Ma Xiao-Jun, Salunga Ranelle, Dahiya Sonika, Wang Wilson, Carney Erin, Durbecq Virginie, Harris Adrian, Goss Paul, Sotiriou Christos, Erlander Mark, Sgroi Dennis
AviaraDx, Inc., San Diego, California, USA.
Clin Cancer Res. 2008 May 1;14(9):2601-8. doi: 10.1158/1078-0432.CCR-07-5026.
Histologic tumor grade is a well-established prognostic factor for breast cancer, and tumor grade-associated genes are the common denominator of many prognostic gene signatures. The objectives of this study are as follows: (a) to develop a simple gene expression index for tumor grade (molecular grade index or MGI), and (b) to determine whether MGI and our previously described HOXB13:IL17BR index together provide improved prognostic information.
From our previously published list of genes whose expression correlates with both tumor grade and tumor stage progression, we selected five cell cycle-related genes to build MGI and evaluated MGI in two publicly available microarray data sets totaling 410 patients. Using two additional cohorts (n = 323), we developed a real-time reverse transcription PCR assay for MGI, validated its prognostic utility, and examined its interaction with HOXB13:IL17BR.
MGI performed consistently as a strong prognostic factor and was comparable with a more complex 97-gene genomic grade index in multiple data sets. In patients treated with endocrine therapy, MGI and HOXB13:IL17BR modified each other's prognostic performance. High MGI was associated with significantly worse outcome only in combination with high HOXB13:IL17BR, and likewise, high HOXB13:IL17BR was significantly associated with poor outcome only in combination with high MGI.
We developed and validated a five-gene reverse transcription PCR assay for MGI suitable for analyzing routine formalin-fixed paraffin-embedded clinical samples. The combination of MGI and HOXB13:IL17BR outperforms either alone and identifies a subgroup ( approximately 30%) of early stage estrogen receptor-positive breast cancer patients with very poor outcome despite endocrine therapy.
组织学肿瘤分级是乳腺癌公认的预后因素，与肿瘤分级相关的基因是许多预后基因特征的共同要素。本研究的目的如下：（a）开发一种用于肿瘤分级的简单基因表达指数（分子分级指数或MGI），以及（b）确定MGI与我们之前描述的HOXB13:IL17BR指数是否共同提供更好的预后信息。
从我们之前发表的与肿瘤分级和肿瘤分期进展均相关的基因列表中，我们选择了五个细胞周期相关基因来构建MGI，并在两个总计410例患者的公开可用微阵列数据集中评估了MGI。使用另外两个队列（n = 323），我们开发了一种用于MGI的实时逆转录PCR检测方法，验证了其预后效用，并研究了其与HOXB13:IL17BR的相互作用。
MGI始终作为一个强大的预后因素，在多个数据集中与更复杂的97基因基因组分级指数相当。在内分泌治疗的患者中，MGI和HOXB13:IL17BR相互改变对方的预后表现。仅在与高HOXB13:IL17BR联合时，高MGI才与显著更差的结果相关，同样，仅在与高MGI联合时，高HOXB13:IL17BR才与不良结果显著相关。
我们开发并验证了一种用于MGI的五基因逆转录PCR检测方法，适用于分析常规福尔马林固定石蜡包埋的临床样本。MGI和HOXB13:IL17BR的联合表现优于单独使用，并且识别出一组（约30%）早期雌激素受体阳性乳腺癌患者，尽管接受了内分泌治疗，但预后非常差。
