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?

85%

Hereditary - known genes

Hereditary - unknown genes

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

5%

10%

1,055

2,100

17,945

Affected relative(s) (on the same side of the family)

Age of affected relative(s) (years)

Cumulative Breast Cancer Risk by 80

(%)

One first-degree <50 13-21>50 9-11

One second-degree <50 10-14>50 8-9

Two first-degree <50 35-48>50 11-24

Two-second-degree <50 21-26>50 9-16

Estimated effect of family history on lifetime risk of developing breast cancer

Cancer 1994. 73:643-651.

Syndrome Gene Cancer manifestations

Breast-Ovarian cancer BRCA1 BRCA2

Breast (female and male) and ovarian cancers

Site-specific breast cancer

BRCA1 BRCA2

Breast cancer (female and male)

Non-polyposis colorectal cancer

"MMR" Colorectal, endometrial, ovarian cancers

Li-Fraumeni TP53 Sarcoma, leukemia, breast, brain, adrenal cancers

Cowden Disease PTEN Breast and thyroid cancers

Cancer Syndromes Featuring Breast/Ovarian Cancer

Seminars in Surgical Oncology 2000. 18:281-286

Gene All casesInherited

casesRisk to age 70

All casesInherited

casesRisk to age 70

NONE 85% - 9.50% 85% - 1.2%

BRCA1 5-10% 35% 50-80% 3-5% 75% 20-50%

BRCA2 5-10% 40% 50-80% 3-5% 10% 10-30%

MMR: MLH1, MSH2, MSH6, PMS1, PMS2

<1% <5% 10% <2% <10% <10%

TP53 <1% <1% 90% <1% <1% <1%

PTEN <1% <1% 50% <1% <1% <5%

Breast cancer Ovarian Cancer

Risk of Breast/Ovarian Cancer in Mutation Carriers

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

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

Male

Female

Affected female

Normal Gene

Mutated Gene

Autosomal Dominant Mode of Inheritance

dx BrCa 57d. 59 mets

dx BrCa36d. 46 mets

dx BrCa 42dx BrCa45d. 49 mets

70 80

32 4235 dx OvCa 52d. 53

39dx BrCa 39

Breast and Ovarian Cancer Risk:Hereditary

BrCa OvCaBy age 50 15-30% <2 %By age 70 28-87% 16-60%

BRCAMutationCarrier

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk:Population

BrCa OvCaBy age 50 2% <1%By age 70 10% <2%

Breast and Ovarian Cancer Risk: Hereditary

Risk of second BrCa in 5 yrs after initial dx: 10-20%

Lifetime risk (by age 70 yrs) of OvCa: 16%

dx BrCa 55

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk: Population

Risk of second BrCa in 5 yrs after initial dx: 5%

Lifetime risk (by age 70 yrs) of OvCa: <2%

BRCAMutationCarrier

74

Family X

57

BRCA Positive Family

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

Syndrome Gene Cancer manifestations

Breast-Ovarian cancer BRCA1 BRCA2

Breast (female and male) and ovarian cancers

Site-specific breast cancer

BRCA1 BRCA2

Breast cancer (female and male)

Non-polyposis colorectal cancer

"MMR" Colorectal, endometrial, ovarian cancers

Li-Fraumeni TP53 Sarcoma, leukemia, breast, brain, adrenal cancers

Cowden Disease PTEN Breast and thyroid cancers

Cancer Syndromes Featuring Breast/Ovarian Cancer

Breast cancer families that feature an ovarian cancer case

most likely harbor BRCA1 mutations

Male

Female

Affected female

Br 48

Br 32

Ov 55Br 36 Br 42Ov 49Br 52

+ + + +

+

+ + + ++

+

+ Carriers of a BRCA1 Mutation

BRCA1 Mutation Positive Family

Breast cancer families that feature no ovarian cancer cases

and/or a male breast cancer case most likely harbor a BRCA2 mutation

Male

Female

Affected female

Br 42

Br 27Br 37 Br 45

+

+ Carrier of a BRCA2 Mutation

BRCA2 Mutation Positive Family

Br 37

Br 34Br 46

Br 34

8

Male

Female

Affected female

Br 39

Br 58Br 40

+

+ Carrier of a BRCA2 Mutation

BRCA2 Mutation Positive Family

Br 45

Br 30

2

+

+2 2

Affected Male

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

• 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

• 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

dx BrCa 57d. 59 mets

dx BrCa36d. 46 mets

dx BrCa 42dx BrCa45d. 49 mets

70 80

32 4235 dx OvCa 52d. 53

39dx BrCa 39

Breast and Ovarian Cancer Risk:Hereditary

BrCa OvCaBy age 50 15-30% <2 %By age 70 28-87% 16-60%

BRCAMutationCarrier

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk:Population

BrCa OvCaBy age 50 2% <1%By age 70 10% <2%

Breast and Ovarian Cancer Risk: Hereditary

Risk of second BrCa in 5 yrs after initial dx: 10-20%

Lifetime risk (by age 70 yrs) of OvCa: 16%

dx BrCa 55

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk: Population

Risk of second BrCa in 5 yrs after initial dx: 5%

Lifetime risk (by age 70 yrs) of OvCa: <2%

BRCAMutationCarrier

74

Family X

57

BRCA Positive Family

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

dx BrCa 57d. 59 mets

dx BrCa36d. 46 mets

dx BrCa 42dx BrCa45d. 49 mets

70 80

32 4235 dx OvCa 52d. 53

39dx BrCa 39

Breast and Ovarian Cancer Risk:Hereditary

BrCa OvCaBy age 50 15-30% <2 %By age 70 28-87% 16-60%

BRCAMutationCarrier

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk:Population

BrCa OvCaBy age 50 2% <1%By age 70 10% <2%

Breast and Ovarian Cancer Risk: Hereditary

Risk of second BrCa in 5 yrs after initial dx: 10-20%

Lifetime risk (by age 70 yrs) of OvCa: 16%

dx BrCa 55

Not a BRCAMutationCarrier

Breast and Ovarian Cancer Risk: Population

Risk of second BrCa in 5 yrs after initial dx: 5%

Lifetime risk (by age 70 yrs) of OvCa: <2%

BRCAMutationCarrier

74

Family X

57

BRCA Positive Family

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

No BRCA Mutation Found

35-48% 35-48%

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

BRCA analysis facilitated by common mutations found at high

frequency in well defined populations

BRCA2 Any Total 185delAG 5382inC 6174delT (%)

Breast cancer 138 28 7 5 40 (29%)

Breast-ovarian 82 43 13 4 60 (73%)

Any 220 71 20 9 100 (45%)

BRCA1

Frequency of recurrent BRCA mutations in Ashkenazi Jewish families with at least 3 cases of breast (dx<65)

and/or ovarian cancer

Nat Med 2:1179-1183, 1996

4446C>T 17 8765delAG 11

2953del3+C 4 6085G>T 4

3768insA 2 2816insA 2

2598C>A 1 6503delTT 1

BRCA1 BRCA2

BRCA Mutations in 97 French Canadian Breast/ovarian Cancer families

Am J Hum Genet 63: 1341-1351, 1998

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)

Are there guidelines for BRCA mutation analysis?

Table 2: National Comprehensive Cancer Network criteria for diagnosis of hereditary breast and/or ovarian cancer syndromesimplicating BRCA1 or BRCA2

Situation Description of personal or family history of cancer*

1Member of known BRCA1 or BRCA2kindred

   

a Diagnosed at or under age 40, with or without a family history

bDiagnosed at or under age 50 or bilateral breast cancer, with one or more closerelatives with breast cancer or one or more close relatives with ovarian cancer

cDiagnosed at any age, with two or more close relatives with ovarian cancer at anyage, or breast cancer diagnosis under age 50 or has bilateral disease

2 Personal history of breast cancer

d Is of Ashkenazi Jewish descent and diagnosed at or under age 50, or at any agewith close relatives with breast and/or ovarian cancer

a One or more relatives with ovarian cancer

b One or more close female relatives with breast cancer diagnosed at or under age50 or with bilateral disease.

c Two or more close relatives with breast cancer

d One or more close male relatives with breast cancer

3 Personal history of ovarian cancer

e Is of Ashenazi Jewish descent, no additional family history is required

a One or more close male relatives with breast cancert4 Male breast cancer

b One or more close female relatives with breast and/or ovarian cancer

a One or more close relatives with breast cancer diagnosed at or underage 40 withbilateral breast cancer

b Two or more close relatives with ovarian cancer

c Two or more close relatives with breast cancer, especially of one or more isdiagnosed at or under age 50

d One or more close relatives with breast cancer and one or more close relativeswith ovarian cancer

5 Family history only

eIs of Ashkenazi Jewish descent, one close relative with breast or ovarian cancer

*Close relations refer to first-degree relatives (mother, sister); second-degree relatives (aunt, grandmother, niece) and third-degree relatives (cousins, grandparental) when accounted in toto and are all paternally or maternally related.

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