Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Ontario Cancer Genetics Network

doi:10.1158/0008-5472.CAN-10-1907

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Ontario Cancer Genetics Network

Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [email protected]

Research output: Contribution to journal › Article › peer-review

160 Citations (Scopus)

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Original language	English
Pages (from-to)	9742-54
Number of pages	13
Journal	Cancer Research
Volume	70
Issue number	23
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-1907
Publication status	Published - 1 Dec 2010

Keywords

Adult
Aged
Aged, 80 and over
Alleles
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Female
Genetic Predisposition to Disease/genetics
Genotype
Heterozygote
High Mobility Group Proteins
Humans
Middle Aged
Mutation
Polymorphism, Single Nucleotide
Receptors, Progesterone/genetics
Risk Assessment
Risk Factors
Sodium-Bicarbonate Symporters/genetics
Survival Analysis
Vesicular Transport Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-10-1907

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@article{6deea11b4159455bbd702b5006619ffd,

title = "Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction",

abstract = "The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.",

keywords = "Adult, Aged, Aged, 80 and over, Alleles, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Female, Genetic Predisposition to Disease/genetics, Genotype, Heterozygote, High Mobility Group Proteins, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Receptors, Progesterone/genetics, Risk Assessment, Risk Factors, Sodium-Bicarbonate Symporters/genetics, Survival Analysis, Vesicular Transport Proteins/genetics",

author = "{Ontario Cancer Genetics Network} and Antoniou, {Antonis C} and Jonathan Beesley and Lesley McGuffog and Sinilnikova, {Olga M} and Sue Healey and Neuhausen, {Susan L} and Ding, {Yuan Chun} and Rebbeck, {Timothy R} and Weitzel, {Jeffrey N} and Lynch, {Henry T} and Claudine Isaacs and Ganz, {Patricia A} and Gail Tomlinson and Olopade, {Olufunmilayo I} and Couch, {Fergus J} and Xianshu Wang and Lindor, {Noralane M} and Pankratz, {Vernon S} and Paolo Radice and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Monica Barile and Alessandra Viel and Anna Allavena and Valentina Dall'Olio and Paolo Peterlongo and Szabo, {Csilla I} and Michal Zikan and Kathleen Claes and Bruce Poppe and Lenka Foretova and Mai, {Phuong L} and Greene, {Mark H} and Gad Rennert and Flavio Lejbkowicz and Gord Glendon and Hilmi Ozcelik and Andrulis, {Irene L} and Mads Thomassen and Anne-Marie Gerdes and Lone Sunde and Dorthe Cruger and {Birk Jensen}, Uffe and Maria Caligo and Eitan Friedman and Bella Kaufman and Yael Laitman and Shirley Hodgson and Hansen, {Thomas V O}",

year = "2010",

month = dec,

day = "1",

doi = "10.1158/0008-5472.CAN-10-1907",

language = "English",

volume = "70",

pages = "9742--54",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "23",

}

TY - JOUR

T1 - Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers

T2 - implications for risk prediction

AU - Ontario Cancer Genetics Network

AU - Antoniou, Antonis C

AU - Beesley, Jonathan

AU - McGuffog, Lesley

AU - Sinilnikova, Olga M

AU - Healey, Sue

AU - Neuhausen, Susan L

AU - Ding, Yuan Chun

AU - Rebbeck, Timothy R

AU - Weitzel, Jeffrey N

AU - Lynch, Henry T

AU - Isaacs, Claudine

AU - Ganz, Patricia A

AU - Tomlinson, Gail

AU - Olopade, Olufunmilayo I

AU - Couch, Fergus J

AU - Wang, Xianshu

AU - Lindor, Noralane M

AU - Pankratz, Vernon S

AU - Radice, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Barile, Monica

AU - Viel, Alessandra

AU - Allavena, Anna

AU - Dall'Olio, Valentina

AU - Peterlongo, Paolo

AU - Szabo, Csilla I

AU - Zikan, Michal

AU - Claes, Kathleen

AU - Poppe, Bruce

AU - Foretova, Lenka

AU - Mai, Phuong L

AU - Greene, Mark H

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Andrulis, Irene L

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Sunde, Lone

AU - Cruger, Dorthe

AU - Birk Jensen, Uffe

AU - Caligo, Maria

AU - Friedman, Eitan

AU - Kaufman, Bella

AU - Laitman, Yael

AU - Hodgson, Shirley

AU - Hansen, Thomas V O

PY - 2010/12/1

Y1 - 2010/12/1

N2 - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

AB - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genotype

KW - Heterozygote

KW - High Mobility Group Proteins

KW - Humans

KW - Middle Aged

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Receptors, Progesterone/genetics

KW - Risk Assessment

KW - Risk Factors

KW - Sodium-Bicarbonate Symporters/genetics

KW - Survival Analysis

KW - Vesicular Transport Proteins/genetics

U2 - 10.1158/0008-5472.CAN-10-1907

DO - 10.1158/0008-5472.CAN-10-1907

M3 - Article

C2 - 21118973

SN - 0008-5472

VL - 70

SP - 9742

EP - 9754

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Abstract

Keywords

UN SDGs

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