Gene Deletion Underlies Loss of P16 Expression in Osteosarcoma Tumors with Poor Response to Neoadjuvant Chemotherapy
Dariusz Borys, Robert Canter, Jeffrey Gregg, Ben Hoch, Ryan Davis, Andrew Horvai. University of California Davis, Sacramento; UC Davis, Sacramento; University of Washington, Seattle; UCSF, San Francisco
Background: Although pathologic response to neoadjuvant chemotherapy predicts survival among patients with osteosarcoma (OS), there are currently no established molecular markers to predict response to chemotherapy. We have previously shown that immunohistochemical (IHC) expression of p16 (the product of the CDKNA2 gene) in OS is significantly correlated with pathologic response to neoadjuvant chemotherapy. The objective of the current study was to assess for copy number alternations at the CDKNA2 gene on chromosome 9 in p16 IHC-expressing and IHC-non-expressing OS specimens.
Design: Genomic DNA was obtained from paraffin-embedded pretreatment biopsy specimens of OS patients prior to receiving neoadjuvant chemotherapy. We selected three cases of p16 IHC-expressing tumors with pathologic response to chemotherapy (≥ 90% tumor necrosis) and three cases of P16 IHC-non-expressing tumors without pathologic response (< 90% tumor necrosis). Human genomic array was performed on 44K arrays using 80 Gb per human genome at 30X coverage. The CDKN2A locus (p16) on chromosome 9 was probed with A_14_P129522 chr9, A_14_P130650 chr9 and A_14_P112983 chr9.
Results: Four of the 6 cases yielded complete copy number information (2 p16 IHC-expressing, 2 p16 IHC-non-expressing). Among p16 expressing tumors, both demonstrated a wildtype CDKNA2 locus, while one of two p16 non-expressing tumors had a deletion on the short arm of chromosome 9 including the CDKNA2 locus.
Conclusions: Deletion of the entire CDKNA2 locus explains loss of p16 expression in some OS patients with poor response to neoadjuvant chemotherapy. However diverse mechanisms may be responsible for loss of p16 expression across the population of OS patients. Additional molecular studies are needed to validate these findings.
Category: Bone & Soft Tissue
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 6, Tuesday Morning