The Influence of Genetic Variation in Thirty Selected Genes on the Clinical Characteristics of Early Onset Breast Cancer

William Tapper; Victoria Hammond; Sue Gerty; Sarah Ennis; Peter Simmonds; Andrew Collins; Diana Eccles

Disclosures

Breast Cancer Res. 2008;10(6) 

In This Article

Abstract and Introduction

Abstract

Introduction: Common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.
Methods: We selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.
Results: We confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.
Conclusions: We have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient groups.

Introduction

Breast cancer arises as a result of multiple somatic molecular events that can be genetic or epigenetic. Further research is required to define the inherited factors that contribute to breast cancer risk. To date, six genes associated with high risk (BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1), four associated with modest risk (PALB2, BRIP1, ATM and CHEK2) and six lower penetrance alleles (CASP8, FGFR2, TOX3, MAP3K1, LSP1 and 8q24 rs13281615) have been identified using various approaches.[1,2,3,4,5] Genetic variability appears to influence not only risk but also the type of breast cancer that develops in an individual. There is compelling data that pathogenic mutations in BRCA1 result in a distinct tumour phenotype, whereas more subtle similarities are seen between BRCA2 cases and among familial non-BRCA1/BRCA2 cancers.[6,7,8,9] In studies of lower penetrance alleles it is clear that most of the increase in breast cancer risk is for oestrogen receptor (ER)-positive breast cancers (which form the majority of most breast cancer cohorts).[10,11,12] There is some evidence that breast cancer prognosis may be influenced by inherited genetic factors. Ethnicity appears to be associated with tumour biology and outcome.[13,14] Recent data from a large Swedish population-based study indicated that the prognosis of mothers with breast cancer influenced the likelihood of survival in their daughters who subsequently developed breast cancer, suggesting an inherited component to prognosis.[15] It is also apparent that inherited genetic factors can influence drug metabolism, and this may affect prognosis after breast cancer diagnosis by influencing the efficacy of treatment.[16,17]

As an example of this it is apparent that ER-modulating drugs reduce the risk for developing ER-positive breast cancer by up to 50%, but they do not alter the incidence of ER-negative breast cancer.[18] If a given genetic risk profile indicates a raised likelihood of developing ER-positive breast cancer specifically, then targeting this group of individuals with tamoxifen or raloxifene treatment as a prevention strategy would give the most benefit.

Early onset breast cancers are more likely to have arisen due to an inherited predisposition and tend to have a worse prognosis, possibly as a result of a different pattern of genomic expression compared with tumours developing in older women.[19] Women with early onset breast cancer are thus an ideal population in which to search for common genetic variants that may influence breast cancer risk and prognosis. The discovery of such genetic markers may allow clinicians to advise patients more accurately about appropriate prevention and screening strategies, tumour prognosis and treatment.

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