Research article

Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer

Nigel PS Crawford^1* , Argyrios Ziogas^2* , David J Peel² , James Hess², Hoda Anton-Culver² and Kent W Hunter¹

¹  Laboratory of Population Genetics, National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA

²  Epidemiology Division, Department of Medicine, University of California, Irvine, California, USA

author email corresponding author email* Contributed equally

Breast Cancer Research 2006, 8:R16doi:10.1186/bcr1389

Published:	21 March 2006

Abstract

Introduction

There is growing evidence that heritable genetic variation modulates metastatic efficiency. Our previous work using a mouse mammary tumor model has shown that metastatic efficiency is modulated by the GTPase-activating protein encoded by Sipa1 ('signal-induced proliferation-associated gene 1'). The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) within the human SIPA1 gene are associated with metastasis and other disease characteristics in breast cancer.

Method

The study population (n = 300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients identified from a larger population-based series. Genomic DNA was extracted from peripheral leukocytes. Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR.

Results

The variant 2760G>A and the -313G>A allele were associated with lymph node involvement (P = 0.0062 and P = 0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P = 0.0012) and with progesterone negative tumors (P = 0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Haplotype 3 defined by variants -313G>A and 2760G>A was associated with positive lymph node involvement (P = 0.0051), and haplotype 4 defined by variant 545C>T was associated with estrogen receptor and progesterone receptor negative status (P = 0.0053 and P = 0.0199, respectively).

Conclusion

Our findings imply that SIPA1 germline polymorphisms are associated with aggressive disease behavior in the cohort examined. If these results hold true in other populations, then knowledge of SIPA1 SNP genotypes could potentially enhance current staging protocols.