An 80-gene set to predict response to preoperative chemoradiotherapy for rectal cancer by principle component analysis

Abstract

Abstract. Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer not only improves the postoperative local control rate, but also induces downstaging. However, it has not been established how to individually select patients who receive effective preoperative CRT. The aim of this study was to identify a predictor of response to preoperative CRT for locally advanced rectal cancer. This study is additional to our multicenter phase II study evaluating the safety and efficacy of preoperative CRT using oral fluorouracil (UMIN ID: 03396). From April, 2009 to August, 2011, 26 biopsy specimens obtained prior to CRT were analyzed by cyclopedic microarray analysis. Response to CRT was evaluated according to a histological grading system using surgically resected specimens. To decide on the number of genes for dividing into responder and non-responder groups, we statistically analyzed the data using a dimension reduction method, a principle component analysis. Of the 26 cases, 11 were responders and 15 non-responders. No significant difference was found in clinical background data between the two groups. We determined that the optimal number of genes for the prediction of response was 80 of 40,000 and the functions of these genes were analyzed. When comparing non-responders with responders, genes expressed at a high level functioned in alternative splicing, whereas those expressed at a low level functioned in the septin complex. Thus, an 80-gene expression set that predicts response to preoperative CRT for locally advanced rectal cancer was identified using a novel statistical method.

Predicting Response to Neoadjuvant Therapy in Colorectal Cancer Patients the Role of Messenger-and Micro-RNA Profiling

“…Apoptosis —the following mRNAs were upregulated in nCRT responders: BAX (encoding for a protein which promotes apoptosis by binding apoptosis repressor Bcl2) [ 19 , 23 ], CFLAR (encoding for a protein structurally similar to caspase 8, although it lacks caspase activity, and acting as an apoptosis regulator by inhibiting TNFRSF6) [ 20 ], ETS2 (transcription factors involved in development and apoptosis through transcriptional activation) [ 19 ], GGCT (encoding for Gamma-Glutamylcyclotransferase, an enzyme that plays a pivotal role in glutathione homeostasis and that induces cytochrome c release from mitochondria, leading to apoptosis induction) [ 20 ], ID1 (encoding for a protein that negatively regulates helix–loop–helix transcription factors through heterodimer formation and consequently inhibition of their transcriptional activity) [ 20 ], SEPTIN7P2 (encoding for a protein involved in the recruitment of other proteins) [ 41 ] and TRIAP1 (encoding for a protein involved in modulation of mitochondrial apoptotic pathway through inhibition of caspase-9) [ 20 ]. Two genes were downregulated in responders, including BAK1 (encoding for a protein inducing apoptosis through accelerating the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c; it also interacts with the tumor suppressor P53 after exposure to cell stress) [ 38 ] and SHF (encoding for a protein playing a role in the regulation of apoptosis in response to PDGF(Platelet Derived Growth Factor)) [ 41 ]. Among genes related to programmed cell death, MTCH1 [ 42 ], PYCARD [ 36 ] and TRAF4 [ 36 ] were identified as part of a gene set correlated with downgrading.…”

“…mRNA levels of CCNK (encoding for Cyclin K, which regulates transcription through phosphorylation of the C-terminal domain of the large subunit of RNA polymerase II) [ 19 ], RIF1 (encoding for a protein that shares homology with the yeast telomere binding protein, Rap1 interacting factor 1, localizing to aberrant telomeres may be involved in DNA repair) [ 19 ], TCF19 (encoding for a protein containing a PHD-type zinc finger domain and likely functioning as a transcription factor, playing a role proliferation and apoptosis of pancreatic beta cells) [ 41 ] and TOE1 (encoding for target of EGR1 Protein 1, which inhibits cell cycle progression and consequently arrests cell growth rate) [ 19 ] were found to be over-expressed in responders. Conversely, SPDYA (encoding for a protein that regulates the G1/S phase transition) were part of a set of 57 genes found downregulated in nCRT responders [ 41 ]. TP53 (tumor suppressor protein) was also downregulated in responders to nCRT [ 32 , 42 , 44 ].…”

A 17-molecule set as a predictor of complete response to neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer

“…We considered that the use of many molecules was more appropriate to predict pCR than the use of a single molecular biomarker. In fact, we have reported an 80-gene set to predict the response to NAC-radiotherapy (RT) in rectal cancer [ 24 ]. We considered exploring a gene set to predict pCR after NAC-DCF for esophageal cancer in this study.…”

Gene-expression profiles of pretreatment biopsies predict complete response of rectal cancer patients to preoperative chemoradiotherapy

“… GS1 was published by Lopes-Ramos et al [ 29 ]; GS2 by Ghadimi et al [ 39 ]; GS3 by Empuko et al [ 40 ]; GS4 by Watanabe et al [ 38 ] and GS5 by Kim et al [ 41 ]. …”