Rb1 and CDKNA2 Gene Deletions Do Not Predict Resistance to Neoadjuvant Chemotherapy in Patients with Osteosarcoma
Dariusz Borys, Robert J Canter, Roger A Schultz, Jeffrey Gregg, John W Bishop, Andrew Horvai. University of California Davis, Sacramento, CA; University of California Davis, Sacramento, CA; PerkinElmer, Spokane, WA; UCSF, San Francisco, CA
Background: Pathologic response to neoadjuvant chemotherapy predicts survival in osteosarcoma (OS) patients. However, as pathologic response can only be assessed after treatment is completed. Thus, a need exists for molecular predictors of chemotherapy response that might be used to guide therapy. Consequently, we have previously shown that immunohistochemical expression of P16 (the product of the CDKNA2 gene) predicts response to chemotherapy in patients with osteosarcoma (OS) undergoing neoadjuvant therapy. The objective of the current study was to determine if copy number variations (CNV) of the CDKNA2 and Rb1 genes correlate with immunohistochemical expression of P16 and to determine whether CNV predict response or resistance to neoadjuvant chemotherapy.
Design: Pre-treatment genomic DNA was available from formalin fixed, paraffin-embedded tissue sections in 31 pre-treatment cases of OS. CNV was determined by array comparative genomic hybridization (CGH). Good pathologic response to neoadjuvant chemotherapy was defined as > 90% tumor necrosis in the post-treatment surgical specimen. Clinical, pathologic, and copy number changes of the CDKNA2 and Rb1 genes were correlated for their association with good or poor response to chemotherapy.
Results: Array CGH was informative in 23 of 31 OS tumors. Of 12 tumors which were P16 positive by IHC, 100% demonstrated good response to chemotherapy, while 7 of 11 (64%) P16 negative tumors demonstrated poor response (P=0.001). Among P16 negative tumors by IHC, CDKNA2 homozygous gene deletion was present in only 1 case (14%), while the remainder had intact CDKNA2 or, in two cases, a gain, and LOH (loss of heterozygosity). Although homozygous Rb1 deletion was identified in 15 cases (65%), there was no difference in the prevalence of Rb1 gene deletions between good (8/12) and poor responders (7/11) to chemotherapy (67% vs. 64%, P=1.0).
Conclusions: Although loss of P16 expression in OS is associated with resistance to chemotherapy, only a minority of cases result from deletion of the CDKNA2 gene. Thus, other mechanisms such as smaller gene mutations or altered transcription, translation, or post-translational modification likely account for loss of expression. Although Rb1 gene deletions are common in OS and are thought to play an oncogenic role, they are not associated with response or resistance to neoadjuvant chemotherapy.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 4, Tuesday Afternoon