Genetics and Breast and Ovarian Cancer

1
Genetics and Breast and Ovarian Cancer

• An Introduction

2
Genetics and Breast Cancer

• Inherited breast/ovarian cancer is an autosomal
  dominant condition
• Occurs as a result of mutations in BRCA1 or BRCA2
  genes
• BRCA 1 - gene on chromosome 17
• BRCA 2 - gene on chromosome 13

BRCA 2 Chromosome 13
BRCA 1 Chromosome 17
3
Genetic Forms of Breast Cancer

• Individuals with one copy of either mutated gene
  are at increased risk of breast and/or ovarian
  cancer.
• 60 lifetime risk breast cancer
• 10-40 lifetime risk ovarian cancer

4
Incidence of BRCA genes

• BRCA1
• 3.5 Hispanic,
• 1.3 to 1.4 African American,
• 0.5 Asian American,
• 2.2 to 2.9 non-Ashkenazi Caucasian, and
• 8.3 to 10.2 Ashkenazi Jewish.
• BRCA2
• 2.6 African American and
• 2.1 Caucasian

5
Heterozygous Individuals

• Theoretically, heterozygous individuals with the
  BRCA 1 or 2 gene will have a normal allele on the
  other paired chromosome.
• FYIIt would be unusual to be homozygous for BRCA
  1 or 2

6
Heterozygous Individuals

• HOWEVER..
• In most breast and ovarian cancers studied, in
  those carrying the mutation the normal allele on
  the homologous chromosome is deleted,
• As a result there is a loss of all function of
  the BRCA 1 or 2 healthy gene product.

7
What do the BRCA genes code for?

• The BRCA genes seem to code for tumor suppressor
  proteins
• Needed to keep cells from becoming cancerous
• BRCA gene products also play a role in
• DNA repair
• Cell Cycle control
• And other functions

8

• Over 2000 different mutations have been
  identified in the BRCA genes
• Not all have the same cancer risk
• The cancer risk associated with each mutation
  depends on the impact of the mutation on the
  proteins structure and function.
• Most BRCA1 and BRCA2 mutations are predicted to
  produce a truncated protein product, and a loss
  of protein function.

9
Alexandra Bests Story

• Alexandra Bests mother and grandmother died from
  breast cancer.
• After visiting the doctor to voice her concerns,
  she discovered that researchers had traced the
  origins of her family's history of breast cancer
  back to three Italian brothers who emigrated to
  England in the 1850s.
• Thirty-one members of her family had developed
  the disease since then - and the researchers said
  she was likely to be carrying the gene.

10
Alexandras Relatives many generations back
11
What she did.

• Alexandra was tested for the BRCA gene and found
  to carry it.
• She decided to have a preventative mastectomy
• During preparation for the operation a cancerous
  lump was found in her breast.
• Lead to a double mastectomy and chemotherapy.

12

• Alexandras extended family was tested and 11
  were found to carry the BRCA gene
• 8 have had preventative surgery
• Another family tree for a real family follows.

13
Family positive for BRCA 1 deleterious mutation

positive for mutation Preventive measure
taken


Ethel E. Laird Breast 28 Death 32

Marjorie Halt Ovarian 64,69 Death 69
Maryann Laird Breast 44, 46 Ovarian 63 Death 64
Paula (59) Breast 48
Barbara Breast 38, 40 Death 44
Susan Halt Davis (53) Breast 49


Linda Halt Nicholson (60)
Steve Halt (57)

BRCA I Neg Julianne
BRCA I Neg Kevin (32) 2 Children
Jeffrey (40) No Children
Gina (30)
Kristi (28)
Amber (28)
Richard Death 3-5-07 Age 25 Car accident
Jennifer, 22