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Birth defects and cancer due to small chromosomal deletions
June 1980 TheJournalofPEDIATRICS
1031
Birth defects and cancer due to small chromosomal deletions
FIFTEEN YEARS AGO the excessive occurrence of Wilms tumor with sporadic aniridia was first demonstrated. 1 A chromosomal anomaly, long suspected, could not be demonstrated until refinements in cytogenetic techniques were developed by Yunis in 19767 His method for preparing chromosomes for study while in the lengthened state during prophase or prometaphase increased the n u m b e r of bands that could be seen from about 300 to
1,500. The technique has revealed a small deletion of chromosome l l as a cause of the Wilms tumor-aniridia synd r o m e ? Something more than chromosomal deletion is needed for development of Wilms tumor in these children, as indicated by the occurrence of the neoplasm in only one m e m b e r of a pair of identical twins with the identical chromosomal abnormality? In this issue of THE JOURNAL, Yunis and Ramsay describe familial Wilms tumor-aniridia syndrome in three first-degree relatives of a w o m a n with a balanced interstitial translocation (from the short arm o f chromosome 1 l to the 10ng arm of chromosome 2). Earlier methods would not have detected the transmissible chromosomal defect that explains this family cluster. A similar circumstance applies to certain children with retinoblastoma and malformations due to a deletion of the long arm of chromosome 137 A m o n g adults, renal cell carcinoma developed in ten members of a family with a seemingly balanced translocation from chromosome 3 to 8. 6 Many questions arise. Are the tumors morphologically and cytogenetically identical to those that occur in patients without the syndrome? Do the patients with Wilms tumor and aniridia exhibit subcapsular renal dysplasia as found in children with the hereditary form of the neoplasm? 7 How do deletions cause cancer? Is it by gene deletion or, as suggested by Riccardi et al) due to gene interactions, a position effect or hemizygosity? According to Gerald, the answers may well come from
D N A sequencing and recombinant D N A technology) F r o m these rare h u m a n disorders for which no animal models are yet known, new information about the pathogenesis of birth defects and cancer is likely to emerge. Meanwhile, the clinician who knows of these recent developments can provide appropriate genetic counseling, can suggest amniocentesis when a parent is known to have certain small chromosomal anomalies, and can detect the tumors earlier than usual for treatment, which can be life-saving. Robert W. Miller, M.D. Clinical Epidemiology Branch National Cancer Institute Betbesda, MD 20205
REFERENCES 1. Miller RW, Fraumeni JF, and Manning MD: Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations, N Engl J Med 270:922, 1964. 2. Yunis JJ: High resolution of human chromosomes, Science 191:1268, 1976. 3. Hinner HM, Riccardi VM, and Francke U: Aniridia caused by a heritable chromosome 11 deletion, Ophthalmology (Rochester), 86:1173, 1979. 4. Francke U, Riccardi VM, Hittner HM, and Borges W: Interstitial del (1 lp) as a cause of the aniridia-Wilms' tumor association: band localization and a heritable basis, Am J Hum Genet 30:81A, 1978. 5. Riccardi VM, Hittner HM, Francke U, Pippin S, Holmquist GP, Kretzer FL, and Ferrell R: Partial triplication and deletion of 13q: study of a family presenting with bilateral retinoblastomas, Clin Genet 15:332, 1979. 6. Cohen AJ, Li FP, Berg S, Marchetto SM, Tsai S, Jacobs SC, and Brown RS: Hereditary renal-cell carcinoma associated with a chromosomal translocation, N Engl J Med 301:592, 1979. 7. Bove KE, and McAdams AJ: The nephroblastomatosis complex and its relationship to Wilms' tumor: A clinicopathological treatise, Perspect Pediatr Pathol 3:185, 1976. 8. McBride G: Chromosome analysis techniques expand; new links to cancer, JAMA 242:1239, 1979.
VoL 96, No. 6, p. 1031
1031
Birth defects and cancer due to small chromosomal deletions
FIFTEEN YEARS AGO the excessive occurrence of Wilms tumor with sporadic aniridia was first demonstrated. 1 A chromosomal anomaly, long suspected, could not be demonstrated until refinements in cytogenetic techniques were developed by Yunis in 19767 His method for preparing chromosomes for study while in the lengthened state during prophase or prometaphase increased the n u m b e r of bands that could be seen from about 300 to
1,500. The technique has revealed a small deletion of chromosome l l as a cause of the Wilms tumor-aniridia synd r o m e ? Something more than chromosomal deletion is needed for development of Wilms tumor in these children, as indicated by the occurrence of the neoplasm in only one m e m b e r of a pair of identical twins with the identical chromosomal abnormality? In this issue of THE JOURNAL, Yunis and Ramsay describe familial Wilms tumor-aniridia syndrome in three first-degree relatives of a w o m a n with a balanced interstitial translocation (from the short arm o f chromosome 1 l to the 10ng arm of chromosome 2). Earlier methods would not have detected the transmissible chromosomal defect that explains this family cluster. A similar circumstance applies to certain children with retinoblastoma and malformations due to a deletion of the long arm of chromosome 137 A m o n g adults, renal cell carcinoma developed in ten members of a family with a seemingly balanced translocation from chromosome 3 to 8. 6 Many questions arise. Are the tumors morphologically and cytogenetically identical to those that occur in patients without the syndrome? Do the patients with Wilms tumor and aniridia exhibit subcapsular renal dysplasia as found in children with the hereditary form of the neoplasm? 7 How do deletions cause cancer? Is it by gene deletion or, as suggested by Riccardi et al) due to gene interactions, a position effect or hemizygosity? According to Gerald, the answers may well come from
D N A sequencing and recombinant D N A technology) F r o m these rare h u m a n disorders for which no animal models are yet known, new information about the pathogenesis of birth defects and cancer is likely to emerge. Meanwhile, the clinician who knows of these recent developments can provide appropriate genetic counseling, can suggest amniocentesis when a parent is known to have certain small chromosomal anomalies, and can detect the tumors earlier than usual for treatment, which can be life-saving. Robert W. Miller, M.D. Clinical Epidemiology Branch National Cancer Institute Betbesda, MD 20205
REFERENCES 1. Miller RW, Fraumeni JF, and Manning MD: Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations, N Engl J Med 270:922, 1964. 2. Yunis JJ: High resolution of human chromosomes, Science 191:1268, 1976. 3. Hinner HM, Riccardi VM, and Francke U: Aniridia caused by a heritable chromosome 11 deletion, Ophthalmology (Rochester), 86:1173, 1979. 4. Francke U, Riccardi VM, Hittner HM, and Borges W: Interstitial del (1 lp) as a cause of the aniridia-Wilms' tumor association: band localization and a heritable basis, Am J Hum Genet 30:81A, 1978. 5. Riccardi VM, Hittner HM, Francke U, Pippin S, Holmquist GP, Kretzer FL, and Ferrell R: Partial triplication and deletion of 13q: study of a family presenting with bilateral retinoblastomas, Clin Genet 15:332, 1979. 6. Cohen AJ, Li FP, Berg S, Marchetto SM, Tsai S, Jacobs SC, and Brown RS: Hereditary renal-cell carcinoma associated with a chromosomal translocation, N Engl J Med 301:592, 1979. 7. Bove KE, and McAdams AJ: The nephroblastomatosis complex and its relationship to Wilms' tumor: A clinicopathological treatise, Perspect Pediatr Pathol 3:185, 1976. 8. McBride G: Chromosome analysis techniques expand; new links to cancer, JAMA 242:1239, 1979.
VoL 96, No. 6, p. 1031