Elsevier

The Lancet Oncology

Volume 12, Issue 5, May 2011, Pages 477-488
The Lancet Oncology

Fast track — Articles
Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence

https://doi.org/10.1016/S1470-2045(11)70076-6Get rights and content

Summary

Background

More than 1000 reports have been published in the past two decades on associations between variants in candidate genes and risk of breast cancer. Results have been generally inconsistent. We did a literature search and meta-analyses to provide a synopsis of the current understanding of the genetic architecture of breast-cancer risk.

Methods

A systematic literature search for candidate-gene association studies of breast-cancer risk was done in two stages, using PubMed on or before Feb 28, 2010. A total of 24 500 publications were identified, of which 1059 were deemed eligible for inclusion. Meta-analyses were done for 279 genetic variants in 128 candidate genes or chromosomal loci that had at least three data sources. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast-cancer risk.

Findings

51 variants in 40 genes showed significant associations with breast-cancer risk. Cumulative epidemiological evidence of an association was graded as strong for ten variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 variants. Additionally, in meta-analyses that included a minimum of 10 000 cases and 10 000 controls, convincing evidence of no association with breast-cancer risk was identified for 45 variants in 37 genes.

Interpretation

Whereas most genetic variants assessed in previous candidate-gene studies showed no association with breast-cancer risk in meta-analyses, 14 variants in nine genes had moderate to strong evidence for an association. Further evaluation of these variants is warranted.

Funding

US National Cancer Institute.

Introduction

Breast cancer is a multifactorial disease caused by complex inherited and environmental factors.1 So far, genetic studies have identified and confirmed four rare high-penetrance genes (BRCA1, BRCA2, TP53, and PTEN), four rare moderate-penetrance genes (CHEK2, ATM, BRIP1, and PALB2), and around 20 common low-penetrance variants in 19 genes or loci that contribute to a woman's risk of breast cancer (Table 1, Table 2).2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Common genetic risk variants have mainly been identified by genome-wide association studies (GWAS). Although the list in the Table 1, Table 2 represents the culmination of our current understanding of the genetic architecture of breast cancer, these genes and loci are estimated to account for only 28% of the inherited causes of the disease.11

Despite the prominence and growing body of results from GWAS, candidate-gene association studies remain the most prevalent type of investigation to identify common breast-cancer susceptibility alleles. More than 1000 candidate-gene breast-cancer association studies have been published in the past two decades, which have evaluated more than 7000 genetic variants (webappendix p 1). Although some of these variants could have true associations with breast-cancer risk, many false-positive associations are identified that do not replicate in additional study populations. Determining if associations are real has generally been done by examining all the epidemiological evidence in conjunction with biological plausibility, in the form of a meta-analysis. Previous meta-analyses mainly focused on one variant, or variants within one gene; however, recent meta-analyses have begun to increase in size and scope.13, 14 Guidelines for the assessment of cumulative evidence for genetic associations, which have become known as the Venice criteria, have been set forth by the Human Genome Epidemiology Network Working Group.15, 16

This study was undertaken in view of the plethora of candidate-gene association studies, the necessity for replication across studies to identify markers truly associated with disease risk,17, 18, 19 and the criteria provided to evaluate genetic associations with disease. We attempted to evaluate all candidate-gene association studies of breast cancer, perform meta-analyses for variants with sufficient data available, and provide a synopsis of our current understanding of the genetic architecture of breast-cancer risk.

Section snippets

Methods

All methods were based on guidelines proposed by the Human Genome Epidemiology Network for systematic review of genetic-association studies and follow PRISMA guidelines.15, 16, 20, 21

Results

A total of 1059 publications including 521 genes or chromosomal loci and 2790 variants were eligible to be included in our analysis (figure). Most of these reports (n=961, 91%) were published since 2000, with the highest number published in 2008 (n=154; webappendix p 1). The mean number of variants analysed per publication was consistently less than five until 2005, and then increased to a maximum of 15·6 in 2008. The median sample size of cases included in the 1059 publications was 461 (range

Discussion

This study is, to the best of our knowledge, the largest and most comprehensive assessment of literature on the genetic architecture of breast-cancer susceptibility done so far. Using methods based on the guidelines for systematic reviews of genetic-association studies, proposed by the Human Genome Epidemiology Network,15, 16, 20, 21 we did a comprehensive research synopsis and meta-analysis of genetic variants and breast-cancer risk. Significant associations with breast-cancer risk were found

References (51)

  • SN Stacey et al.

    Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer

    Nat Genet

    (2008)
  • B Gold et al.

    Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33

    Proc Natl Acad Sci USA

    (2008)
  • W Zheng et al.

    Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1

    Nat Genet

    (2009)
  • S Ahmed et al.

    Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

    Nat Genet

    (2009)
  • G Thomas et al.

    A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

    Nat Genet

    (2009)
  • C Turnbull et al.

    Genome-wide association study identifies five new breast cancer susceptibility loci

    Nat Genet

    (2010)
  • AC Antoniou et al.

    A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    Nat Genet

    (2010)
  • L Bertram et al.

    Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database

    Nat Genet

    (2007)
  • NC Allen et al.

    Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

    Nat Genet

    (2008)
  • JP Ioannidis et al.

    Assessment of cumulative evidence on genetic associations: interim guidelines

    Int J Epidemiol

    (2008)
  • MJ Khoury et al.

    Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases

    Am J Epidemiol

    (2009)
  • SJ Chanock et al.

    Replicating genotype-phenotype associations

    Nature

    (2007)
  • KE Lohmueller et al.

    Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease

    Nat Genet

    (2003)
  • JP Ioannidis et al.

    Replication validity of genetic association studies

    Nat Genet

    (2001)
  • GS Sagoo et al.

    Systematic reviews of genetic association studies. Human Genome Epidemiology Network

    PLoS Med

    (2009)
  • Cited by (0)

    View full text