Volume 9 Supplement 2

Annual Conference on Hereditary Cancers 2009

Open Access

Identification of new genes associated with breast and ovarian cancer risk. Advances of BCAC, CIMBA and OCAC

  • A Jakubowska1,
  • J Gronwald1,
  • K Jaworska1 and
  • K Durda1
Hereditary Cancer in Clinical Practice20119(Suppl 2):A1

https://doi.org/10.1186/1897-4287-9-S2-A1

Published: 1 June 2011

Breast and ovarian cancers belong to the most common malignancies diagnosed in women. The major inherited susceptibilities to breast and ovarian cancers are germline mutations in either BRCA1 or BRCA2 which however, explain only small number of breast and ovarian cancer cases. Data suggest that majority breast and ovarian cancers are caused by low or moderate penetrance gene mutations. Identification of such mutations provides cancer risk assessment and will help in prophylactic, early diagnosis and treatment.

In 2005 three international multidisciplinary consortia have been initiated: Breast Cancer Association Consortium (BCAC), Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and Ovarian Cancer Association Consortium (OCAC) which are forums of investigators from centers over the world, including International Hereditary Cancer Center in Szczecin. The aim of these consortia’s is to combine data from many studies, to provide a reliable assessment of the breast and ovarian cancer risks associated with different genetic and environmental factors, and to identify potential modifiers of cancer risk in carriers of BRCA1 and BRCA2 mutation.

BCAC includes 54 centers (table 1) over the world and focuses on identification of genes associated with breast cancer risk.
Table 1

Centers collaborating in BCAC

Name

Acronym

Country

Australian Breast Cancer Family Study

ABCFS

Australia

Amsterdam Breast Cancer Study

ABCS

Netherlands

Australian Breast Cancer Tissue Bank

ABCTB

Australia

Asia Cancer Program

ACP

Thailand

Bavarian Breast Cancer Cases and Controls

BBCC

Germany

British Breast Cancer Study

BBCS

UK

Breast Cancer In Galway Genetic Study

BIGGS

Ireland

Breast Cancer Study of the University Clinic Heidelberg

BSUCH

Germany

CECILE Breast Cancer Study

CECILE

France

Copenhagen General Population Study

CGPS

Denmark

Spanish National Cancer Centre Breast Cancer Study

CNIO-BCS

Spain

California Teachers Study

CTS

USA

ESTHER Breast Cancer Study

ESTHER

Germany

ICR Familial Breast Cancer Study

FBCS

UK

German Consortium for Hereditary Breast & Ovarian Cancer

GC-HBOC (GFBCS)

Germany

Gene Environment Interaction and Breast Cancer in Germany

GENICA

Germany

Genetic Epidemiology Study of Breast Cancer by Age 50

GESBC

Germany

Hannover Breast Cancer Study

HABCS (HBCS)

Germany

Helsinki Breast Cancer Study

HEBCS

Finland

Hannover-Minsk Breast Cancer Study

HMBCS

Belarus

Hannover-Ufa Breast Cancer Study

HUBCS

Russia

Karolinska Breast Cancer Study

KARBAC

Sweden

Kuopio Breast Cancer Project

KBCP

Finland

kConFab/AOCS

kConFab/AOCS

Australia

Leuven Multidisciplinary Breast Centre

LMBC

Belgium

Mammary Carcinoma Risk Factor Investigation

MARIE

Germany

Milan Breast Cancer Study Group

MBCSG

Italy

Mayo Clinic Breast Cancer Study

MCBCS

USA

Melbourne Collaborative Cohort Study

MCCS

Australia

Multi-ethnic Cohort

MEC

USA

Memorial Sloan-Kettering Cancer Center

MSKCC

USA

Mexican Case Control Study of Breast Cancer

MXCCS

Mexico

Malaysian Breast Cancer Genetic Study

MYBRCA

Malaysia

Norwegian Breast Cancer Study

NBCS

Norway

Northern California Breast Cancer Family Registry

NC-BCFR

USA

Nurses Health Study

NHS

USA

Nigerian Breast Cancer Study

NGBCS

Nigeria

Oulu Breast Cancer Study

OBCS

Finland

Ontario Familial Breast Cancer Registry

OFBCR

Canada

Leiden University Medical Centre Breast Cancer Study

ORIGO (LUMCBCS)

Netherlands

NCI Polish Breast Cancer Study

PBCS

Poland

Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer

POSH

UK

Rotterdam Breast Cancer Study

RBCS

Netherlands

Singapore and Sweden Breast Cancer Study

SASBAC

Sweden

Sheffield Breast Cancer Study

SBCS

UK

Study of Epidemiology and Risk factors in Cancer Heredity

SEARCH

UK

Seoul Breast Cancer Study

SEBCS (SBCP)

Korea

IHCC-Szczecin Breast Cancer Study

SZBCS

Poland

IARC-Thai Breast Cancer Study

TBCS

Thailand

Taiwanese Breast Cancer Study

TWBCS

Taiwan

UCI Breast Cancer Study

UCIBCS

USA

UK Breakthrough Generations Study

UKBGS

UK

US Three State Study

US3SS

USA

US Radiologic Technologists Study

USRTS

USA

Currently, BCAC database includs demographic, clinical and epidemiological data from 73,000 breast cancer patients and 80,000 unaffected women. Up to now, 125 genetic alterations (SNPs) localized in different genes have been examined. These SNPs have been selected based on its positive association with breast cancer risk detected in preliminary analyses or Genome-Wide Association Study (GWAS). Results have been presented in 12 manuscripts published in high impact journals, e.g. J Natl Cancer Inst, Nature and Nat Genet (http://www.srl.cam.ac.uk/consortia/bcac/pubs/pubs.html).

Ten SNPs have been found to be associated with breast cancer risk overall or by clinical and pathological characteristics (table 2).
Table 2

BCAC SNPs associated with breast cancer risk overall or by clinical and pathological characteristics

Gene / SNP

Breast cancer risk

BCAC manuscript

CASP8 D302H

CG v. GG: OR 0.89, 95% CI 0.85-0.94

CC v. GT: OR 0.74, 95% CI 0.62-0.87

Cox et al., Nat Genet 2007

FGFR2, rs2981582

TNRC9, rs3803662

MAP3K1, rs889312

LSP, rs3817198

8q24, rs13281615

ORhom 1.63, 95% CI 1.53-1.72, p=4.1 × 10-76

ORhom 1.39, 95% CI 1.25-1.45, p=1.4 × 10-36

ORhom 1.27, 95% CI 1.19-1.36, p=4.1 × 10-20

ORhom 1.17, 95% CI 1.08-1.25, p=4.1 × 10-9

ORhom 1.18, 95% CI 1.10-1.25, p=4.1 × 10-12

Easton et al., Nat Genet 2007

FGFR2, 2981582

8q24, 13281615

TNRC9, rs3803662

ER positive:p=10-13

PGR positive: p=10-5

low grade: p=10-8

metastases: p=0.013

ER positive: p=0.001

PGR positive: p=0.011

low grade: p=10-4

ER negative: OR 1.14, 95% CI 1.09-1.21

Garcia-Closas et al., PLoS Genet 2008

AKAP9 M463I

TT v. GG:

OR 1.17, 95% CI 1.08-1.27, p=0.0003

familial cases: OR 1.27, 95% CI 1.12-1.45, p=0.0003

TT v. GT:

OR 1.10, 95% CI 1.04-1.17, p=0.001

familial cases: OR 1.16, 95% CI 1.06-1.27, p=0.001

Frank et al., JNCI 2008

3p24, rs4973768

17q23, rs6504950

ORper-allele 1.11, 95% CI 1.08-1.13, p=4.1 × 10-23

ORper-allele 0.95, 95% CI 0.92-0.97, p=1.4 × 10-8

Ahmed et al., Nat Genet 2009

2q35, rs13387042

OR per-allele 1.12, 95% CI 1.09 -1.15; ptrend 1.0 × 10-19 (European Caucasian)

ER positive: OR 1.14, 95% CI 1.10-1.17; p=10-15

ER negative: OR 1.10, 95% CI 1.04-1.15; p=0.0003

PGR positive: OR 1.15, 95% CI 1.11-1.19; p=5 × 10-14

PGR negative: OR 1.10, 95% CI 1.06-1.15; p=0.00002

Milane et al., JNCI 2009

CIMBA database contains demographic, clinical and epidemiological data from 15,700 BRCA1 and 8,600 BRCA2, mutation carriers including 12,700 breast cancer patients, 2,500 ovarian cancer patients and 9,100 unaffected patients from 42 centers over the world (table 3).
Table 3

Centers collaborating in CIMBA

Study

Acronym

Country

Breast Cancer Family Registry

BCFR

USA/Australia

Baltic Familial Breast Ovarian Cancer Consortium

BFBOCC

Latvia/Lithuania

BRCA-gene mutations and breast cancer in South African women

BMBSA

South Africa

Rigshospitalet

CBCS

Denmark

Spanish National Cancer Centre

CNIO

Spain

CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella

CONSIT TEAM

Italy

German Cancer Research Center

DKFZ

Germany

Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland

DNA HEBON

Netherlands

Epidemiological Study of Familial Breast Cancer

EMBRACE

UK

Fox Chase Cancer Center

FCCC

USA

German Familial Breast Group

GC-HBOC

Germany

Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers

GEMO

France/Greece/USA

Georgetown University

GEORGETOWN

USA

Gynecologic Oncology Group

GOG

USA

Hospital Clinico San Carlos

HCSC

Spain

Helsinki Breast Cancer Study

HEBCS

Finland

Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia

HRBCP

Hong Kong

Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary

HUNBOCS

Hungary

Institut Català d'Oncologia

ICO

Spain

International Hereditary Cancer Centre

IHCC

Poland

Iceland Landspitali - University Hospital

ILUH

Iceland

INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility

INHERIT

Canada

Istituto Oncologico Veneto

IOVHBOCS

Italy

Kathleen Cuningham Consortium for Research into Familial Breast Cancer

KCONFAB

Australia/New Zealand

Korean Hereditary Breast Cancer Study

KOHBRA

Korea

Modifiers and Genetics in Cancer

MAGIC

USA

Mayo Clinic

MAYO

USA

Modifier Study of Quantitative Effects on Disease

MOD SQUAD

USA

Memorial Sloane Kettering Cancer Center

MSKCC

USA

General Hospital Vienna

MUV

Austria

National Cancer Institute

NCI

USA

National Israeli Cancer Control Center

NICCC

Israel

N.N. Petrov Institute of Oncology

NNPIO

Russia

Ontario Cancer Genetics Network

OCGN

Canada

The Ohio State University Comprehensive Cancer Center

OSU CCG

USA

Odense University Hospital

OUH

Denmark

Università di Pisa

PBCS

Italy

South East Asian Breast Cancer Association Study

SEABASS

Malaysia/Singapore

Sheba Medical Centre

SMC

Israel

Swedish Breast Cancer Study

SWE-BRCA

Sweden

University of California Irvine

UCI

USA

University of California San Francisco

UCSF

USA

UK and Gilda Radner Familial Ovarian Cancer Registries

UKGRFOCR

UK/USA

University of Pennsylvania

UPENN

USA

Cedars-Sinai Medical Center

WCRI

USA

Results have been presented in 9 manuscripts published in high impact journals, e.g. Am. J Hum Genet, Hum Mol Genet (http://www.srl.cam.ac.uk/consortia/cimba/pubs/pubs.html).

Six SNPs have been found to be associated with breast cancer risk (table 4).
Table 4

SNPs associated with breast cancer risk in BRCA1/2 carriers

Gene / SNP

Breast cancer risk

CIMBA manuscript

RAD51, rs11683487

BRCA2: HRhom 3.18, 95% CI 1.39-7.27, p=0.0007

Antoniou et al. AJHG 2007

TNRC9, rs3803662

FGFR2, rs2981582

MAP3K1, rs889312

BRCA1/2: HR 1.13, 95% CI: 1.06-1.20, ptrend= 5 × 10-5

BRCA2: HR 1.32, 95% CI: 1.20-1.45, ptrend=1.7 × 10-8

BRCA2: HR 1.12, 95% CI: 1.02-1.24, ptrend=0.02

Antoniou et al. AJHG 2008

2q35, rs13387042

LSP1, rs3817198

2q35, rs13387042

BRCA1: HR 1.14, 95% CI: 1.04-1.25, p=0.0047

BRCA2: HR 1.16, 95% CI: 1.07-1.25, ptrend=2.8 × 10-4

HR 1.18 95% CI: 1.04-1.33, p=0.0079

Antoniou et al. Hum Mol Genet 2008

OCAC includes 24 centers over the world and focuses on identification of genes that may be related to the risk of ovarian cancer (table 5).
Table 5

Centers collaborating in OCAC

Name

Acronym

OCAC Acronym

Country

Australian Ovarian Cancer Study and Australian Cancer Study (Ovarian Cancer)

AOCS/ACS

AUS

Australia

Bavarian Ovarian Cancer Cases and Controls

BOCC

BAV

Germany

Belgian Ovarian Cancer Study

BELOCS

BEL

Belgium

Connecticut Ovary Study

(none)

CON

USA

Diseases of the Ovary and their Evaluation Study

DOVE

DOV

USA

German Ovarian Cancer Study

GOCS

GER

Germany

Hawaii Ovarian Cancer Study

(none)

HAW

USA

Hannover-Jena Ovarian Cancer Study

HJOCS

HJO

Germany

Hannover-Minsk Ovarian Cancer Study

HMOCS

HMO

Germany

Helsinki Ovarian Cancer Study

HOCS

HOC

Finland

Hormones and Ovarian Cancer Prediction

HOPE

HOP

USA

Polish Ovarian Cancer Study

POCS

JAC

Poland

Women's Cancer Research Institute (Cedars-Sinai Medical Center)

WCRI

LAX

USA

The Danish Malignant Ovarian Tumour Study

MALOVA

MAL

Denmark

Mayo Clinic Ovarian Cancer Case Control Study

(none)

MAY

USA

Melbourne Collaborative Cohort Study

MCCS

MCC

Australia

Memorial Sloan Kettering Cancer Center Gynecology Tissue Bank

MSKGTB

MSK

USA

North Carolina Ovarian Cancer Study

NCOCS

NCO

USA

New England-based Case-Control Study of Ovarian Cancer

NECC

NEC

USA

Nurses Health Study

NHS

NHS

USA

New Jersey Ovarian Cancer Study

NJOCS

NJO

USA

Nijmegen Polygene Study & Nijmegen Biomedical Study

POLYGENE

NTH

Netherlands

Prognostic Factors in Epithelial Ovarian Cancer

EOC

NTX

Netherlands

Ovarian Cancer in Alberta and British Columbia Study

OVAL-BC

OVA

Canada

NCI Ovarian Case-Control Study in Poland

NCI-OCS

POL

Poland

Roswell Park Cancer Institute Cases

RPCI

RPX

USA

UK SEARCH Ovarian Cancer Study

SEARCH

SEA

UK

Southampton Ovarian Cancer Study

(none)

SOC

UK

Genetic Epidemiology of Ovarian Cancer

GEOCS

STA

USA

Tampa Bay Ovarian Cancer Study

TBOCS

TBO

USA

Familial Ovarian Tumour Study

FOTS

TOR

Canada

UC Irvine Ovarian Cancer Study

(none)

UCI

USA

UK Ovarian Cancer Population Study

UKOPS

UKO

UK

Los Angeles County Case-Control Studies of Ovarian Cancer

LAC-CCOC

USC

USA

Currently, OCAC database includs demographic, clinical and epidemiological data from 22,000 ovarian cancer patients and 18,000 unaffected women. Several genetic alterations (SNPs) localized in different genes have been examined. Results have been presented in 13 manuscripts published in high impact journals, e.g. Nat Genet, Cancer Res, In J Cancer (http://www.srl.cam.ac.uk/consortia/ocac/pubs/pubs.html).

Seven SNPs have been found to be associated with ovarian cancer risk overall or by clinical and pathological characteristics (table 6).
Table 6

SNPs associated with ovarian cancer risk

Gene / SNP

Ovarian cancer risk

OCAC manuscript

CDKN2A, rs3731257

CDKN1B, rs2066827

OR 0.91, 95% CI 0.85-0.98, p=0.008

OR 0.93, 95% CI 0.87-0.995, p=0.036

Gayther et al., Cancer Res 2007

TP53, 23 SNPs:

rs2287498

rs12951053

ORper-allele 1.30, 95% CI 1.07-1.57

ORper-allele 1.19, 95% CI 1.01-1.38

Schildkraut et al., Cancer Res 2009

NMI, rs11683487

OR 0.89, 95% CI 0.80-0.99, p=0.032

Quaye et al., BJC 2009

CYP3A4, rs2740574

ORhom 2.81, 95% CI 1.20-6.56, p=0.017

Pearce et al., BJC 2009

9p22.2, rs3814113

OR 0.82, 95% CI 0.79-0.86, p=5.1×10-19

serous tumors: OR 0.77, 95% CI 0.73-0.81, p=4.1×10-21

Song et al., Nat Genet 2009

Declarations

Acknowledgements

Katarzyna Jaworska was supported by Postgraduate School of Molecular Medicine (SMM).

Authors’ Affiliations

(1)
International Hereditary Cancer Center, Pomeranian Medical University

Copyright

© Jakubowska et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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