Abstract B47: Genomic screen of colorectal tumors and adenomas: Disproportionate frequency of 1p35-1pter deletion in synchronous advanced adenomas Free

B47

The development of somatic colorectal cancer (CRC) has been characterized by the sequential acquisition of non-random gene mutations that over time lead to widespread genomic instability. Long-oligonucleotide microarrays for comparative genomic hybridization (oligo-aCGH) provide simultaneous gene dosage measures at high genomic resolution (average resolution 6 kb). Utilizing specialized protocols we routinely co-hybridize FFPE sample DNA with sex-mismatched genomic reference DNA to generate sensitive gene dosage measures at the individual gene level. Standard analyses by built-in bioinformatics allow uniform data analysis at the gene, chromosome and genome levels. Stringent quality control measures provide strong confidence of our experimental techniques in profiling >100 colorectal archival samples stored in the paraffin block 4 to 11 years. FFPE samples included non-advanced adenomas to 3 mm diameter (n = 21), advanced adenomas (n = 33), invasive CRCs (n = 42) and normal margin (n = 10). We have previously reported on the most frequent recurrent alteration of low level gain of the HOXA genes at 7p15 in all 40 - 65% of adenoma subtypes as well as invasive CRC. Subsequent functional studies have shown crucial biologic significance of HOXA9 based on cell line and shRNAi experiments. Here we report on the disproportionate frequency of 1p terminal deletions in 6 of 13(45%) of the synchronous advanced adenoma (SAA) subset. In the advanced adenoma (AA) subset, the 1p35-1pter deletion was found exclusively in the SAA. The same 1p deletion was detected in 2 / 42 (6%) of the invasive CRCs and was not detected in non-advanced adenomas. Historically, the 1p region is commonly altered in solid tumors, including CRCs, and reports link the loss of terminal 1p to development of anueploidy and increased genomic instability. For example, SAA patient #1 presented with multiple advanced adenomas but without known family history CRC. Analysis of 3 separate SAAs showed a common 1p terminal deletions with hemizygous loss starting at position 29.92 MB to 35.4 MB. These SAA showed variable losses or gains of whole chromosomes (gain of 7, loss of 10q, loss of 18, and gain of 20q) to suggest increased genomic instability. The 1p deletion, however, was the only large scale alteration in common. Numerous past studies have examined allelic imbalances at 1p loci in colorectal adenomas and CRC; however, isolating a putative tumor suppressor remains elusive. Our strategy includes further analyses of the enriched subset of SAA with more detailed analysis of the high resolution (6 kb average probe coverage) oligo-aCGH data to detect homozygous loss within the 1p region of hemizygous loss. Candidate genes identified in our screens partially confirm those previously described in the literature and include p73, MAD2L2, AK2. In addition, we will describe several novel tumor suppressors identified from the commonly deleted 1p region.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B47.