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Genomic organization and mutation analysis of Hel-N1 in lung cancers with chromosome 9p21 deletions
1Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Abstract:
Allelic loss of chromosome 9p21 is common in small cell lung cancer (SCLC), but inactivation of the tumor suppressor gene CDKN2a is rare, implying the existence of another target gene at 9p21. A recent deletion mapping study of chromosome 9p has also identified a site of deletion in non-small cell lung cancer (NSCLC) centered around D9S126. The Hel-N1 (human elav-like neuronal protein 1) gene encodes a neural-specific RNA binding protein that is expressed in SCLC. We have mapped this potentially important gene in lung tumorigenesis to within 100 kb of the D9S126 marker at chromosome band 9p21 by using homozygously deleted tumor cell lines and fluorescence in situ hybridization to normal metaphase spreads. Hel-N1 is, therefore, a candidate target suppressor gene in both SCLC and NSCLC. We have determined the genomic organization and intron/exon boundaries of Hel-N1 and have screened the entire coding region for mutations by sequencing 14 primary SCLCs and cell lines and 21 primary NSCLCs preselected for localized 9p21 deletion or monosomy of chromosome 9. A homozygous deletion including Hel-N1 and CDKN2a was found in a SCLC cell line, and a single-base polymorphism in exon 2 of Hel-N1 was observed in eight tumors. No somatic mutations of Hel-N1 were found in this panel of lung tumors. Hel-N1 does not appear to be a primary inactivation target of 9p21 deletion in lung cancer.
Insights
Loss of chromosome 9p21 is common in lung cancer, but the Hel-N1 gene is not a primary target. Researchers investigated Hel-N1 as a potential tumor suppressor gene in small cell lung cancer and non-small cell lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Allelic loss at chromosome 9p21 is frequent in small cell lung cancer (SCLC), yet CDKN2a inactivation is uncommon, suggesting other 9p21 targets.
- Deletion mapping in non-small cell lung cancer (NSCLC) identified a deletion site near D9S126 on chromosome 9p.
- The Hel-N1 gene, encoding a neural-specific RNA binding protein, is expressed in SCLC and considered a candidate in lung tumorigenesis.
Purpose of the Study:
- To map the Hel-N1 gene to chromosome band 9p21, within 100 kb of the D9S126 marker.
- To investigate Hel-N1 as a potential tumor suppressor gene in both SCLC and NSCLC.
- To determine the genomic organization of Hel-N1 and screen for mutations in lung tumors.
Main Methods:
- Fluorescence in situ hybridization (FISH) and homozygously deleted tumor cell lines were used to map the Hel-N1 gene.
- Genomic organization and intron/exon boundaries of Hel-N1 were determined.
- Mutation screening of the Hel-N1 coding region was performed via sequencing in 14 SCLC and 21 NSCLC samples.
Main Results:
- Hel-N1 was mapped to chromosome band 9p21, near the D9S126 marker.
- A homozygous deletion encompassing Hel-N1 and CDKN2a was identified in one SCLC cell line.
- A single-base polymorphism in Hel-N1 exon 2 was found in eight tumors, but no somatic mutations were detected.
Conclusions:
- Hel-N1 is located within a commonly deleted region on chromosome 9p21 in lung cancer.
- Despite its location and expression in SCLC, Hel-N1 does not appear to be a primary inactivation target in the studied lung tumors.
- Further research may be needed to fully elucidate the role of Hel-N1 in lung cancer development.