Biomedical subjects

Luc Girard

Publications and source records attributed to Luc Girard.

21 records · Page 2Linked to original sources

PubMed2003

Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer.

The underlying molecular mechanisms leading to microsatellite alteration and mutations in human lung cancer remain unknown. Since Flap endonuclease1 (Fen1), which functions in the base excision repair system, has been shown to be involved in tumor progression of mouse models with microsatellite instability in a haplo-insufficient manner, we performed expression and mutation analyses for FEN1 in human lung cancer cell lines. Reverse transcriptase PCR analysis revealed that all 49 lung cancer cell lines (20 small cell lung cancers (SCLCs) and 29 non-small cell lung cancers (NSCLCs)) expressed FEN1. In addition, microarray analysis showed that FEN1 expression was elevated significantly by 1.65-fold (P=0.001) in SCLC cell lines compared to normal lung controls (normal human lung cultures and immortalized normal human bronchial epithelial cell lines). FEN1 protein was abundantly expressed in all 23 lung cancer cell lines (10 SCLCs and 13 NSCLCs) and was expressed at lower levels in three of four normal lung epithelial culture controls. Direct sequencing of genomic DNAs revealed no FEN1 mutation in seven SCLCs and nine NSCLCs. As part of this analysis we discovered and sequenced a FEN1 pseudogene (GenBank accession #AY249897) located at 1p22.2. This pseudogene is amplified from cDNA preparations contaminated with genomic DNA and must be taken into account in any FEN1 mutation analysis studies. Our results suggest that alterations of FEN1 are not likely to contribute to development of lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed2002

Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations.

The Ahi-1 locus was initially identified as a common helper provirus integration site in Abelson pre-B-cell lymphomas and shown to be closely linked to the c-myb proto-oncogene. Since no significant alteration of c-myb expression was found in Abelson murine leukemia virus-induced pre-B-lymphomas harboring a provirus inserted within the Ahi-1 locus, this suggested that it harbors another gene whose dysregulation is involved in tumor formation. Here we report the identification of a novel gene (Ahi-1) targeted by these provirus insertional mutations and the cloning of its cDNA. The Ahi-1 proviral insertions were found at the 3' end of the gene, in an inverse transcriptional orientation, with most of them located around and downstream of the last exon, whereas another insertion was within intron 22. In addition, another previously identified provirus insertion site, Mis-2, was found to map within the 16th intron of the Ahi-1 gene. The Ahi-1 cDNA encodes a 1,047-amino-acid protein. The predicted Ahi-1 protein is a modular protein that contains one SH3 motif and seven WD40 repeats. The Ahi-1 gene is conserved in mammals and encodes two major RNA species of 5 and 4.2 kb and several other shorter splicing variants. The Ahi-1 gene is expressed in mouse embryos and in several organs of the mouse and rat, notably at high levels in the brain and testes. In tumor cells harboring insertional mutations in Ahi-1, truncated Ahi-1/viral fused transcripts were identified, including some splicing variants with deletion of the SH3 domain. Therefore, Ahi-1 is a novel gene targeted by provirus insertion and encoding a protein that exhibits several features of a signaling molecule. Thus, Ahi-1 may play an important role in signal transduction in normal cells and may be involved in tumor development, possibly in cooperation with other oncogenes (such as v-abl and c-myc) or with a tumor suppressor gene (Nf1), since Ahi-1 insertion sites were identified in tumors harboring v-abl defective retroviruses or a c-myc transgene or in tumors exhibiting deletion of Nf1.

Adaptor Proteins, Vesicular Transport↗

PubMed2002

Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women.

PURPOSE: The purpose of this research was to examine the DNA methylation profiles of primary sporadic ovarian cancers and ovarian tissues from high-risk women. EXPERIMENTAL DESIGN: We analyzed the DNA methylation status of nine cancer-related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues obtained from 16 women with no known risk and from 23 high-risk women with a strong family history of breast and/or ovarian cancer or BRCA1 germ-line mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR. RESULTS: Our findings are as follows: (a) methylation rates of four of nine genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were significantly higher in tumors compared with controls. At least one of the four genes was methylated in 76% of the tumors; (b) a low frequency of methylation was present in nonmalignant tissues; (c) no significant differences in methylation frequencies were seen between the nonmalignant ovarian tissues from women at high-risk and those with no known risk of developing ovarian cancer; (d) methylation of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines showed a similar frequency of methylation to ovarian tumors except for the HIC1 gene. CONCLUSIONS: Our results suggest that aberrant methylation of specific genes, including two not described previously, may be important in ovarian cancer pathogenesis but not in ovaries at risk for cancer development.

DNA↗