Genetics and Ovarian Cancer
Jeanne M. Schilder, M.D.
Associate Professor, Gynecologic Oncology
Indiana University Medical Center
September 19, 2012

Introduction
 Review of ovarian cancer risk factors
 What decreases risk?
 What increases risk?
 What is the role of family history?
 What is the role of genetic mutations?

Female Lifetime Risk of Cancer
 Ovarian Cancer
 General population-1.4%
 One first-degree relative-4.2%
 Breast Cancer
 General population-12.4%
 One first-degree relative-24%
 Lung Cancer-6.4%
 Colon Cancer-4.8%
 Endometrial Cancer-2.6%

Ovarian Cancer Risk Factors:
Decreased Risk
Factor
Pregnancies
None
1 full term pregnancy
Relative Risk
1.0
0.6
>5 full term pregnancies 0.29
Use of birth control pills
Never
Ever
3 mo-4 yrs
>10 years
Bilateral Tubal Ligation
Hysterectomy
1.0
0.75
0.6-0.7
0.2
0.5
0.5

Ovarian Cancer Risk Factors:
Increased Risk
 Age
25
20
15
10
5
0
45
40
35
30
30 40 50 60 70 80 90+
Cases/100,000

Ovarian Cancer Risk Factors:
Increased Risk
Factor
Hx of Breast Cancer
None
1 st Degree Relative
Personal History
Hx of Ovarian Cancer
None
One 1 st Degree Relative
>2 1 st Degree Relatives
Hereditary Cancer Syndrome
Relative Risk
1.0
2.1
10
1.0
3.1
4-15
12-30

Hereditary Gynecologic Cancer
Syndromes
 1. Hereditary Breast/Ovarian Cancer
Syndrome (HBOC)
 2. Hereditary Site-Specific Ovarian
Cancer Syndrome
 3. Hereditary Nonpolyposis Colon
Cancer Syndrome (HNPCC or Lynch II)

HBOC
 ~90% of hereditary ovarian cancers
 30-70% of hereditary breast cancers
 Increased risk of prostate and possibly colon cancer in some HBOC families
 Responsible genes: BRCA1, BRCA2

Hereditary Site-Specific Ovarian
Cancer
 Variant of HBOC
 Families with clusters of ovarian cancer, no breast cancer cases
 < 5% of hereditary ovarian cancer cases
 Responsible genes: BRCA1, BRCA2

BRCA 1 and BRCA 2 Function
 Tumor suppressor genes
 Regulate normal cell growth and proliferation
 Counteract stimulatory effects of oncogenes
 Play a role in DNA repair
 Interact with RAD51, a known DNA repair protein
 “Caretaker genes”

BRCA Mutation Prevalence:
Populations
General population 0 .125%
(1/800)
Ashkenazi Jewish
Ancestry
2.5%
(1/40)

BRCA Mutation Prevalence:
Personal Cancer History
Breast Cancer
Dx < 50 years
Dx > 50 years
20%
7%
Ovarian Cancer
Both Breast and
Ovarian Cancer
10%
90%

BRCA Mutation Prevalence:
Family Cancer History
Breast Cancer
One 1 st degree relative 3.8%
> 3 relatives 20%
Bilateral 18%
Breast + ovarian cancer 40%

HNPCC or Lynch Syndrome
 ~7% of hereditary ovarian cancer cases
 5% of all colorectal cancer cases
 Most common cancers: COLON and
ENDOMETRIAL
 Increased incidence of other adenocarcinomas, including stomach, small bowel, and bile duct malignancies ( not breast )

HNPCC
 Responsible genes: Mismatch repair genes (MMR) including MLH1, MSH2, and MSH6
 Autosomal dominant
 Prevalence in the general population:
0.1% (1/1000)

Penetrance by age 70
 BRCA 1 and BRCA 2
 Ovarian cancer:
 Breast cancer:
 Male breast cancer:
16-63%
82-87%
6%
 HNPCC
 Colorectal cancer:
 Endometrial cancer:
 Stomach cancer:
 Ovarian cancer:
68-75%
43-60%
13-19%
9-12%
 Second primary: 90%
 Most commonly colorectal or endometrial

Red Flags for Hereditary
Cancers
 Multiple cases within the family
 Autosomal dominant transmission
 Early age of onset; earlier in successive generations
 Bilateral cancers
 Synchronous cancers (> 2 at once)
 Metachronous cancers (more than one, diagnosed at different times)

Obtaining a Family History of
Cancer
 3-generation family history
 1 st Generation : Parents, siblings, children
 50% genetic link
 2 nd Generation : Grandparents, grandchildren, aunts, uncles, nieces, nephews, ½ siblings
 25% genetic link
 3 rd Generation : Great-grandparents, greatgrandchildren, great aunts/uncles, grand nieces/nephews, first cousins
 12.5% genetic link

Obtaining a Family History of
Cancer
 Maternal and paternal data
 Include race, ethnic background, current age, all types of cancers, age at diagnosis, age at death
 Update at each visit
 Confirm with medical records and pathology reports when possible

Elevated HNPCC Risk:
Amsterdam Criteria
 1. At least two successive generations with colorectal cancer
 2. Diagnosis of at least one individual before age 50
 3. Colon cancer in at least 3 relatives
 4. Family history of other cancers including ovarian, endometrial, stomach, urinary tract, small bowel, and bile duct

Elevated HNPCC Risk:
Bethesda Criteria
 1. Very small families with two cases of colon cancer OR two 1 st degree relatives with colon cancer
AND
 2. A third relative with early-onset cancer or endometrial cancer

Identifying Individuals at Risk
 Personal and Family History
 The most important and cost-effective tool in risk assessment
 Risk Factors for BRCA1 and BRCA2
 Amsterdam Criteria or Bethesda
Criteria for HNPCC
 Gail Model for Breast Cancer Risk

When might genetic testing be considered?
 Personal or family hx of pre-menopausal breast cancer AND ovarian cancer (any age)
 1 st -degree relative with BRCA1 or 2 mutation
 Family hx of > 2 cases of pre-menopausal breast cancer
 Family hx of > 2 cases of ovarian cancer

Genetic Testing (con’t)
 Personal or family hx of bilateral breast cancer
 Family hx of male breast cancer
 Ashkenazi Jewish ancestry in the setting of a personal or family hx of breast or ovarian cancer

Clinical Management
 Now that you’ve got it, what do you do with it?!
 Genetic counseling/testing
 Screening
 Prophylactic measures/chemoprevention
 Consider clinical trials

Possible Outcomes of Genetic
Testing
 Definitive
 True positive: Deleterious mutation identified
 True negative: No mutation, individual from family with a known mutation
 Uninformative
 No mutation in individual after full gene sequencing, no mutation in family
 Mutation of uncertain significance

Risk-Reducing Measures
 Prophylactic oophorectomy following completion of child-bearing
 Chemoprophylaxis in young patients
 Interruption of ovulatory cycles

Oral Contraceptives
 OC use for > 5 years reduces risk of ovarian cancer by 60% in the general population
 Protective effect increases with increasing duration of use
 Protection continues for 10 years following discontinuation

Clinical Trials for Women at
High Risk for Ovarian Cancer
 GOG 199
 Prospective study of RRSO and longitudinal CA-125
 GOG 8199
 Extended follow-up of GOG 199 participants
 GOG 214
 Double-blind randomized trial of levonorgestrel vs. placebo prior to RRSO

Clinical Management of Women with HNPCC: Screening
 Annual ultrasound or endometrial biopsy beginning at age 25-35
 Hysterectomy and BSO when childbearing complete
 Reduces risk of endometrial cancer
 Reduces risk of ovarian cancer

Summary
 Identifying women at risk for BRCA and HNPCC mutations can often be done in the primary care setting.
 Referral is often appropriate.
 Genetic counseling
 Clinical trials
 Long-term follow-up
 Screening and/or prophylaxis can be life saving.

Acknowledgments
 Melissa Ade
 In The Family, a film by Joanna
Rudnick
 Screening privileges/copyright privileges obtained from Kartemquin Films, Chicago
 www.inthefamilyfilm.com