Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status

Abstract

Global gene expression measured by DNA microarray platforms have been extensively used to classify breast carcinomas correlating with clinical characteristics, including outcome. We generated a breast cancer Serial Analysis of Gene Expression (SAGE) high-resolution database of f2.7 million tags to perform unsupervised statistical analyses to obtain the molecular classification of breast-invasive ductal carcinomas in correlation with clinicopathologic features. Unsupervised statistical analysis by means of a random forest approach identified two main clusters of breast carcinomas, which differed in their lymph node status (P = 0.01); this suggested that lymph node status leads to globally distinct expression profiles. A total of 245 (55 up-modulated and 190 down-modulated) transcripts were differentially expressed between lymph node (+) and lymph node (À) primary breast tumors (fold change, z2; P < 0.05). Various lymph node (+) up-modulated transcripts were validated in independent sets of human breast tumors by means of real-time reverse transcription-PCR (RT-PCR). We validated significant overexpression of transcripts for HOXC10 (P = 0.001), TPD52L1 (P = 0.007), ZFP36L1 (P = 0.011), PLINP1 (P = 0.013), DCTN3 (P = 0.025), DEK (P = 0.031), and CSNK1D (P = 0.04) in lymph node (+) breast carcinomas. Moreover, the DCTN3 (P = 0.022) and RHBDD2 (P = 0.002) transcripts were confirmed to be overexpressed in tumors that recurred within 6 years of follow-up by real-time RT-PCR. In addition, meta-analysis was used to compare SAGE data associated with lymph node (+) status with publicly available breast cancer DNA microarray data sets. We have generated evidence indicating that the pattern of gene expression in primary breast cancers at the time of surgical removal could discriminate those tumors with lymph node metastatic involvement using SAGE to identify specific transcripts that behave as predictors of recurrence as well. (Mol Cancer Res 2007;5(9):881 -90)

Overexpression of DEK is an indicator of poor prognosis in patients with gastric adenocarcinoma

“…Kavanaugh et al (21) demonstrated that overexpression of DEK induces human keratinocyte transformation and that DEK-knockout mice are partially resistant to chemically induced papilloma formation. Previous studies have revealed that DEK mRNA expression is increased in invasive ductal breast cancer, and has an increased gene expression in high-grade and late-stage breast cancer, therefore implicating it as a potential novel target in recurrent tumors (5,(22)(23)(24). In addition, Shibata et al (25) identified that DEK overexpression affects the activity of global transcriptional regulators and is associated with tumor development and a poor prognosis of patients with high-grade neuroendocrine carcinoma.…”

Differential Gene Expression in Ductal Carcinoma in Situ of the Breast Based on ERBB2 Status

“…The age of those in the ERBB2-positive group was not significantly different from the other 2 groups. The median age of the control group was significantly younger when compared with the other groups (30.5 years [range, [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]). Two patients were lost during follow-up, and the remaining patients were followed-up for 23 to 50 months after surgical excision, with an average follow-up time of 41 months.…”

“…13,[23][24][25][26][27][28][29][30][31][32] The natural history, progression, and mechanism underlying DCIS are poorly understood, although several studies have shown that the transition from DCIS to invasive disease is associated with quantitative rather than qualitative differences in gene expression. 2,14,25,33 Biological markers to predict the presence of occult invasive disease or to identify patients at higher risk of developing invasive cancer are needed so that clinicians can better tailor the management of these lesions.…”

Análise De Expressão Gênica Na Identificação De Potenciais Marcadores Preditivos Em Neoplasias Malignas Mamárias

“…Contudo, a maioria dos trabalhos de expressão gênica avalia somente o potencial prognóstico dos genes, enquanto uma quantidade reduzida analisa o poder preditivo de genes em amostras de neoplasias primárias e metástases de linfonodos em câncer de mama (BERTUCI et al, 2000;HUANG et al, 2003;ABBA et al, 2007;FENG et al, 2007;WANG et al, 2013;VALENTE et al, 2014;CHEN et al, 2017;PAULA et al, 2017). Além disso, o significado biológico do envolvimento dos linfonodos e sua utilidade na orientação da terapia adjuvante e sistêmica tem sido objeto de muitos resultados discordantes (BERTUCI et al, 2000;HUANG et al, 2003;ABBA et al, 2007).…”