Transcript map and complete genomic sequence for the 310 kb region of minimal allele loss on chromosome segment 11p15.5 in non-small-cell lung cancer

Abstract

Molecular, functional, and clinical analyses strongly suggest that chromosome segment 11p15.5 contains a gene involved in lung cancer pathogenesis. The critical region of allele loss is 310 kb in size. We used our contig of P1-phage arti®cial chromosome (PAC) clones together with newly identi®ed bacterial arti®cial chromosome (BAC) clones and the draft human genome sequence to complete a contiguous string of 380 407 bp. Three PAC clones that span the region were used to identify transcripts by exon trapping. Computational gene prediction algorithms were used to query the sequence for potential genes and exons. Screening for expression was performed with tissue-speci®c and cell line derived mRNA arrays. The region contains the complete SSA/Ro52 and RRM1 genes, exons 7 ± 12 of the GOK gene, and the crad pseudo-gene. A cluster of six nearly identical genes with an intact open reading frame (ORF) of 585 bp that share 75% identity with the HSPC182 gene was found. In addition, ®ve putative novel genes were identi®ed. Sequence tagged sites (STS) and polymorphic markers were used to screen 117 lung cancer cell lines for homozygous deletions and none were identi®ed. These data provide the basis for the identi®cation of a lung cancer suppressor gene on 11p15.5. Oncogene (2001) 20, 8154 ± 8164.

Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNFα-Induced Apoptosis

“…The 11p15.4 region, in which the PRKCDBP gene is located, undergoes frequent allelic losses in a variety of human malignancies including breast, lung, and gastric cancer (19)(20)(21)(22). Therefore, PRKCDBP was predicted as a target of deletion in many cancer types displaying frequent LOH at 11p15.4, and allelic loss of the gene was suggested as a plausible mechanism underlying its low expression in tumor cells.…”

“…The chromosomal region 11p15 shows frequent deletion in many types of human cancer, including breast, lung, and bladder cancers (1,19,20) In particular, 11p15.5-p15. 4, in which the PRKCDBP gene is located, is a critical region of loss of heterozygosity (LOH) for chromosome 11 in several cancers, suggesting that PRKCDBP might be a target tumor suppressor gene in this region (21)(22)(23).…”

RRM1-induced metastasis suppression through PTEN-regulated pathways

“…One of the genes in the deleted region is RRM1 (Pitterle et al, 1999;Zhao and Bepler, 2001), and stable expression of a biologically Figure 5 Balb/c mice were subcutaneously injected at a single site with the syngeneic lung adenocarcinoma cell line Line1 and the two transgene-carrying cell lines Line1-Ct and Line1-R1. These lines had been stably transfected with the in-frame (Line1-R1) and outof-frame (Line1-Ct) human RRM1 cDNA constructs.…”

“…We also recently reported the completed sequence and transcripts from this region (GenBank Accession numbers AF 391283-5), and that patients with resected stage I NSCLC and allele loss had a survival similar to resected stage II patients (Zhao andBepler, 2001, Bepler et al, 2002). Together, these results suggested that this region contains a gene involved in the regulation of metastasis formation.…”

Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer

“…RRM1 also acts as a putative tumor suppressor and has been identified within the centromeric part of chromosome segment 11p15.5 . This region, called LOH11A, is frequently lost in NSCLC; it has been completely mapped and sequenced (Zhao and Bepler, 2001), and loss of heterozygosity in this region has been shown to be highly predictive of poor survival in resected NSCLC patients (Bepler et al, 2002). RR overexpression was related to gemcitabine resistance in human oropharyngeal epidermoid carcinoma KB cells (Goan et al, 1999).…”