Molecular Genetic Analysis of a Cell Adhesion Molecule With Homology to L1CAM, Contactin 6, and Contactin 4 Candidate Chromosome 3p26pter Tumor Suppressor Genes in Ovarian Cancer

Abstract

Loss of heterozygosity (LOH) analyses of epithelial ovarian cancers (EOCs) previously identified a candidate tumor suppressor gene (TSG) locus within the chromosomal region 3p25.3-pter. Loss of heterozygosity analysis was performed to define the locus and identify candidates for further study. Loss of heterozygosity analysis of 124 malignant EOC samples of different histopathologic subtypes using 12 polymorphic microsatellite repeat markers identified a 330-kilobase minimal region of overlapping deletions at 3p26.3 that contained contactin 4 (CNTN4) as the only known TSG candidate. However, evaluation of the LOH patterns in the serous EOC samples, the most common subtype, enabled the identification of a second, broader region of LOH also included the cell adhesion molecule with homology to L1CAM (CHL1) and CNTN6 as candidates. Gene expression by reverse transcription polymerase chain reaction was not detectable in primary cultures of normal ovarian surface epithelial cells for any of these candidates. CNTN6 expression was also not detectable in serous EOC samples. In contrast, gene expression of CNTN4 and CHL1, particularly overexpression of CHL1, was observed in serous EOC samples. Mutation and gene expression analyses of well-defined EOC cell lines (OV-90, TOV-112D, TOV-21G, and TOV-81D) that differ in their tumorigenic potential and chromosome 3p26-pter genomic content revealed CNTN4 expression and a novel mutation only in the tumorigenic EOC cell line TOV-21G. This mutation was neither observed in controls (n = 105) nor detected by sequencing analysis of complementary DNA. Taken together, these results do not support the candidacy of CHL1, CNTN6, and CNTN4 as TSGs in the 3p26-pter region. However, the overexpression of CHL1, a member of the L1 cell adhesion molecule (L1CAM) family, warrants further investigation.