DrTerespolsky
Upcoming SlideShare
Loading in...5
×
 

DrTerespolsky

on

  • 1,602 views

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

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

Statistics

Views

Total Views
1,602
Views on SlideShare
1,602
Embed Views
0

Actions

Likes
0
Downloads
54
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Sue’s family history
  • Mary’s first pedigree
  • Mary’s second pedigree

DrTerespolsky DrTerespolsky Presentation Transcript

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