i17q REPA/REPB Rearrangement in Medulloblastoma: A Marker for Early Recurrence.
Gabriel A Bien-Willner, James R Lupski, John Pfeifer. Washington University, St Louis; Baylor College of Medicine, Houston
Background: Medulloblastoma is the most common malignant brain tumor in children, accounting for 20 percent of all pediatric central nervous system tumors. Despite its relatively high incidence, the biology of this entity is poorly understood. Diagnosis is made based on histology, and prognosis is dependent on staging, tumor size, and age of onset. However, clinical factors do not accurately predict which standard-risk patients will have early relapse and die. Outcome is believed to be influenced by grading and the presence of certain molecular markers, including the i17q chromosome. i17q has been shown to correlate with poor prognosis; however, data demonstrating that it is of prognostic value independently of anaplasia are lacking. In a majority of cases, i17q is not a true isochromosome but an isodicentric chromosome (idic(17)(p11.2)), with rearrangement breakpoints within the REPA/REPB low-copy repeat element region in 17p11.2. Low-copy repeat elements are large DNA elements (larger than 1 kb) with greater than 90% homology that facilitate rearrangements by non-allelic homologous recombination. We recently described a FISH-based approach to identify this rearrangement in medulloblastoma and showed it to be both sensitive and specific compared with G-banding analysis.
Design: Using our FISH-based assay, we analyzed 60 consecutive cases of medulloblastoma for the presence of i17q. All cases had a minimum 5-year clinical follow-up. The presence of of i17q, idic(17)(p11.2), and histological grade were compared to the clinical outcome.
Results: 14 (23%) of the cases had i17q, with 10 (17%) having the common rearrangement. All groups, regardless of grade or stage, had worse outcomes with the presence of i17q. Of the standard-risk patients, tumors with i17q had remission, recurrence, and mortality rates of 33%, 67%, and 42%, compared to 54%, 43% and 31%, for those without. Mean time to recurrence and time to mortality were 23.75 and 17.6 months compared to 49.0 and 55.5 months, respectively. Tumors with the common rearrangement had remission, recurrence, and mortality rates of 30%, 70%, and 40%. At five years' post diagnosis, nearly 70% of standard risk patients without i17q were disease-free compared to 45% with the rearrangement. No correlation was present between anaplasia and i17q.
Conclusions: Medulloblastoma patients with i17q have worse outcomes than those without, independent of tumor grade. Our test for i17q may be useful to identify average-risk patients who are more likely to have early relapse.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 212, Monday Morning