Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Erasmus MC, Building BE, Room 400, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Breast Cancer Res Treat. 2012 Jun;133(3):843-51. doi: 10.1007/s10549-011-1663-3. Epub 2011 Jul 12.
To understand the biology of low-risk breast cancer alleles, and to investigate whether these loci also contribute to disease progression that was once established, we examined the association of SNPs tagging the low-risk breast cancer loci in or near FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, MYC, and 2q35, with clinical, pathological characteristics, prognosis, and mRNA expression of the nearest genes. Tumor DNA samples of 2,480 breast cancer patients were available. Out of this cohort, 1,290 patients with lymph-node negative disease who did not receive adjuvant systemic therapy, the SNP status was associated with metastasis-free survival (MFS). In 1,401 patients, the mRNA expression levels of FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, and MYC were determined and correlated with SNP genotypes. The SNP rs2981582 in FGFR2 was significantly associated with positive ER and PgR status (P < 0.001 and P = 0.003, respectively). No other significant associations with patient or tumor characteristics were observed. Only rs2107425 near H19 was significantly associated with shorter MFS in uni- and multi-variate analysis (HR: 1.53, CI: 1.12-2.08, P = 0.006 and HR: 1.59, CI: 1.16-2.20, P = 0.004, respectively), with the more aggressive minor allele displaying a recessive trait. The minor allele of SNP rs3803662 located near the TOX3 gene was associated with lower mRNA expression of this gene. In conclusion, except for the association of rs13283662 with TOX3 gene expression indicating a tumor suppressor role of TOX3, our findings suggest that breast cancer low-risk loci generally do not affect expression of the nearest gene in breast tumor tissue. Also the prognosis of patients is largely not affected by low-risk breast cancer loci except for the SNP near H19. How, this SNP affects prognosis warrants further study as it does not operate through altering H19 mRNA expression.
为了了解低风险乳腺癌等位基因的生物学特性，并研究这些基因座是否也与曾经确定的疾病进展有关，我们检测了 FGFR2、LSP1、MAP3K1、H19、TOX3、POU5F1P1、MYC 和 2q35 附近或之内的低风险乳腺癌基因座的标记 SNP 与临床、病理特征、预后以及最近基因的 mRNA 表达之间的关联。有 2480 例乳腺癌患者的肿瘤 DNA 样本可用。在这个队列中，有 1290 例淋巴结阴性且未接受辅助全身治疗的患者，SNP 状态与无转移生存（MFS）相关。在 1401 例患者中，测定了 FGFR2、LSP1、MAP3K1、H19、TOX3、POU5F1P1 和 MYC 的 mRNA 表达水平，并与 SNP 基因型相关。FGFR2 中的 SNP rs2981582 与 ER 和 PgR 阳性状态显著相关（P < 0.001 和 P = 0.003）。未观察到与患者或肿瘤特征的其他显著关联。只有 H19 附近的 rs2107425 与单变量和多变量分析中的较短 MFS 显著相关（HR：1.53，CI：1.12-2.08，P = 0.006 和 HR：1.59，CI：1.16-2.20，P = 0.004），显示出更具侵袭性的次要等位基因具有隐性特征。位于 TOX3 基因附近的 SNP rs3803662 的次要等位基因与该基因的 mRNA 表达降低相关。总之，除了 SNP rs13283662 与 TOX3 基因表达的关联表明 TOX3 具有肿瘤抑制作用外，我们的研究结果表明，低风险乳腺癌基因座通常不会影响乳腺癌组织中最近基因的表达。除了附近的 SNP 之外，患者的预后也在很大程度上不受低风险乳腺癌基因座的影响。这个 SNP 如何影响预后，值得进一步研究，因为它不是通过改变 H19 mRNA 表达来起作用的。
