Correspondence
The APC Gene in Turcot's Syndrome
N Engl J Med 1995; 333:524August 24, 1995
- Article
To the Editor:
Hamilton et al. (March 30 issue)1 demonstrat-ed frequent mutations of the APC gene in patients with Tur-cot's syndrome and showed that medulloblastoma is the predominant brain tumor in families with that syndrome who have APC mutations. In most hereditary tumor syndromes, a germ-line mutation predisposes a family to a unique panoply of tumor types. In the corresponding sporadic tumors, the same gene is usually mutated on a somatic basis.2 Thus, in the same issue of the Journal, Groden3 raised the possibility that the APC gene may also be involved in sporadic medulloblastomas.
We explored this hypothesis after an earlier study showed germ-line mutations of the APC gene in patients with both Turcot's syndrome and medulloblastomas.4 We studied 27 paired blood–tumor DNA samples from 23 patients with sporadic medulloblastomas by assessing the loss of allelic heterozygosity with four highly informative microsatellite markers from chromosome 5q: D5S299, D5S82, D5S346, and interleukin-9. These loci, which had been used to show the linkage between Turcot's syndrome and the APC gene region,5 flank the APC locus on chromosome 5q; D5S346 is located only 30 to 70 kilobases from APC.
In sporadic tumors, the loss of allelic heterozygosity is common at chromosomal loci where mutant tumor-suppressor genes are found. We therefore predicted that allelic loss of the APC region on chromosome 5q would be frequent in patients with sporadic medulloblastomas. No such loss was noted, however, for any of these markers in any of the medulloblastomas, although the same tumors had previously showed allelic losses on other chromosomes such as 17p. Furthermore, Mori et al. screened the mutational hot-spot region of the APC gene in 47 sporadic medulloblastomas and detected no mutations.4 These findings argue against the involvement of the APC gene in the majority of sporadic medulloblastomas, although this possibility cannot be completely ruled out without sequencing the DNA of the entire gene in a large number of medulloblastomas.
The role of the APC gene in medulloblastoma may be analogous to those of the BRCA1 gene in breast carcinoma and the WT1 gene in Wilms' tumor. Germ-line mutations of these genes predispose patients to breast cancer and Wilms' tumor, respectively, but somatic mutations in the corresponding sporadic tumors are rare.6 The absence of APC region loss in sporadic medulloblastomas may thus be another exception to the rule that germ-line mutations in a tumor-suppressor gene result in the same tumor types as somatic mutations in the gene.2
6 ReferencesWilliam H. Yong, M.D.
Massachusetts General Hospital, Boston, MA 02114Corey Raffel, M.D., Ph.D.
Children's Hospital of Los Angeles, Los Angeles, CA 91011Andreas von Deimling, M.D.
Institute for Neuropathology, Bonn, GermanyDavid N. Louis, M.D.
Massachusetts General Hospital, Boston, MA 021141
Hamilton SR ,Liu B ,Parsons RE , et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995;332:839-847
Full Text | Web of Science | Medline2
Knudson AG . All in the (cancer) family. Nat Genet 1993;5:103-104
CrossRef | Web of Science | Medline3
Groden J . Colon-cancer genes and brain tumors. N Engl J Med 1995;332:884-885
Full Text | Web of Science | Medline4
Mori T ,Nagase H ,Horii A , et al. Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosomes Cancer 1994;9:168-172
CrossRef | Web of Science | Medline5
Lasser DM ,DeVivo DC ,Garvin J ,Wilhelmsen KC . Turcot's syndrome: evidence for linkage to the adenomatous polyposis (APC) locus. Neurology 1994;44:1083-1086
Web of Science | Medline6
Boyd J . BRCA1: more than a hereditary breast cancer gene? Nat Genet 1995;9:335-336
CrossRef | Web of Science | Medline
To the Editor:
The work by Hamilton et al. demonstrates nicely that hereditary lesions in different genes ( APC and DNA mismatch-repair genes) may cause the same phenotype, predisposing patients to hereditary cancer (Turcot's syndrome).1 It is regrettable, however, that no germ-line mutation of p53 was sought in the one pedigree (Family 5) in which there was no evidence of a lesion in APC or a DNA mismatch-repair gene, since a hereditary lesion in p53 might cause Turcot's syndrome.2-4 For surveillance of Family 5, it may be important to have this information. The patient we described previously3,5 is still in remission 19 years after treatment for glioblastoma and after surgery for two colon carcinomas, 5 and 14 years ago.
5 ReferencesH. Peter Rutz, M.D.
Basel University Hospital, CH-4031 Basel, SwitzerlandTetsuro Kikuchi, M.D.
Jikei University School of Medicine, Tokyo 105, Japan1
Hamilton SR ,Liu B ,Parsons RE , et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995;332:839-847
Full Text | Web of Science | Medline2
Rosenfeld M ,Schlegel U ,Malkin M , et al. p53 Mutations in glioma polyposis (Turcot syndrome). Neurology 1991;41:Suppl 1:304-304 abstract.3
Kikuchi T ,Rempel SA ,Rutz H-P , et al. Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene. Cancer Res 1993;53:957-961
Web of Science | Medline4
Rochlitz CF ,Heide I ,de Kant E , et al. Molecular alterations in a patient with Turcot's syndrome. Br J Cancer 1993;68:519-523
CrossRef | Web of Science | Medline5
Rutz HP ,de Tribolet N ,Calmes JM ,Chapuis G . Long-time survival of a patient with glioblastoma and Turcot's syndrome. J Neurosurg 1991;74:813-815
CrossRef | Web of Science | Medline
- Citing Articles (10)
Citing Articles
1
Lara Lipton, Ian Tomlinson. (2006) The genetics of FAP and FAP-like syndromes. Familial Cancer 5:3, 221-226
CrossRef2
D. Ellison. (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathology and Applied Neurobiology 28:4, 257-282
CrossRef3
Arend Koch, Anke Waha, J
rg C. Tonn, Nils S
CrossRef4
Robert Wechsler-Reya, Matthew P. Scott. (2001) T
HE DEVELOPMENTAL BIOLOGY OF BRAIN TUMORS . Annual Review of Neuroscience 24:1, 385-428
CrossRef5
Michael D. Taylor, Todd G. Mainprize, James T. Rutka. (2000) Molecular Insight into Medulloblastoma and Central Nervous System Primitive Neuroectodermal Tumor Biology from Hereditary Syndromes: A Review. Neurosurgery 47:4, 888-901
CrossRef6
Huatao Huang, Betania M. Mahler-Araujo, Anna Sankila, Leila Chimelli, Yasuhiro Yonekawa, Paul Kleihues, Hiroko Ohgaki. (2000) APC Mutations in Sporadic Medulloblastomas. The American Journal of Pathology 156:2, 433-437
CrossRef7
Alexander O. Vortmeyer, Theodora Stavrou, Dena Selby, Guang Li, Robert J. Weil, Won-Sang Park, Young-Wan Moon, Roma Chandra, Alisa M. Goldstein, Zhengping Zhuang. (1999) Deletion analysis of the adenomatous polyposis coli andPTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma. Cancer 85:12, 2662-2667
CrossRef8
Michael D. Taylor, James Perry, Magdalena C. Ƶlatescu, Anat O. Stemmer-Rachamimov, L. C. Ang, Yasushi Ino, Michael Schwartz, Laurence E. Becker, David N. Louis, J. Gregory Cairncross. (1999) The hPMS2 exon 5 mutation and malignant glioma. Journal of Neurosurgery 90:5, 946-950
CrossRef9
Dalit Barel, Ian J. Cohen, Celia Mor, Sidi Stern, Rivka Shapiro, Ruth Shomrat, Yaron Galanti, Cyril Legum, Rina Zaizov, Smadar Avigad. (1998) Mutations of the adenomatous polyposis coli and p53 genes in a child with Turcot's syndrome1This work is in partial fulfillment of the requirements for the Ph.D. degree of D. Barel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.1. Cancer Letters 132:1-2, 119-125
CrossRef10
Erwin Van Meir. (1998) Turcot's syndrome: Phenotype of brain tumors, survival and mode of inheritance. International Journal of Cancer 75:1, 162-164
CrossRef
