Utilizing array comparative genomic hybridization (aCGH) to characterize chromosomal stability in microsatellite stable (MSS) young onset rectal cancer. L. Boardman^1,2, R. Johnson^1,3, K. Hafner^1,3, A. Oberg^1,4, B. Morlan^1,4, R. Jenkins^1,3, S. Thibodeau^1,3. 1) Mayo Clinic College of Medicine, Rochester, MN; 2) Division of Gastroenterology and Hepatology; 3) Division of Laboratory Medicine and Pathology; 4) Cancer Center Statistics.
   Approximately 80% of CRC is MSS. MSS CRC has been considered to have chromosomal instability (CIN), as opposed to microsatellite instability (MSI). Tumor phenotyping studies have depicted a portion of MSS CRC as having little or no genetic changes, being chromosomally stable (CIN-), while others exhibited large gains/ losses of genetic material, being CIN+. We selected a group of MSS rectal cancers from people 50 years old with stage II or Stage III disease to assess DNA copy number changes using the Spectral Genomics aCGH which contains nearly 3000 BACs. In all cases, DNA was extracted from chemoradiotherapy naïve rectal cancer. Eight tumors were diploid, 3 were tetraploid and 9 were aneuploid by flow cytometry. Seven tumors (35%) had low levels of chromosomal disruption with < 1% to 17% of the clones having DNA copy number changes and were classified as CIN-. Five tumors (25%) had > 20 % and 30% < of the clones showing DNA alterations, being intermediate CIN. Eight tumors (40%) had a high frequency of alterations in 30-49% of clones and were classified as CIN+. Copy number gains in >40% of tumors were found in chromosome arms 7p/ q, 13q and 20 p/ q and shared smaller consensus regions of gain. 18 p/ q losses were noted in all CIN + tumors but no CIN- tumors, and 17p was lost in all but 1 CIN+ tumor but only 1 CIN-CRC Consensus regions of loss were shared for 17p/ 18 p/q for all CRC showing loss on these arms. Arms more uniformly affected in CIN+ tumors than CIN- CRC included 4p and/or 4q loss in 75%; 7p and/or q gain in 75%; gain of 13q and 20q in 88% of CIN + CRC. Conclusions: These results substantiate that a subset of MSS CRC will have no or little evidence of CIN and represent the molecular subtype of MSS CIN- CRC. Certain chromosomal arms alterations important in CIN+ do not appear to be affected in CIN - CRC, suggesting that the genes involved in CIN- CRC may differ from those in CIN+ CRC.