Transcriptional census of 36 microdissected colorectal cancers yields a gene signature to distinguish UICC II and III

Abstract

UICC stage II and III colorectal cancers (CRC) differ fundamentally in prognosis and therapeutic concepts. To analyze differential gene expression between both stages and to establish a relationship between molecular background and clinical presentation, tumor material from 36 unselected consecutive patients presenting with sporadic CRC, 18 UICC stage II and 18 UICC stage III, were laser microdissected to separate epithelial tumor cells. Gene expression levels were measured using U133A Affymetrix gene arrays. Twelve CRC associated signal transduction pathways as well as all 22,000 probe sets were screened for differential gene expression. We identified a signature consisting of 45 probe sets that allowed discrimination between UICC stage II and stage III with a rate of correct classification of about 80%. The most distinctive elements in this signature were the gene GSTP-binding elongation factor (GSPT2) and the transcription factor HOXA9. Differential expression of these genes was confirmed by quantitative real-time polymerase chain reaction (p (HOXA9) 5 0.04, p (GSTP2) 5 0.02). Despite the reliability of the presented data, there was no substantial differential expression of genes in cancer-related pathways. However, the comparison with recently published data corroborates the 45 gene signature showing structural agreement in the direction of fold changes of gene expression levels for our set of genes chosen to discriminate between both stages. ' 2006 Wiley-Liss, Inc.Key words: colorectal cancer; gene expression analysis; gene signature; classification; UICC stage II; UICC stage III In colorectal cancer (CRC), the prognosis and the type of adjuvant treatment is highly dependent upon the stage of disease. The current staging of CRC is predominantly based on clinical and pathological parameters such as local tumor extension, lymph node involvement and distant metastases. 1,2 More than 70% of patients with curative resection of CRC are classified as UICC stage II and III. While UICC stage II CRC is generally considered to be local and less aggressive with 5-year recurrence rates of 20-25%, tumors of stage UICC III are more dynamic by spreading metastases to lymph nodes. This results in a 5-year recurrence rate of more than 40% after radical resection 3 and constitutes the reason for recommendation of adjuvant therapy.

Identification and Rational Redesign of Peptide Ligands to CRIP1, A Novel Biomarker for Cancers

“…CRIP1 overexpression has also been demonstrated to be the most highly differentially expressed gene in invasive cervical carcinomas; 100-fold up-regulation relative to normal cervical keratinocytes measured in 34 cervical tissues from different clinically defined stages [5],[6]. CRIP1 was also found to have high levels of expression in pancreatic adenocarcinoma, lung cancers and colorectal cancers [7]–[9]. These data strongly support the development of imaging probes targeting CRIP1 to improve cancer detection.…”

“…Human CRIP1, primarily a cytosolic protein, was cloned in 1997 [1] using RT-PCR of human small intestine RNA and oligonucleotides whose sequence was derived from the human heart homolog of this protein, CRHP [2]. Recently CRIP1 has been identified as a very exciting biomarker for human breast cancers [3],4, cervical cancers [5],[6], pancreatic cancers [7],[8] and potentially other cancers [4],[9]. In experiments comparing CRIP1 expression in human breast cancer to matched normal breast tissue the mRNA for this target was overexpressed 8–10-fold in approximately 90% of both invasive and ductal carcinoma in situ [3].…”

CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients

“…In the last years, deregulated CRIP1 expression was reported to characteristically occur in several malignant tumors, including breast, cervical, prostatic, colorectal, and pancreatic cancer [9, 11, 12, 14, 15]. Interestingly, CRIP1 was also considered a bone-specific breast cancer metastasis gene [18, 19].…”

The Impact of Cysteine-Rich Intestinal Protein 1 (CRIP1) on Thyroid Carcinoma

“…CRIP1 may be involved in intestinal zinc transport [10, 13-15], and is observed to be overexpressed in various types of tumors [16-22] including breast cancer [20, 21], osteosarcoma [19], prostate cancer [17], pancreatic cancer [16], and colorectal cancer [23]. Numerous studies have indicated that CRIP1 is an important transcriptional regulation factor during tumor development.…”