SHORT REPORT Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer Stephan Wolf, 1,  Daniel Mertens, 1,  Armin Pscherer 1 , Petra Schroeter 1 , Dirk Winkler 2 , Hermann-Josef Gr€ one 3 , Christof Hofele 4 , Kari Hemminki 5 , Rajiv Kumar 5 , Gunnar Steineck 6,7 , Hartmut D€ ohner 2 , Stephan Stilgenbauer 2 and Peter Lichter 1 * 1 Abteilung ‘‘Molekulare Genetik’’, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, Germany 2 Innere Medizin III, University of Ulm, Ulm, Germany 3 Abteilung ‘‘Zellul € are und Molekulare Pathologie’’, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, Germany 4 Klinik f € ur Mund-, Kiefer- und Gesichtschirurgie, Universit € atsklinikum Heidelberg, Im Neuenheimer Feld 400, Heidelberg, Germany 5 Abteilung ‘‘Molekular-Genetische Epidemiologie’’, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, Heidelberg, Germany 6 Karolinska Institutet and G€ oteborg University, Department of Oncology and Pathology Division of Clinical Cancer Epidemiology, Karolinska Hospital, Stockholm, Sweden 7 Department of Oncology, Division of Clinical Cancer Epidemiology, Onkologiskt centrum, G€ oteborg, Sweden Allelic loss of chromosome 8p21–22 is a frequent event in various human cancers including mantle cell lymphoma (MCL), prostate cancer, head and neck squamous cell carcinoma (HNSCC) and bladder cancer. The tumor necrosis factor-related apoptosis induc- ing ligand (TRAIL) receptors, including TNFRSF10A and TNFRSF10B, are located within this chromosomal region. Since recent studies demonstrate that chronic lymphocytic leukemia (CLL) and prostate cells are TRAIL induced apoptosis, TRAIL- receptors are strong tumor suppressor candidate genes in human cancers exhibiting loss of chromosomal material in 8p21.3. How- ever, no mutation of the TRAIL receptor genes has been reported in CLL, MCL, prostate cancer, HNSCC so far. In this study we analyzed the complete coding region of TNFRSF10A and TNFRSF10B in a series of 32 MCL and 101 CLL samples and detected a single nucleotide polymorphism (SNP) in TNFRSF10A (A683C) with tumor specific allele distribution. We examined allele distribution in 395 samples of different tumor entities (pros- tate cancer, n 5 43; HNSCC, n 5 40; bladder cancer, n 5 179) and compared them to 137 samples from healthy probands. We found the rare allele of TNFRSF10A is more frequent in CLL, MCL, prostate cancer, bladder cancer and HNSCC. The A683C polymorphism did not cosegregate with other TNFRSF10A poly- morphisms previously described. Thus screening for 683AfiC nucleotide exchanges may become important in diagnosis and/or treatment of these malignancies. ' 2005 Wiley-Liss, Inc. Key words: TRAIL receptor; Ala228 variant; cancer; polymorphism CLL is associated with an accumulation of mature, noncycling CD5/CD19-positive B lymphocytes. 1 The accumulation of these malignant cells results from impairment of apoptosis rather than from the excessive cellular proliferation that is postulated for the related MCL. 2–5 CLL is characterized by the accumulation of mature, G0 resting B-cells in peripheral blood (PB), bone marrow, spleen and lymph nodes. 6 Standard treatments for CLL include the alkylating agent chlorambucil (CLB) and the nucleoside analog fludarabine (FLU, F-ara-AMP). 7,8 Both agents promote apoptosis via activation of caspases. 9 CLL and MCL have a closely related pattern of genomic abnormalities with frequent loss of material in 13q14.3, 11q22.3-q23.1, 6q21-q23 and 17p13, 10 whereas loss of material in chromosomal band 8p21-22 has been recurrently observed only in MCL. 11 In prostate cancer, loss of heterozygosity (LOH) for markers on 8p is one of the most frequent somatic mutations, occurring in >60% of these tumors, 12 and deletions of 8p22 revealed to be the strongest parameter predictive of disease progression. 13 For HNSCC, a LOH at marker NEFL on 8p21.2 exhibits the most significantly decreased time of survival. 14 In bladder cancer the deletions of chromosome 8p with allelic loss of at least one marker was found in 25% of the cases. These cases are often associated with progressive disease. Invasive tumor growth and an association with papillary growth pattern in patients with invasive disease seems to be correlated with 8p deletions. 15 All these data strongly suggest the presence of a tumorsupressor gene on chromosome band 8p21. Within this chromosomal region, the TRAIL-induced death receptors TNFRSF10A and TNFRSF10B are localized. 16 For TNFRSF10A there are 3 common polymor- phisms described, exhibiting an association with different tumor entities: A C626G single nucleotide polymorphism in exon 4 of TNFRSF10A near the main receptor–ligand interface regions of the protein is associated with a decreased risk of bladder can- cer. 17,18 An additional SNP (G422A) cosegregates with SNP C626G, which is associated with lung cancer, HNSCC and gastric adenocarcinomas. 17 For CLL and MCL an increased occurrence of A1322G polymorphism residing in the death receptor domain of TNFRSF10A is characterized by Fernandez et al. in a very recent study. 19 On the basis of its induction of cell death in various tumor cell lines and its lack of toxicity to most normal cells, TRAIL has recently emerged as a novel potential anticancer agent. 20,21 TRAIL interacts with at least 4 membrane-bound receptors: TNFRSF10A (DR4), TNFRSF10B (DR5, TRICK2), TNFRSF10C (TRID, DcR1, LIT) and TNFRSF10D (DcR2, TRUNDD). 22 Both TNFRSF10A and TNFRSF10B contain a con- served death domain. Binding of TRAIL to its receptors results in trimerization of the receptors and clustering of their intracellular death domains. This leads to the formation of death-inducing sig- naling complexes 23,24 followed by the recruitment of the adaptor molecule Fas-associated death receptor and subsequent binding and activation of caspase-8 and caspase-10. Recently, CLL cells as well as prostate and bladder cancer cells were shown to be resistant to TRAIL induced apoptosis. 25,26 In CLL, this inhibition of apoptosis has to be upstream of caspase-8 activation, since little Grant sponsor: BMBF; Grant number: 01KW9934/8; Grant sponsor: Wilhelm Sander Stiftung; Grant number: 2002.095.1.   The first 2 authors contributed equally to this work. *Correspondence to: Abteilung ‘‘Molekulare Genetik’’, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany. Fax: 149-6221-42-4639. E-mail: s.wolf@dkfz.de Received 3 March 2005; Accepted after revision 29 July 2005 DOI 10.1002/ijc.21502 Published online 10 October 2005 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 118, 1831–1835 (2006) ' 2005 Wiley-Liss, Inc. Publication of the International Union Against Cancer