Correlation of loss of heterozygosity at 11 p with tumour progression and survival in non‐small cell lung cancer

Chromosomal loss of heterozygosity (LOH) is a common mechanism for the inactivation of tumor suppressor genes in human epithelial cancers. Hybridization to singlenucleotide polymorphism (SNP) arrays is an efficient method to detect genome-wide cancer LOH. Here, we survey LOH patterns in a panel of 33 human lung cancer cell lines using SNP array hybridization containing 1500 SNPs. We compared the LOH patterns generated by SNP array hybridization to those previously obtained by 399 microsatellite markers and find a high degree of concordance between the two methods. A novel informatics platform, dChipSNP, was used to perform hierarchical tumor clustering based on genome-wide LOH patterns. We demonstrate that this method can separate non-small-cell and small-cell lung cancer samples based on their shared LOH. Furthermore, we analysed seven human lung cancer cell lines using a novel 10 000 SNP array and demonstrate that this is an efficient and reliable method of high-density allelotyping. Using this array, we identified small regions of LOH that were not detected by lower density SNP arrays or by standard microsatellite marker panels.

Section: Introductionmentioning

confidence: 99%

High-resolution single-nucleotide polymorphism array and clustering analysis of loss of heterozygosity in human lung cancer cell lines

Jänne

Zhao

et al. 2004

“…The minimal region of LOH was 650 kb and¯anked by the markers D11S988 (centromeric) and D11S860 (telomeric). Numerous investigators have reported LOH in this region for non-SCLC with frequencies ranging from 17% to 82% (Bepler and Garcia-Blanco, 1994;Fong et al, 1994;Ludwig et al, 1991;Shiraishi et al, 1987;Skinner et al, 1990;Tran and Newsham, 1996;Weston et al, 1989). LOH in or near this region has also been described for breast, ovarian, esophageal, stomach, and other cancers arising in adults (Ali et al, 1987;Fearon et al, 1985;Karnik et al, 1998;Lu et al, 1997;Ranzani et al, 1993;Shibagaki et al, 1994;Tran and Newsham, 1996;Viel et al, 1992;Winqvist et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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

Zhao

Bepler

2001

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.

“…TSG101 was localized to chromosome 11p15 (Li et al, 1997), a region frequently lost in several human tumor types including breast cancer (Winqvist et al, 1995;Gudmundsson et al, 1995) and NSCLC (Sundareshan and Augustus, 1996;Fong et al, 1994;Bepler et al, 1994;Izuka et al, 1995). It has been suggested that the 11p allele loss is associated with disease progression in NSCLC (Fong et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that the 11p allele loss is associated with disease progression in NSCLC (Fong et al, 1994). While the normal function of TSG101 is unknown, several structural motifs have been identi®ed including a proline-rich region and a predicted coiled-coil domain nearly identical to that of its murine homolog.…”

Section: Introductionmentioning

confidence: 99%

TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer

Proctor

Fan

et al. 1998

TSG101 is a candidate tumor suppressor gene whose deletion in NIH3T3 cells leads to spontaneous lung metastases in nude mice. Aberrant transcripts of TSG101 have been identi®ed in 47% of primary breast carcinomas, without evidence of intragenic deletions at the TSG101 locus on 11p15. To investigate the possible role of TSG101 in lung cancer, which often shows 11p allele loss, we performed transcript analysis and mutational analysis of TSG101 in lung cancer cell lines. Reverse transcriptase RT ± PCR and Northern analysis detected a common TSG101 transcript, shortened because of an internal deletion, which was expressed simultaneously with the wild-type transcript in 89% of small cell lung cancer (SCLC) lines. In contrast, the wild-type transcript was expressed alone in normal tissues, primary non-small cell lung cancer (NSCLC) specimens, and the majority of NSCLC cell lines. Sequence of the shortened SCLC transcript was identical to that of the most common aberrant transcript identi®ed in breast cancer, consisting of a deletion of exons 2 ± 4 and part of 1 and 5. Southern analysis of SCLC lines expressing the shortened transcript did not detect any intragenic deletions. Single strand conformational polymorphism (SSCP) analysis and direct sequencing of TSG101 cDNAs also identi®ed no mutations or deletions. These results suggest that TSG101 is not mutated in lung cancer but that aberrant splicing of TSG101 occurs in SCLC.