Your SlideShare is downloading. ×
0
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
DrTerespolsky
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

DrTerespolsky

1,204

Published on

http://www.oma.org/Health/Womens_Issues/DrTerespolsky.ppt

http://www.oma.org/Health/Womens_Issues/DrTerespolsky.ppt

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,204
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
55
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • Sue’s family history
  • Mary’s first pedigree
  • Mary’s second pedigree
  • Transcript

    • 1. Hereditary Breast & Ovarian Cancer Debbie Terespolsky Clinical Geneticist
    • 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. 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. 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. 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. 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. Sporadic cancer At birth 30 – 50 years 50 – 70 years
    • 8. 2-hit hypothesis At birth 30 – 50 years 50 – 70 years
    • 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. 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. 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. Breast and ovarian Cancer
    • 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. Ovarian Cancer <ul><li>1 in 70 women </li></ul><ul><li>2,300 new cases in 2006 </li></ul>
    • 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. Hereditary cancer
    • 17. Hereditary susceptibility to breast cancer 30 - 70 UNDISCOVERED <1 PTEN CHEK2 <1 TP53 10 - 30 BRCA2 20 - 40 BRCA1 % CONTRIBUTION GENE
    • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Cancer Br @ 33,35 Br @68, 69 2 ovarian 3 Br, died at 33
    • 42. 63 40 Cancer Br @62 2 Br @46 2 Stroke @82 2 Ov Abd MI @76
    • 43. 63 40 Cancer Br @62 2 Br @51 2 Stroke @82 2 cervical stomach MI @76
    • 44. 2 2 2 dx34 2 5 3 3 40
    • 45. 42 40 35 dx57 dx40’s 38 3 65 69 2 65 62
    • 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. 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. 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. 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. 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>

    ×