the genetics of breast and ovarian cancer susceptibility patricia tonin, phd associate professor...
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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
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