IPGIPGIPGIPG

Karin Dahan

Hérédité et

cancer du sein

d.43y dx.

58y

dx.

35y

IPGIPGIPGIPG

Considerations in risk assessment and in indentifying

a family history of gynecologic cancer risk

High-penetrance gynecologic cancer susceptibility

genes

Low- and Moderate-penetrance genes associated with

gynecologic cancer

Objectives

IPGIPGIPGIPG

http://www.acog.org/-/media/Committee-Opinions/Committee-on-Genetics/co634.pdf?

IPGIPGIPGIPG

Dominant with incomplete penetrance

• May appear to « skip » generations

• Individuals inherit altered cancer susceptibility gene, not cancer

IPGIPGIPGIPG

Pitfall

Small family sizes and premature deaths or adoption may limit the information

Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than seen on the maternal side

A reported family history may be

erroneous, or a person may be unaware of relatives affected with cancer

http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq

IPGIPGIPGIPG

d.43y

dx.32y

1. Family size and premature death

IPGIPGIPGIPG

Early onset

Walsh T et al , JAMA 2006. 295:1379-1388 Antoniou et al, Am J Hum Genet 2003.72(5): 1117–1130

TP53

IPGIPGIPGIPGCopyright ©2003 American Association for Cancer Research

Olivier, M. et al. Cancer Res 2003;63:6643-6650

IPGIPGIPGIPG

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

DelE13_15DelE13_15

d.43y

dx.32y

IPGIPGIPGIPG

2. Accuracy of family

cancer histories

≥3 relatives with BC

2 relatives with BC, one of whom was diagnosed ≤ age 50 yrs

First degree relative with bilateral BC

A history of BC in a male relative

Combination of both breast and ovarian or fallopian tube or primary peritoneal cancer among first and second degree relatives

Combination of 2 relatives with ovarian or fallopian tube or primary peritoneal cancer

2013 NCCN criteria for HBOC

JAMA 292:1480-85, 2004

IPGIPGIPGIPG

Ovarian, fallopian tube and peritoneal carcinoma

Walsh et al, PNAS. 2011;108:18032-18037

N: 85 /360 (24%)

IPGIPGIPGIPG

Cumulative risk of Breast and Ovarian Cancer

Antoniou et al, Am J Hum Genet, 2003, 72(5): 1117–1130

BRCA1 BRCA2

IPGIPGIPGIPG

Lynch syndrome pedigree

Colon dx35y Colon dx57y

Breast dx45y

Ovary dx46y Colon dx81y

Bonadona et al, JAMA. 2011;305(22):2304-2310

IPGIPGIPGIPG

Conclusion: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women. Based on the results reported here, we recommend screening for colorectal cancer for women with a BRCA1 mutation be initiated at an age of 40 years.

IPGIPGIPGIPG

Harkness EF, et al. J Med Genet 2015;52:553–556

IPGIPGIPGIPG

Early onset BC ( ≤ age 35)

Two BC with the first ≤ age 50

High grade serous or papillary epithelial

ovarian/fallopian tube/primary peritoneal

cancer at any age

Both BC and either ovarian cancer,

fallopian tube cancer, or primary

peritoneal cancer

Triple negative breast cancer <age 50

Men with BC at any age

27 may 2015

3. Identification of high-risk individuals

IPGIPGIPGIPG

Triple negative breast cancer

Breast Cancer Res Treat 2013, 137 (1): 119-25 J Clin Oncol 2015,33 (4): 304-11

The prevalence of germline BRCA mutations : 9-35%

In women (241) between ages 50 to 59 with no known family history

18 (7.5%) had detectable mutations in BRCA1/2

The most relevant gene apart BRCA1/2 is PALB2 : 1.2% of patients

Carriers Median age at diagnosis

Triple negative

BRCA1 (3797 patients) 40 yrs 69%

BRCA2 (2392 patients) 43 yrs 16%

Cancer Epidemiol Biomarkers Prev 2012, 21(1):134-47

IPGIPGIPGIPG

High-penetrance gynecologic cancer

susceptibility genes

PTEN

BRCA1

BRCA2 PALB2

CDH1

MLH1

MSH2 MSH6

MUTyH

BRCA1

BRCA1

BRCA2 TP53

STK11

Endometrium

Ovary

Breast

IPGIPGIPGIPG

Bilateral breast cancer

dx 45 and 55 years

Breast cancer

dx 44 years

Multiple hamartomatous polyps

small bowel

stomach

colon

Mucocutaneous hyperpigmentation

IPGIPGIPGIPG

Peutz-Jeghers Syndrome

Incidence 1-9 in 100,000

Polyps in the intestine

Pigmentation (brown or bluish spots)

Lifetime risk of BC : 40 - 50%

Other cancers ; colon, pancreas, stomach,

ovary, small intestine, lung, cervix, testes,

uterus, and esophagus Boardman et al, Ann Intern Med. 1 June 1998;128(11):896-899

IPGIPGIPGIPG

Summary

http://www.acog.org/-/media/Committee-Opinions/Committee-on-Genetics/co634.pdf?

IPGIPGIPGIPG

IPGIPGIPGIPG

Low penetrance cancer susceptibility gene

Prevalence of PALB2 mutations : 0.8% overall in a series of 1479

patients

Increasing to 1.05% in those with a strong family history

Cumulative risk of BC among 154 families

14% by 50 years of age

and 35% by 70 years of age

Breast cancer risks were higher in those with a significant family history

Cancer 2014, 120:963–967 N Engl J Med 2014, 371:497–506

IPGIPGIPGIPG

Depuis le 1/1/2015

IPGIPGIPGIPG

Notre expérience

IPGIPGIPGIPG

Futur

IPGIPGIPGIPG

Lancet Oncol 2011 , 12(5):477-88

Intermediate and low risk

IPGIPGIPGIPG

For many of the genes in categories 1 and 2,

risks of breast/ovarian cancer are not well defined

it is unclear if women who test negative for a mutation that

was found in an affected relative are really at general population

risk

IPGIPGIPGIPG

Summary

Genetic counseling and high penetrance genes

o Well-defined guidelines

o At-risk family members by predictive testing

o Screening and prevention programs

New developments and their challenges

o high-speed sequencing technologies and moderate penetrance genes

o analyses of somatic and germline data

Direct-to-consumer format over the internet