7150 Vol. 10, 7150–7156, November 1, 2004 Clinical Cancer Research Featured Article Genetic Analysis of the RNASEL Gene in Hereditary, Familial, and Sporadic Prostate Cancer Fredrik Wiklund,1 Bjo¨rn-Anders Jonsson,2 0.77; 95% confidence interval, 0.59–1.00) and reduced risk Anthony J. Brookes,3 Linda Stro¨mqvist,3 of prostate cancer in carriers of two different haplotypes being completely discordant. Jan Adolfsson,4 Monica Emanuelsson,1 5 5 Conclusions: Considering the high quality in genotyp- Hans-Olov Adami, Katarina Augustsson-Ba¨lter, ing and the size of this study, these results provide solid 1 and Henrik Gro¨nberg evidence against a major role of RNASEL in prostate cancer Department of 1Radiation Sciences, Oncology, and 2Medical etiology in Sweden. Biosciences, Pathology, University of Umeå, Umeå, Sweden; and 3Center for Genomics and Bioinformatics, 4Oncologic Center, Department of Surgical Sciences, and 5Department of Medical INTRODUCTION Epidemiology and Biostatistics, Karolinska Institutet, Sweden Accumulating evidence from epidemiologic and genetic studies indicates that hereditary predisposition has a consider- ABSTRACT able impact on the development of prostate cancer. Linkage analyses suggest that a number of chromosomal regions harbor Purpose: The RNASEL gene has been proposed as a prostate cancer susceptibility genes. However, lack of consis- candidate gene for the HPC1 locus through a positional tency between studies additionally indicates that prostate cancer cloning and candidate gene approach. Cosegregation be- is a genetically heterogeneous disorder, with multiple genetic tween the truncating mutation E265X and disease in a he- and environmental factors involved in its etiology (1). In 1996, reditary prostate cancer (HPC) family and association be- the first prostate cancer susceptibility locus, HPC1, was mapped tween prostate cancer risk and the common missense to chromosome 1q24-25 (2). Subsequent studies of linkage to variant R462Q has been reported. To additionally evaluate HPC1 have proven inconclusive; some confirmed linkage (3– the possible role of RNASEL in susceptibility to prostate 6), although others did not (7–11). However, in a pooled anal- cancer risk, we performed a comprehensive genetic analysis ysis of 772 families from nine international groups confirmatory of sequence variants in RNASEL in the Swedish population. linkage evidence was found with a maximum heterogeneity Experimental Design: Using 1624 prostate cancer cases logarithm of odds score of 1.4 (12). and 801 unaffected controls, the truncating mutation E265X RNASEL maps to HPC1 and is involved in the IFN-regu- and five common sequence variants, including the two missense lated 2Ј-5Ј–linked oligoadenylates system that mediates cell mutations R462Q and D541E, were evaluated for association proliferation and apoptosis (13, 14) and has been suggested as a between genotypes/haplotypes and prostate cancer risk. candidate tumor suppressor gene (15). RNASEL was recently Results: The prevalence of E265X carriers among un- identified as a candidate gene for HPC1 through a positional affected controls and prostate cancer patients was almost cloning and candidate gene approach. A truncating mutation identical (1.9 and 1.8% in controls and cases, respectively), (E265X) and an initiation codon mutation (M1I) was reported to and evidence for segregation of E265X with disease was not cosegregate within two hereditary prostate cancer (HPC; ref. 2) observed within any HPC family. Overall, the analyses of families linked to HPC1 (16). Furthermore, loss of the wild-type common sequence variants provided limited evidence for allele and reduced RNASEL activity was observed in microdis- association with prostate cancer risk. We found a marginally sected tumors carrying a germ-line mutation. In Finnish HPC significant inverse association between the missense muta- families, RNASEL mutations did not explain disease segrega- tion D541E and sporadic prostate cancer risk (odds ratio, tion; however, the truncating mutation E265X was associated with prostate cancer risk (17). In addition to rare mutations, several polymorphisms in RNASEL have been reported. A common missense variant of Received 5/19/04; accepted 7/26/04. RNASEL, R462Q, has been associated both with increased (17, Grant support: F. Wiklund received support from Swedish Cancer 18) and decreased (19, 20) risk of HPC. Recently, Xiang et al. Society (Cancerfonden), Lion’s Cancer Foundation, and Stiftelsen fo¨r (21) reported that the R462Q variant reduces the ability of Strategisk Forskning (Genome Program). RNase L to cause apoptosis in response to activation by 2-5A. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Hence, this polymorphism might have a functional role in pros- advertisement in accordance with 18 U.S.C. Section 1734 solely to tate cancer development. Another missense variant, D541E, was indicate this fact. associated with an increased risk for prostate cancer in a study Requests for reprints: Fredrik Wiklund, Department of Radiation from Japan (19), although several other studies found no asso- Sciences, Oncology, University of Umeå, 901 87 Umeå, Sweden. Phone: 46-90-7852270; Fax: 46-90-127464; E-mail: fredrik.wiklund@ ciation (17, 18, 20). oc.umu.se. Additional evaluation of the impact that the RNASEL gene ©2004 American Association for Cancer Research. have on prostate cancer risk are required. Our aim was to assess Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 7151 the possible role of RNASEL sequence variants on prostate (same as for cases). Subsequently, eight controls were excluded cancer risk in a Swedish population. We used a large popula- because linkage to the Swedish Cancer Registry revealed that tion-based case-control study, composed of 1624 prostate cancer they were diagnosed with a cancer of the prostate before inclu- cases and 801 controls. The truncating mutation E265X and sion. At the time of this study, DNA samples were available for several common polymorphisms in RNASEL were evaluated, 801 controls and 1427 cases (1247 sporadic prostate cancer both for individual association and through haplotype analyses. cases, 131 familial prostate cancer cases, and 49 HPC cases). Patients with Familial Prostate Cancer and HPC. Re- MATERIALS AND METHODS cruitment of Swedish families with prostate cancer is an ongo- Patients with Prostate Cancer and Controls. This ing activity that started at the Department of Oncology, Univer- study used men enrolled into the population based case-control sity of Umeå, in 1995. Identification of families has been based study Cancer Prostate in Sweden. A detailed description of the mainly on referrals by collaborating urologists and oncologists Cancer Prostate in Sweden study has been given elsewhere (22). throughout Sweden but also on self-reported family history of The Cancer Prostate in Sweden study is composed of all prostate prostate cancer from cases included into the Cancer Prostate in cancer patients, ages Յ 79 years, diagnosed between July 1, Sweden study, described above. Blood has been collected for as 2001, and September 30, 2002, from the central and northern many family members as possible. For the present study, all part of Sweden and all patients, ages Յ 65 years, diagnosed in affected family members with DNA information available (ex- the same calendar period from the southeastern part of Sweden cluding cases from the Cancer Prostate in Sweden cohort al- and the area of Stockholm. In total, 1961 prostate cancer pa- ready selected for this study) were included, resulting in 184 tients were invited for participation and 1444 (74%) agreed to HPC cases and 25 familial prostate cancer cases. All diagnoses participate. All these cases donated a blood sample and an- of prostate cancer in the families were confirmed both by swered a questionnaire, including questions regarding family reference to the Cancer Registry and by direct examination of history for prostate cancer. For all cases with at least one medical records. reported family member with prostate cancer, based on the Total Study Population. Our total study population is initial questionnaire, a more detailed family history was ob- composed of 1636 prostate cancer patients and 801 unaffected tained through a second questionnaire followed by a telephone controls. Of the 1636 prostate cancer patients, 156 (9.5%) and interview. 233 (14.2%) were classified as familial prostate cancer and HPC Of the 1444 cases included in the study, 143 were classified cases, respectively. Pertinent characteristics of the study popu- as familial prostate cancer cases (two relatives with verified lation are given in Table 1. Written informed consent was prostate cancer in a nuclear family) and 51 as HPC cases (three obtained from each subject. The ethical committee at the Karo- or more members with prostate cancer in a nuclear family). linska Institutet and University of Umeå approved the study. Detailed clinical data, including tumor-node-metastasis stage, Selection of RNASEL Single Nucleotide Polymorphisms Gleason score, prostate-specific antigen level at time of diag- (SNPs). Located on chromosome 1q22, the RNASEL gene nosis, means of diagnosis and primary treatment were obtained with eight exons is ϳ13 kb. To comprehensively evaluate as- through linkage to the National Prostate Cancer Registry. Cases sociation