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Analysis of 1p, 19q, 9p, and 10q as prognostic markers for high-grade astrocytomas using fluorescence in situ hybridization on tissue microarrays from Radiation Therapy Oncology Group trials

Radiation Therapy Oncology Group (RTOG) Translational Research Program, Philadelphia, PA: Departments of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 (D.J.B.); RTOG Statistical Division, Philadelphia, PA 19107 (W.F.S.); Division of Neuropathology, Washington University School of Medicine, St. Louis, MO 63110 (A.P.); Department of Pathology, LDS Hospital, Salt Lake City, UT 84143 (E.H.H.); Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226 (K.J.M.); Department of Radiation Oncology, SUNY Health Sciences Center, Brooklyn, NY 11203 (A.R.S.); Department of Human Oncology, University of Wisconsin Medical School, Madison, WI 53792 (M.P.M.); Department of Radiation Oncology, Jefferson Medical College, Philadelphia, PA 19107 (W.J.C.); USA

² Address correspondence to Daniel J. Brat, Department of Pathology and Laboratory Medicine, Emory University Hospital H-176, 1364 Clifton Road NE, Atlanta, GA 30322 (dbrat{at}emory.edu).

Abstract

Survival periods vary considerably for patients with high-grade astrocytomas, and reliable prognostic markers are not currently available. We therefore investigated whether genetic losses from chromosomes 1p, 19q, 9p, or 10q were associated with survival in 89 high-grade astrocytomas using tissue microarrays (TMAs) derived from Radiation Therapy Oncology Group clinical trials. Cases included 15 anaplastic astrocytomas (AAs) and 74 glioblastomas (GBMs) selected on the basis of survival times significantly shorter or longer than the expected median. Genetic analysis was performed by TMA-fluorescence in situ hybridization (FISH) on array sections using 8 DNA probes, including those directed at 1p32, 19q13.4, 9p21 (p16/CDKN2A), and 10q (PTEN and DMBT1). Genetic status for each locus was correlated with patient survival group, and data were analyzed by using Fisher's exact test of association (adjusted P = 0.025). Losses of chromosome 1p, either alone or in combination with 19q, were encountered in only 2 cases, both AAs. This contrasts with oligodendrogliomas, in which combined 1p and 19q losses are frequent and predictive of prolonged survival. Solitary 19q loss was noted in 3/15 AAs and in 7/70 GBMs and was more frequent in the long-term survival group (P = 0.041, AA and GBM combined). Chromosome 9p loss was seen in 5/8 AAs and 39/57 GBMs, whereas chromosome 10q loss was detected in 4/15 AAs and 48/68 GBMs. The 9p and 10q deletions were slightly more frequent in short-term survivors, though none of the comparisons achieved statistical significance. Long-term and short-term survival groups of high-grade astrocytomas appear to have dissimilar frequencies of 19q, 9p, and 10q deletions. TMA-FISH is a rapid and efficient way of evaluating genetic alterations in such tumors.

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