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ARLTS1 Trp149Stop Mutation and the Risk of Ovarian Cancer

Bartomiej Masoj, Krzysztof Mdrek, Tadeusz Dbniak and Jan Lubiski

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

Lucjan S. Wyrwicz, Grzegorz Koczyk, Marcin Hoffmann and Leszek Rychlewski

BioInfoBank Institute, Poznan, Poland

To the Editor:

In a recent report, Petrocca et al. (1) provided data on involvement of the ARLTS1 (ARL11) gene alterations in development of both ovarian and breast cancers. The authors clearly showed the tumor-suppressor function of ARLTS1 in ovarian cancer and the biological importance of Trp149Stop(G446A) polymorphism in both ovarian and breast cancer models. The authors also discussed possible counterpart roles of common nonsense polymorphisms in the pathogenesis of both hereditary breast and ovarian cancers.

In contrast, our previous study (2) did not support the important role of the G446A variant in inherited susceptibility to cancer—a similar frequency of the G446A allele was observed among 1,686 patients with unselected tumors (breast, prostate, thyroid, larynx, and melanoma), 462 cases with familial aggregations of cancers, and 552 controls. Several studies reported no association of G446A variant with chronic lymphocytic leukemia (3), colorectal cancer (4), and malignant melanoma (5). One study reported a positive association of the G446A with bilateral breast cancer (6).

To investigate if the G446A variant acts as a low-risk ovarian cancer susceptibility allele, we genotyped 250 women with unselected ovarian cancer and 552 controls using the methodology as described previously (2). The G446A allele was seen in 1.2% (3 of 250) of cases and in 1.45% (8 of 552) of controls (odds ratio, 0.83; 95% confidence interval, 0.2–3.1; P = 1.0, Fisher's exact test).

Additionally, to investigate the molecular effect of ARLTS1 polymorphism, we constructed a protein model using homology modeling with ARF6 protein as a template (7). According to the obtained model (Fig. 1 ), a nonsense mutation Trp149Stop resulted in a truncated protein product, lacking the fragment responsible for GTP binding. The likely loss of function resulting from truncation was confirmed by analysis of known human ADP-ribosylation factors. The truncated open-reading frames corresponding to the mutant allele were observed neither among the transcripts nor among their alternative splicing products. We conclude that the G446A is likely a mutated, dysfunctional product, due to its inability to bind GTP and consequently to perform GTP-mediated ribosylation, described to be essential for protein trafficking (8).

View larger version (45K): [in this window] [in a new window] [Download PPT slide]   Figure 1. ARLTS1 (ARF11) modeled with Modeller 6.2 on the template of the ARF6 protein (PDB code: 2a5dA). The selection of the template was confirmed with the confident 3D-Jury score of 122.40 (7). Red, the COOH-terminal fraction of protein product removed by the G446A mutation. GTP (pink) and Mg2+ ion (orange) were located according to the template coordinates. Gray, Trp149.

Footnotes

¹ Protein models are available in Supplementary Materials at http://lucjan.bioinfo.pl/supplemental/ARF11. The authors thank the support of EC (LSHG-CT-2003–503265) and MNiSW (PBZ-MNiI-2/1/2005) grants. L.S. Wyrwicz is a fellow of the Young Scientist Award from The Foundation for Polish Science.

References

1. Petrocca F, Iliopoulos D, Qin H, et al. Alterations of the tumor-suppressor gene ARLTS1 in ovarian cancer. Cancer Res 2006;66:10287–91.[Abstract/Free Full Text]
2. Masojc B, Mierzejewski M, Cybulski C, et al. Cancer familial aggregation (CFA) and G446A polymorphism in ARLTS1 gene. Breast Cancer Res Treat 2006;99:59–62.[CrossRef][Medline]
3. Sellick GS, Catovsky D, Houlston RS. Relationship between ARLTS1 polymorphisms and risk of chronic lymphocytic leukemia. Leuk Res 2006;30:1573–6.[CrossRef][Medline]
4. Frank B, Hemminki K, Brenner H, et al. ARLTS1 variants and risk of colorectal cancer. Cancer Lett 2006;244:172–5.[CrossRef][Medline]
5. Frank B, Meyer P, Boettger M, et al. ARLTS1 variants and melanoma risk. Int J Cancer 2006;119:1736–7.[CrossRef][Medline]
6. Frank B, Hemminki K, Meindl A, et al. Association of the ARLTS1 Cys¹⁴⁸Arg variant with familial breast cancer risk. Int J Cancer 2006;118:2505–8.[CrossRef][Medline]
7. von Grotthuss M, Pas J, Wyrwicz L, et al. Application of 3D-Jury GRDB, Verify3D in fold recognition. Proteins 2003;53:418–23.[CrossRef][Medline]
8. D'Souza-Schorey C, Chavrier P. ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 2006;7:347–58.[CrossRef][Medline]
9. Calin G, Trapasso F, Shimizu M, et al. Familial cancer associated with a polymorphism in ARLTS1. N Engl J Med 2005;352:1667–76.[Abstract/Free Full Text]

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