Originally published as JCO Early Release 10.1200/JCO.2005.01.2799 on August 29 2005

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Loss of Heterozygosity for Chromosomes 1p and 16q Is an Adverse Prognostic Factor in Favorable-Histology Wilms Tumor: A Report From the National Wilms Tumor Study Group

Paul E. Grundy, Norman E. Breslow, Sierra Li, Elizabeth Perlman, J. Bruce Beckwith, Michael L. Ritchey, Robert C. Shamberger, Gerald M. Haase, Giulio J. D'Angio, Milton Donaldson, Max J. Coppes, Marcio Malogolowkin, Patricia Shearer, Patrick R.M. Thomas, Roger Macklis, Gail Tomlinson, Vicki Huff, Daniel M. Green

From the Department of Pediatrics, Roswell Park Cancer Institute; School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York; Departments of Pediatrics and Oncology, Cross Cancer Institute and the University of Alberta, Edmonton; Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; Department of Biostatistics, University of Washington; Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pathology, Children's Memorial Hospital, Chicago, Illinois; Department of Pathology, Loma Linda University, Loma Linda; Department of Pediatrics, Los Angeles Children's Hospital; Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles, California; Department of Pediatric Surgery, The University of Texas at Houston Health Science Center, Houston; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas; Department of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Department of Surgery, Children's Hospital, Boston, Massachusetts and the Department of Surgery, Harvard Medical School, Boston, Massachusetts; Department of Pediatric Surgery, Denver Children's Hospital, Denver, Colorado; Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Cooper Hospital, Camden, New Jersey; Ochsner Clinic Foundation; Tulane University School of Medicine, New Orleans, Louisiana; Department of Radiation Medicine, St Joseph's Hospital, Tampa, Florida; and the Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio

Address reprint requests to Paul Grundy, MD, Department of Pediatrics, 2C3.86 WMC, Stollery Children's Hospital, Edmonton, Alberta, Canada T6G 0E3; e-mail: pgrundy{at}cha.ab.ca.

PURPOSE: To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth National Wilms Tumor Study (NWTS-5).

PATIENTS AND METHODS: Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q.

RESULTS: LOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04).

CONCLUSION: Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.

Supported in part by US Public Health Service Grant No. CA-42326.

Presented at the United Kingdom Children's Cancer Study Group Biology of Childhood Cancer Meeting, London, United Kingdom, December 1-3, 2002, and at the Annual Meeting of the International Society of Pediatric Oncology, Cairo, Egypt, September 10-13, 2003.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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