Crawford Nigel P S, Ziogas Argyrios, Peel David J, Hess James, Anton-Culver Hoda, Hunter Kent W
Laboratory of Population Genetics, National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA.
Breast Cancer Res. 2006;8(2):R16. doi: 10.1186/bcr1389. Epub 2006 Mar 21.
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.
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.
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).
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.
越来越多的证据表明，可遗传的基因变异会调节转移效率。我们之前使用小鼠乳腺肿瘤模型的研究表明，转移效率受Sipa1（“信号诱导增殖相关基因1”）编码的GTP酶激活蛋白调节。本研究的目的是确定人类SIPA1基因内的单核苷酸多态性（SNP）是否与乳腺癌的转移及其他疾病特征相关。
研究人群（n = 300）由从一个更大的基于人群的系列中随机选择的非西班牙裔白人乳腺癌患者组成。基因组DNA从外周血白细胞中提取。使用SNP特异性PCR对SIPA1内先前描述的三个SNP（一个在启动子区域[-313G>A]，两个在外显子区域[545C>T和2760G>A]）进行特征分析。
变异体2760G>A和-313G>A等位基因与淋巴结受累相关（分别为P = 0.0062和P = 0.0083），变异体545C>T与雌激素受体阴性肿瘤（P = 0.0012）和孕激素受体阴性肿瘤（P = 0.0339）相关。确定了由这三个SNP定义的单倍型与疾病进展之间的关联。由变异体-313G>A和2760G>A定义的单倍型3与阳性淋巴结受累相关（P = 0.0051），由变异体545C>T定义的单倍型4与雌激素受体和孕激素受体阴性状态相关（分别为P = 0.0053和P = 0.0199）。
我们的研究结果表明，在所研究的队列中，SIPA1种系多态性与侵袭性疾病行为相关。如果这些结果在其他人群中也成立，那么SIPA1 SNP基因型的知识可能会潜在地改进当前的分期方案。
