Abstract 2139: Loss at chr16p13.2 is frequently observed in colorectal neoplasia and is associated with poor prognosis
Authors: Claus Lindbjerg Andersen, Philppe Lamy, Kasper Thorsen, Bodil Øster, Søren Laurberg, Torben F. Ørntoft
Journal: Cancer Research (2010)

Abstract To better understand the clinicopathological and biological significance of genomic alterations in colorectal tumors, we performed high resolution SNP array analysis on a well characterized set of colorectal lesions. Thirty-seven microsatellite stabile (MSS) adenomas, 22 MSS and 6 MSI stage II and III adenocarcinomas and 39 CRC cell lines were investigated by SNP6.0 arrays (Affymetrix). A subset of the tumors was further analyzed by exon arrays (Affymetrix), genomic and reverse transcription real-time PCR, and Sanger sequencing. The SNP6.0 array analysis identified many regions of the genome already known to harbor copy number alterations e.g. gains at chr7, chr8q, chr13, chr20q and losses at chr4, chr5q, chr8p, chr17p, and chr18. But also many novel regions were identified. In adenomas the most frequently observed novel copy number alteration was loss at chr16p13.2, observed in 32% of cases. The carcinomas and CRC cell lines showed this loss even more frequently (41% of MSS, 66% of MSI and 50% in CRC cell lines). This indicated that chr16p loss was an early event, whose presence was associated with an increased probability of disease progression. Furthermore, the data indicated that chr16p loss represented an advantage for both mismatch repair proficient (MSS) and deficient tumors (MSI). Correlation to the available histopathological and outcome data indicated that the presence of the chr16p loss was associated with an aggressive phenotype. In adenomas chr16p loss was most frequently observed in the villous adenoma subtype (44%, 8/18), which has the largest malignancy potential. Only 22% (2/9) of tubulo-villous and 20% (2/10) tubular adenomas showed the loss. Among the stage II and III MSS carcinomas loss was observed in 60% (6/10) of cases with metastatic recurrence and in only 25% (3/12) of non-recurrent cases. Genomic real-time PCR confirmed the losses identified by the SNP6.0 arrays. It was hypothesized that the functional consequence of the chr16p loss could be reduced or lost function of a gene encoded by the locus. The affected locus contains one known and 30 predicted genes (GENESCAN). A thorough transcriptional analysis of these genes was performed using Affymetrix Exon arrays. None of the 434 unique probesets covering the locus indicated differential expression between loss and no-loss cases. For the known gene this finding was confirmed by real-time RT-PCR. Moreover, mutational screening of the coding region of the known gene did not reveal any somatic mutations. In summary, the results indicate that loss of chr16p occurs early in the development of colorectal cancer, provides a selective advantage to both MSS and MSI tumors, and is associated with poor prognosis. The functional consequence of the loss remains unclear, as the expression level of the transcripts encoded by the regions seems to be unaffected by the loss. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2139.