© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 9, 669-674,
May 7, 2003
© 2003 Oxford University Press
ARTICLE |
Association Between Osteosarcoma and Deleterious Mutations in the RECQL4 Gene in Rothmund–Thomson Syndrome
Affiliations of authors: L. L. Wang, A. Gannavarapu, M. M. Chintagumpala (Texas Children’s Cancer Center and Department of Pediatrics), C. A. Kozinetz (Department of Pediatrics), M. L. Levy (Departments of Pediatrics and Dermatology), R. A. Lewis (Departments of Pediatrics, Ophthalmology, and Molecular and Human Genetics), Baylor College of Medicine, Houston, TX; R. R. Maldanado, Department of Dermatology, National University of Mexico, Mexico City; J. C. Ruiz, Department of Dermatology, Hospital General "Dr. Manuel Gea Gonzalez," Mexico City, Mexico; C. Cunniff, R. P. Erickson, University of Arizona College of Medicine, Tucson; D. Lev, Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; M. Rogers, Department of Dermatology, Children’s Hospital at Westmead, Westmead, Australia; E. H. Zackai, Division of Human Genetics and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia; S. E. Plon, Texas Children’s Cancer Center, and Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine.
Correspondence to: Sharon E. Plon, M.D., Ph.D., F.A.C.M.G., Texas Children’s Cancer Center, 6621 Fannin St., MC 3–3320, Houston, TX 77030 (e-mail: splon{at}bcm.tmc.edu).
Background: Rothmund–Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. Methods: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1–30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan–Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. Results: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P = .037; two-sided log-rank test). Conclusions: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.
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