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The Genetics of Breast and Ovarian Cancer Susceptibility Patricia Tonin, PhD Associate Professor Depts. Medicine, Human Genetics & Oncology McGill University McGill University Health Centre patricia.tonin@mcgill.ca How common is hereditary cancer? 1,055 Hereditary - known genes 2,100

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the genetics of breast and ovarian cancer susceptibility

The Genetics of Breast and Ovarian Cancer Susceptibility

Patricia Tonin, PhD

Associate Professor

Depts. Medicine, Human Genetics & Oncology

McGill University

McGill University Health Centre

patricia.tonin@mcgill.ca

slide2

How common is hereditary cancer?

1,055

Hereditary - known genes

2,100

5%

Hereditary -

unknown genes

10%

Sporadic - Most cancers are caused by unknown factors likely due to a combination of genetic and environmental factors!

17,945

85%

slide5

*Breast cancer risk to age 50 years : 30% for BRCA carriers compared with 2% for general population!!!!!!

features of families with genetic predisposition
Features of Families with Genetic Predisposition
  • Cancer occurs in first, second or third degree relatives in relation to cancer case
      • Minimum of 3 cases per family
  • Cancers occur in same branch of the family
      • Maternal OR Paternal
  • Average age of diagnosis is often younger than average age of diagnosis of all cancers of same site (< 55 yrs of age)
  • Mendelian mode of inheritance
      • Autosomal dominant
management of high risk women 30 years of age 50 years of age
Screening

Mammography (MRI?)

yearly

Pelvic examination, CA125 serum test, transvaginal ultrasonography

every 6 months

Cancer prevention

Breast cancer

prophylactic mastectomy

chemoprevention?

Ovarian cancer:

prophylactic oophorectomy

Management of High Risk Women[> 30 years of age < 50 years of age]
slide13
Breast cancer families that feature no ovarian cancer cases and/or a male breast cancer case most likely harbor a BRCA2 mutation
genetic testing
Genetic Testing
  • Commercially available via Myriad Genetics
      • Provided at no cost to the individual but on a per case basis via genetic counsel ling centers in Quebec
      • Time-line - very good (~ 1 month)
      • Testing not comprehensive???
  • Research laboratories
      • Provided at no cost to the individual
      • Time-line is usually longer (> 3 months)
      • Testing may be more comprehensive
assessing sequence variants
Assessing Sequence Variants
  • NO FUNCTIONAL ASSAY!
  • Deleterious mutation
      • Predicted change in function based on deduced amino acid sequence
      • Segregates with cancer cases in families
  • Sequence variant of unknown significance
  • Polymorphism
      • No net change in amino acid sequence
      • Does not segregates with cancer cases in families
      • Frequency in unaffected controls and breast cancer cases is similar
when a deleterious mutation is found
When a deleterious mutation is found
  • Mutation detection is offered to other members of the family to assess risk based on carrier status
  • Management strategies discussed based on carrier status
  • Mutation analysis can distinguished carriers (highest risk) from non-carriers (lowest risk) and thus improved risk assessment of members of this family
when no sequence variant is found
When NO sequence variant is found
  • Risk assessment remains based on family history of cancer alone.
  • Mutation analysis has not improved assessment for family members in this situation as a genetic test cannot distinguish highest risk from lowest risk individuals in this family
slide21

No BRCA Mutation Found

BRCA Positive Family

Risk estimates is based on empiric risk estimate ‘tables’.

35-48%

35-48%

genetic testing22
Genetic Testing
  • Confirmation of cancer cases in family
      • Pathology reports
      • Death certificates
  • Individuals to test
      • Breast cancer case, preferably youngest age of diagnosis in family (<55 years)
      • Ovarian cancer case (any age)
      • Male breast cancer
      • Obligate carrier (example, father of affected daughters)
  • DNA/RNA Samples tested
      • Peripheral blood leukocytes
      • Paraffin embedded or archived tissues discouraged
genetic testing at mcgill genetic counseling service
Genetic Testing at McGill: Genetic Counseling Service
  • Per case basis by referral
      • Family history of cancer
  • Specific mutation analysis:
      • Panel of common mutations for Ashkenazi Jewish population or French Canadian population
      • Previously identified mutation
  • Myriad Genetic Testing:
      • Other populations
      • Mutation-negative cases (Ashkenazi Jewish or French Canadian)
summary
Summary
  • 85% of breast cancers ‘sporadic’
  • 15% of breast cancers occur in context of family history of breast cancer attributable to transmission of highly penetrant gene
      • 5-10% attributed to germline mutations in BRCA1 and BRCA2
      • ~1% other known genes
      • ~5% unknown genes
  • Mutation analysis and interpretation facilitated by
      • Nature mutations
      • Common mutations found in well defined populations