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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.

Germline polymorphisms in SIPA1are associated with metastasis and other indicators of poor prognosis in breast cancer