Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

Abstract

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. Abstract Breast cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth whereas others are causal for the various steps of metastasis. In a fraction of tumors deregulation of the same genes might be caused by epigenetic modulations, point mutations or the influence of other genes. We have investigated the relation of gene expression and chromosomal position, using eight datasets including more than 1200 breast tumors, to identify chromosomal regions and candidate genes possibly causal for breast cancer metastasis. By use of ''Gene Set Enrichment Analysis'' we have ranked chromosomal regions according to their relation to metastasis. Overrepresentation analysis identified regions with increased expression for chromosome 1q41-42, 8q24, 12q14, 16q22, 16q24, 17q12-21.2, 17q21-23, 17q25, 20q11, and 20q13 among metastasizing tumors and reduced gene expression at 1p31-21, 8p22-21, and 14q24. By analysis of genes with extremely imbalanced expression in these regions we identified DIRAS3 at 1p31, PSD3, LPL, EPHX2 at 8p21-22, and FOS at 14q24 as candidate metastasis suppressor genes. Potential metastasis promoting genes includes RECQL4 at 8q24, PRMT7 at 16q22, GINS2 at 16q24, and AURKA at 20q13.

Characterization of a carcinogenesis-associated long non-coding RNA

“…Consistent with previous reports, 3,16 extensive DNA gains occurred at the Yiya locus in all the cancer samples. The highest levels of genomic DNA amplification were found in rectal and gastric cancer (Fig.…”

“…3 Supporting the data, a more recent genome-wide association study also found 1q41 as a susceptibility locus in colorectal cancers, suggesting its potential role in carcinogenesis. 2 Even with this and other convincing association evidence, no cancer-causing genes have been characterized in this region, which suggests that other genetic elements may be involved in this process.…”

“…15,16 Supporting these observations, a recent study of 1200 breast cancer patients further characterized enhanced expression of chromosome 1q41 in metastasizing breast cancers, therefore establishing it as a metastasis-associated genomic region. 3 Considering its high abundance in mammalian cells and potential involvement in carcinogenesis, Yiya was chosen for further study. To obtain the full-length sequence, rapid amplification of 5' and 3' cDNA ends (5' and 3' RACE) were performed, using the SMART RACE cDNA amplification kit from Clontech (Mountain View, CA).…”

“…This result is in agreement with a recent study showing high expression levels of chromosome 1q41 in metastasizing breast cancers. 3 Enhanced mRNA levels of Yiya in cancers. Given the fact that Yiya was originally identified in a cancer susceptibility region, its relationship with carcinogenesis was first evaluated by profiling its expression in cancer samples of four tissue origins.…”

“…2, 3 A metaanalysis comparing 1,200 breast cancer patients to healthy controls identified several chromosomal regions with altered expression levels in metastasizing tumors, including 1q41-42. 3 Supporting the data, a more recent genome-wide association study also found 1q41 as a susceptibility locus in colorectal cancers, suggesting its potential role in carcinogenesis.…”