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Previous Volume 352:1667-1676 April 21, 2005 Number 16 Next

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ABSTRACT

Background The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene.

Methods We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant.

Results We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles.

Conclusions A genetic variant of ARLTS1 predisposes patients to familial cancer.

Source Information

From Thomas Jefferson University, Philadelphia (G.A.C., F.T., M.S., C.D.D., S.Y., D.C., S.R., H.A., H.M., T.S., R.B., C.-G.L., F.B., M.N., C.M.C.); Fox Chase Cancer Center, Philadelphia (A.K.G., B.M.); University of Ferrara, Ferrara, Italy (M.F., G. Bernardi, M.N.); the National Cancer Institute, Aviano, Italy (G. Baldassarre); Aarhus University, Aarhus, Denmark (L.L.H., J.O.); Fundeni Hospital, Bucharest, Romania (V.H.); University La Sapienza, Rome (F.R.M.); the Pasteur Institute, Paris (G.D.); the University of California San Diego, La Jolla (L.R., T.K.); the University of Catanzaro, Catanzaro, Italy (A.F.); Kyushu University, Beppu, Japan (M.M.); Istituto di Ricovero e Cura a Carattere Scientifico, Rome (G.R.); and the Dana–Farber Cancer Institute, Boston (D.N.).

Address reprint requests to Dr. Croce at Ohio State University Comprehensive Cancer Center, 385K Wiseman Hall, 400 W. 12th Ave., Columbus, OH 43210, or at carlo.croce{at}osumc.edu.

Full Text of this Article

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Familial Cancer and ARLTS1
De Brakeleer S., Teugels E., De Grève J., Frank B., Klaes R., Burwinkel B., Calin G. A., Croce C. M., Neuberg D.
Extract | Full Text | PDF  
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N Engl J Med 2006; 354:1204-1205, Mar 16, 2006. Correspondence

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