multidisciplinary team <ul><li>Family physician </li></ul><ul><li>Oncologist </li></ul><ul><li>Surgeon </li></ul><ul><li>Gynaecologist </li></ul><ul><li>Geneticist </li></ul><ul><li>Psychologist/social worker </li></ul>
    47. 47. Family physician’s role <ul><li>Family history </li></ul><ul><li>Assess likelihood of inherited breast cancer </li></ul><ul><li>Offer referral if appropriate </li></ul><ul><li>Pre-referral discussion of what to expect at genetics appointment </li></ul><ul><li>Post-referral counselling </li></ul><ul><li>Implementation of surveillance/treatment plans </li></ul>
    48. 48. Perspective <ul><li>20% women have a family history of breast cancer </li></ul><ul><li><5% of women are at high risk for a genetic predisposition </li></ul>
    49. 49. Management: general population <ul><li>Annual CBE not later than age 30. If family history, begin 10 years earlier than youngest age at diagnosis of affected relative </li></ul><ul><li>Annual or bi-annual mammogram starting from age 40-50, or 10 years earlier than youngest age at diagnosis of affected relative </li></ul><ul><li>BSE </li></ul>
    50. 50. The Future <ul><li>Education of population </li></ul><ul><ul><li>Risk assessment </li></ul></ul><ul><ul><li>surveillance </li></ul></ul><ul><li>New surveillance </li></ul><ul><li>New treatments </li></ul><ul><li>Genotype phenotype correlation </li></ul><ul><li>BRCA3/4 </li></ul>

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