Distinct inherited metastasis susceptibility exists for different breast cancer subtypes: a prognosis study
Distinct inherited metastasis susceptibility exists for different breast cancer subtypes: a prognosis study
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DOI：
10.1186/bcr2412
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发表时间：
2009-01-01
影响因子：
7.4
通讯作者：
Hunter, Kent W.
中科院分区：
文献类型：
--
作者：
Hsieh, Szu-Min;Look, Maxime P.;Hunter, Kent W.
介绍先前在小鼠模型和试点流行病学研究中的研究表明，遗传多态性与遗传性肿瘤进展风险和人类乳腺癌预后不良相关。为了扩展这些研究，并获得更好地了解遗传多态性在乳腺癌进展的功能，验证预后研究进行了一个大的独立的乳腺癌患者population.Methods研究人群包括1863荷兰原发性乳腺癌患者从鹿特丹，荷兰。采用SNP特异性PCR方法检测RRP 1B错义Pro436 Leu单核苷酸多态性（SNP）rs 9306160和内含子SIPA 1 SNP rs 2448490。结果RRP 1B基因多态性与无转移生存率显著相关（P = 0.012），验证了RRP 1B与遗传转移易感性的关系。患者分层显示，与患者生存的相关性被发现特别限于雌激素受体阳性，淋巴结阴性（ER+/LN-）患者（P = 0.011）。仅在ER+/LN-患者中与无转移生存的特异性相关性在SIPA 1中得到复制，SIPA 1是已知与RRP 1B物理相互作用的第二个转移易感基因（P = 0.006）。结论SIPA 1和RRP 1B基因分型可作为肿瘤转移的易感基因，并可作为其他临床和分子预后指标的补充。研究结果还表明，淋巴和造血转移是不同的基因，可能涉及不同的机制。如果是真的，这些结果表明转移性疾病，如原发性乳腺癌，可能是多种疾病，因此可能需要对晚期患者进行分层，以充分了解乳腺癌的进展和转移。
Introduction Previous studies in mouse models and pilot epidemiology studies have demonstrated that inherited polymorphisms are associated with inherited risk of tumor progression and poor outcome in human breast cancer. To extend these studies and gain better understanding of the function of inherited polymorphism in breast cancer progression, a validation prognosis study was performed in a large independent breast cancer patient population.Methods The study population consisted of 1863 Dutch patients with operable primary breast cancer from Rotterdam, The Netherlands. Genomic DNA was genotyped for the missense Pro436Leu RRP1B single nucleotide polymorphism (SNP) rs9306160 and the intronic SIPA1 SNP rs2448490 by SNP-specific PCR.Results A significant association of variants in RRP1B with metastasis-free survival was observed (P = 0.012), validating the role of RRP1B with inherited metastatic susceptibility. Stratification of patients revealed that association with patients' survival was found to be specifically restricted to estrogen receptor positive, lymph node-negative (ER+/LN-) patients (P = 0.011). The specific association with metastasis-free survival only in ER+/LN- patients was replicated for SIPA1, a second metastasis susceptibility gene known to physically interact with RRP1B (P = 0.006). Combining the genotypes of these two genes resulted in the significant ability to discriminate patients with poor metastasis-free survival (HR: 0.40, 95% CI: 0.24 to 0.68, P = 0.001).Conclusions These results validate SIPA1 and RRP1B as metastasis susceptibility genes and suggest that genotyping assays may be a useful supplement to other clinical and molecular indicators of prognosis. The results also suggest that lymphatic and hematogeneous metastases are genetically distinct that may involve different mechanisms. If true, these results suggest that metastatic disease, like primary breast cancer, may be multiple diseases and that stratification of late stage patients may therefore be required to fully understand breast cancer progression and metastasis.