FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

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

	Full Text PDF PDA Full Text PowerPoint Slide Set Letters Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

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

Related Letters:

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  
N Engl J Med 2005; 353:313-314, Jul 21, 2005. Correspondence

Familial Cancer Associated with a Polymorphism in ARLTS1
Sellick G. S., Catovsky D., Houlston R. S., Calin G. A., Croce C. M., Neuberg D.
Extract | Full Text | PDF  
N Engl J Med 2006; 354:1204-1205, Mar 16, 2006. Correspondence

This article has been cited by other articles:

• Hanlon, K., Harries, L. W., Ellard, S., Rudin, C. E. (2009). Evaluation of 13q14 Status in Multiple Myeloma by Digital Single Nucleotide Polymorphism Technology. J. Mol. Diagn. 11: 450-457 [Abstract] [Full Text]  
• Crowther-Swanepoel, D., Houlston, R. S. (2009). The molecular basis of familial chronic lymphocytic leukemia. haematol 94: 606-609 [Full Text]  
• Libe, R., Fratticci, A., Coste, J., Tissier, F., Horvath, A., Ragazzon, B., Rene-Corail, F., Groussin, L., Bertagna, X., Raffin-Sanson, M. L., Stratakis, C. A., Bertherat, J. (2008). Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors. Clin. Cancer Res. 14: 4016-4024 [Abstract] [Full Text]  
• Calin, G. A., Croce, C. M. (2008). MicroRNA-Cancer Connection: The Beginning of a New Tale. aacredbook 2008: 667-675 [Abstract] [Full Text]  
• Hauswirth, A. W., Jager, U. (2008). Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia. haematol 93: 14-19 [Full Text]  
• Yendamuri, S., Trapasso, F., Ferracin, M., Cesari, R., Sevignani, C., Shimizu, M., Rattan, S., Kuroki, T., Dumon, K. R., Bullrich, F., Liu, C.-g., Negrini, M., Williams, N. N., Kaiser, L. R., Croce, C. M., Calin, G. A. (2007). Tumor Suppressor Functions of ARLTS1 in Lung Cancers. Cancer Res. 67: 7738-7745 [Abstract] [Full Text]  
• Castellvi-Bel, S., Castells, A., de Cid, R., Munoz, J., Balaguer, F., Gonzalo, V., Ruiz-Ponte, C., Andreu, M., Llor, X., Jover, R., Bessa, X., Xicola, R. M., Pons, E., Alenda, C., Paya, A., Carracedo, A., Pique, J. M., for the Gastrointestinal Oncology Group of the Spa, (2007). Association of the ARLTS1 Cys148Arg variant with sporadic and familial colorectal cancer. Carcinogenesis 28: 1687-1691 [Abstract] [Full Text]  
• Bowzard, J. B., Cheng, D., Peng, J., Kahn, R. A. (2007). ELMOD2 Is an Arl2 GTPase-activating Protein That Also Acts on Arfs. J. Biol. Chem. 282: 17568-17580 [Abstract] [Full Text]  
• Masojc, B., Medrek, K., Debniak, T., Lubinski, J., Wyrwicz, L. S., Koczyk, G., Hoffmann, M., Rychlewski, L. (2007). ARLTS1 Trp149Stop Mutation and the Risk of Ovarian Cancer. Cancer Res. 67: 4533-4533 [Full Text]  
• Petrocca, F., Calin, G. A., Croce, C. M. (2007). ARLTS1 Trp149Stop Mutation and the Risk of Ovarian Cancer. Cancer Res. 67: 4534-4534 [Full Text]  
• Ng, D., Toure, O., Wei, M.-H., Arthur, D. C., Abbasi, F., Fontaine, L., Marti, G. E., Fraumeni, J. F. Jr, Goldin, L. R., Caporaso, N., Toro, J. R. (2007). Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia. Blood 109: 916-925 [Abstract] [Full Text]  
• Petrocca, F., Iliopoulos, D., Qin, H. R., Nicoloso, M. S., Yendamuri, S., Wojcik, S. E., Shimizu, M., Di Leva, G., Vecchione, A., Trapasso, F., Godwin, A. K., Negrini, M., Calin, G. A., Croce, C. M. (2006). Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer. Cancer Res. 66: 10287-10291 [Abstract] [Full Text]  
• Calin, G. A., Croce, C. M. (2006). MicroRNA-Cancer Connection: The Beginning of a New Tale.. Cancer Res. 66: 7390-7394 [Abstract] [Full Text]  
• Corral, J., Gonzalez-Conejero, R., Soria, J. M., Gonzalez-Porras, J. R., Perez-Ceballos, E., Lecumberri, R., Roldan, V., Souto, J. C., Minano, A., Hernandez-Espinosa, D., Alberca, I., Fontcuberta, J., Vicente, V. (2006). A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis. Blood 108: 177-183 [Abstract] [Full Text]  
• Sellick, G. S., Catovsky, D., Houlston, R. S., Calin, G. A., Croce, C. M., Neuberg, D. (2006). Familial cancer associated with a polymorphism in ARLTS1.. NEJM 354: 1204-1205 [Full Text]  
• Wirtenberger, M., Tchatchou, S., Hemminki, K., Klaes, R., Schmutzler, R. K., Bermejo, J. L., Chen, B., Wappenschmidt, B., Meindl, A., Bartram, C. R., Burwinkel, B. (2006). Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer. Carcinogenesis 27: 593-598 [Abstract] [Full Text]  
• Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. I., Fabbri, M., Iuliano, R., Palumbo, T., Pichiorri, F., Roldo, C., Garzon, R., Sevignani, C., Rassenti, L., Alder, H., Volinia, S., Liu, C.-g., Kipps, T. J., Negrini, M., Croce, C. M. (2005). A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 353: 1793-1801 [Abstract] [Full Text]  
• De Brakeleer, S., Teugels, E., De Greve, J., Frank, B., Klaes, R., Burwinkel, B., Calin, G. A., Croce, C. M., Neuberg, D. (2005). Familial Cancer and ARLTS1. NEJM 353: 313-314 [Full Text]