9 research outputs found
A SMAD4
BACKGROUND: Colorectal cancer is the secondâleading cause of cancerârelated mortality in the United States and a leading cause of cancerârelated mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factorâbeta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNAâbased profile associated with SMAD4 expression could be used to better identify highârisk colorectal cancer patients. AIM: Identify a gene expressionâbased SMAD4âmodulated profile and test its association with patient outcome. METHODS AND RESULTS: Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMADâbinding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patientâderived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Diseaseâfree survival was analyzed by the KaplanâMeier method. In vitro analysis of three genes identified in the SMAD4âmodulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with diseaseâfree survival (p = .02, logârank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with diseaseâfree survival (p = .013, logârank test). CONCLUSIONS: A SMAD4âmodulated gene expression profile identified highârisk stage II and III colorectal cancer patients, can predict diseaseâfree survival, and has prognostic potential for stage II and III colorectal cancer patients
Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors: A Paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology
The majority of colorectal cancer (CRC) cases have chromosomal instability, in which the tumor genome is characterized by gross chromosomal aberrations such as gains in 20q, 13q, 8q, and 7, and losses in 4, 8p, 18q, and 17p. These somatic copy number changes (gains, losses, and somatic uniparental disomies) are crucial to CRC progression as they drive genes toward cancer-promoting (oncogenic or tumor suppressive) states. Numerous studies have shown that the loss of 18q or 8p is associated with poorer clinical outcome in CRCs. Either chromosomal arm may contain a tumor suppressor gene (or genes), whose deactivation by copy loss (loss of wild-type allele, decreased expression) can be crucial to the later stages of cancer progression. Our own integrated genomic analysis (single nucleotide polymorphism array, expression array) of more than 200 CRC tumor and normal samples indicates that the overall down-regulation of genes within the 8p or 18q arm is associated with lower survival rate. Among the often down-regulated, poor prognosis-associated 8p genes is MTUS1, whose gene product (a mitotic spindle-associated protein) was recently demonstrated to have a tumor suppressive property. Within 18q is ATP5A1, which codes for the catalytic a component of mitochondrial H+-ATP synthase. Like SMAD4 (also in 18q), the decreased expression of ATP5A1 appears to be a marker of unfavorable clinical outcome in CRCs