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Development of a high-resolution array of chromosome 1p and its application to the identification of genetic alterations in cancer Henderson, Laura-Jane Walker

Abstract

Genetic alterations such as deletions, amplifications, and translocations occurring on human chromosome arm 1p are common in many types of cancer, including lung, head and neck, breast, neuroblasotma and colorectal. Current methods for mapping alterations, including loss of heterozygosity, comparative genomic hybridization, and fluorescence in situ hybridization are limited by low resolution, and inaccurately mapped markers and probes that are insufficient in number. Mapping using currently available markers leads to the identification of chromosomal regions too large for easy definition of candidate genes. Very few sub-megabase regions have been detected using conventional means, and doing so is very labour intensive. Developing resources such as array-based comparative genomic hybridization (aCGH) can facilitate fine mapping of genetic alterations on this chromosome arm. This approach will accelerate the discovery of tumour suppressors and oncogenes by identifying small altered regions. We have constructed an array of 642 ordered and fingerprint-verified bacterial artificial chromosome clones mapped to chromosome arm 1p, from 1p11.2-p36.33, covering approximately 120 megabases of the human genome. This array was applied by the use of aCGH to the investigation of DNA copy number alterations on 1p in 15 small cell lung cancer cell lines. Two regions of recurrent amplification, at 1p34.2-p34.3 and at 1p11.2, were detected in at least 50% of the samples. The regions were 580 Kb and 270 Kb in size, respectively. This study has demonstrated the power of high resolution aCGH to detect small regions of alteration and that these small regions are recurrent on the l p arm. The genes implicated in these regions will be investigated for their potential roles in cancer and the aCGH technique will be further applied to investigation of the whole human genome.

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