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Nucleotide Variations in Genes Encoding Plasminogen Activator Inhibitor-2 and Serine Proteinase Inhibitor B10 Associated with Prostate Cancer

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Nucleotide Variations in Genes Encoding Plasminogen Activator Inhibitor-2 and Serine Proteinase Inhibitor B10 Associated with Prostate Cancer J Hum Genet (2005) 50: 507–515 DOI 10.1007/s10038-005-0285-1 ORIGINAL ARTICLE Go Shioji Æ Yoichi Ezura Æ Toshiaki Nakajima Kenji Ohgaki Æ Hiromichi Fujiwara Æ Yoshinobu Kubota Tomohiko Ichikawa Æ Katsuki Inoue Æ Taro Shuin Tomonori Habuchi Æ Osamu Ogawa Æ Taiji Nishimura Mitsuru Emi Nucleotide variations in genes encoding plasminogen activator inhibitor-2 and serine proteinase inhibitor B10 associated with prostate cancer Received: 2 May 2005 / Accepted: 25 July 2005 / Published online: 20 September 2005 Ó The Japan Society of Human Genetics and Springer-Verlag 2005 Abstract Genes encoding the serine proteinase inhibitor variations within SERPINB loci at 18q21 might be Bfamily(SERPINBs) are mainly clustered on human associated with risk of prostate cancer in Japanese men. chromosome 18 (18q21). Several serpins are known to A case-control study involving 292 prostate-cancer pa- affect malignant phenotypes of tumor cells, so aberrant tients and 384 controls revealed significant differences in genetic variants in this molecular family are candidates regard to distribution of four missense variations in genes for conferring susceptibility for risk of cancer. We encoding plasminogen activator inhibitor 2 (PAI2)and investigated whether eight selected non-synonymous SERPINB10. The most significant association was de- tected for the N120D polymorphism in the PAI2 gene À5 G. Shioji Æ Y. Ezura Æ T. Nakajima Æ K. Ohgaki (P=5.0·10 ); men carrying the 120-N allele (120-N/N H. Fujiwara Æ M. Emi and 120-N/D genotypes) carried a 2.4-fold increased risk Department of Molecular Biology, Institute of Gerontology, of prostate cancer (95% confidence interval 1.45–4.07). Nippon Medical School, Kawasaki, Japan Associations were also detected for three other missense polymorphisms in those two genes. Strong linkage dis- G. Shioji Æ K. Ohgaki Æ H. Fujiwara Æ T. Nishimura Department of Urology, Nippon Medical School, Tokyo, Japan equilibrium in the region encompassing PAI2 and SER- PINB10 extended to about 50 kbp. The results suggested Y. Ezura (&) that missense variations in one or both of these genes Department of Molecular Pharmacology, confer important risks for prostate cancer, and may be Medical Research Institute, Tokyo Medical and Dental University, themselves tumorigenic. Although confirmative replica- 2-3-10 Kanda-Surugadai, Chiyoda-ku, tion studies on larger cohorts are awaited, clinical Tokyo 101-0062, Japan examination of these variations may become useful for E-mail: [email protected] identifying individuals at high risk for prostate cancer. Tel.: +81-35280-8067 Fax: +81-35280-8067 Keywords Serine proteinase family Æ PAI2 Æ Y. Kubota SERPINB10 Æ Missense polymorphism Æ Linkage Department of Urology, Yokohama City University Medical disequilibrium School, Yokohama, Japan T. Ichikawa Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan Introduction K. Inoue Department of Urology, Showa University Fujigaoka Hospital, Prostate cancer is the most frequently observed malig- Yokohama, Japan nancy among elderly men, especially in advanced na- tions. In order to better understand the etiology of this T. Shuin prevalent disease, epidemiological approaches have Department of Urology, Kochi Medical University, Kochi, Japan established certain factors for susceptibility that include T. Habuchi age, ethnicity, country of origin, and family history. A Department of Urology, Akita University, Akita, Japan hereditary component is indicated by considerable evi- dence (Lichtenstein et al. 2000; Ostrander and Stanford O. Ogawa Department of Urology, University of Kyoto Medical School, 2000). Five chromosomal regions were defined by Kyoto, Japan familial mapping studies (Smith et al. 1996; Berthon 508 et al. 1998; Xu et al. 1998; Gibbs et al. 1999), from which (Tokyo), Yokohama City University Hospital, Akita the ribonuclease L gene (RNASEL) (Carpten et al. 2002) University Hospital, Kyoto University Hospital, Kochi and the elaC homologue 2 gene (ELAC2) (Tavtigian Medical School Hospital, Nagoya City University et al. 2001) were later identified as the genetic elements Hospital, and Chiba University Hospital. Diagnoses conferring susceptibility at hereditary prostate cancer were ascertained by histo-pathological validation of loci 1 (HPC1) and 2 (HPC2). However, since aberrant material from trans-rectal needle biopsies or resected alleles of those two genes may account only for 5–10% tumor tissues. The age at diagnosis, available for 249 of of prostate cancers (Carter et al. 1992), additional, low- the patients, was 66.1±6.76 [0.43] (mean±SD [SE]), penetrance susceptibility genes must be sought. ranging from 45–90 years; tumor-grading scores (Glea- Case-control studies of sporadic cases have examined son’s scores) for 208 subjects ranged from 1–9 common variations in a number of candidate genes; (mean±SD=6.4±1.9). Clinical staging of tumors from examples are the androgen receptor (AR) gene and the 244 patients according to the Jewett Staging System kallikrein 3 gene (also known as prostate specific anti- indicated that 7 were Stage A, 99 were Stage B, 73 were gen). Several independent studies have shown that Stage C, and 65 were Stage D. Healthy control subjects variations in ELAC2, AR, steroid-5-alpha-reductase, (n=384) were recruited from health check programs alpha polypeptide 2 (SRD5A2), and a cytochrome P450 held in three different areas in eastern Japan, basically gene (CYP17) show relatively good reproducibility in matching the sampling areas. All participants gave terms of conferring susceptibility to prostate cancer, written, informed consent prior to the study, which was although the significance of the results has not been fully approved by the Institutional Review Boards of the validated. Additional candidates should be examined Research Consortium. We regarded these subjects as because having a reasonable number of reliable suscep- representative of the general population and thus the tibility genes may enable us to evaluate the combined predictive prevalence of prostate-cancer risks at age 60– contribution of multiple risk factors for this disease. 70 years was expected to be at a negligible level (about Among the important candidates are matrix prote- 0.1%). Therefore, although the mean age of the control ases and their inhibitors, which are responsible for subjects (58.4±8.58 [0.44]; range 32–69 years) was sig- degradation of the extracellular matrix and thus would nificantly different from that of prostate-cancer patients be related to tumor invasion. Serine proteinase inhibi- (P<0.0001, Mann-Whitney test), contamination by in- tors (SERPINs), a large superfamily of proteinase dividuals who have prostate-cancer risk at age 66 would inhibitors (family A-I), are involved in multiple funda- be negligible. The possibility for an area-dependent mental processes such as angiogenesis, inflammation, difference in genotype frequency was tested by geno- activation of complement, and fibrinolysis. Among the typing these subjects for 100 different, randomly selected nine serpin families, many members of class B (SER- SNPs. No significant difference was detected between PINBs; also called ovalbumine-like serpins) are often any combinations of SNPs and areas when Bonferroni’s implicated in cancer etiology (Silverman et al. 2001). approximation was considered; among 100 SNPs, gen- Genes encoding SERPINBs are clustered in two chro- otype frequency of five to seven SNPs distributed dif- mosomal regions, 18q21 and 6q25. Moreover, all of the ferentially per area at the level of P<0.05, but not at the SERPINB genes that appear to be involved in cancer adjusted level of P<0.0005 (P>0.003). etiology, i.e., plasminogen activator inhibitor-2 (PAI-2), squamous cell carcinoma antigens 1 and 2 (SCCA1 and SCCA2), and maspin (SERPINB5), localize together at Selection of SNPs and predictive analysis 18q21. Therefore, intense examination of genetic varia- of amino acid changes tions in that region should be fruitful. In the work reported here, we investigated nucleotide Within a cluster of eight SERPINB genes at 18q21, 25 variations in SERPINB genes at chromosome 18q21. By missense nucleotide variations have been archived in the focusing on several single-nucleotide polymorphisms dbSNP database (Table 1). To select the most likely (SNPs) with non-synonymous coding sequences (mis- candidates for risk of prostate cancer from among these sense cSNPs) present in SERPINB10 and PAI2,we variations, we evaluated the likely effect of each amino analyzed potential associations between SNP genotypes acid alteration, using the ‘‘Sorting Intolerant From and the risk of prostate cancer among 676 Japanese Tolerant’’ computer program (SIFT: http://blocks.fhcrc. men. We also examined linkage disequilibrium (LD) in org/sift/SIFT.html; Ng and Henikoff 2001). Amino acid the region encompassing those variations. sequences encoded by these eight SERPINB genes were obtained from the RefSeq database of NCBI, and each Subjects and methods of the entire sequences in FASTA format was imputed to run the SIFT program under its default settings. The Subjects SIFT algorithm estimates differences between original and altered sequences, based on the assumption that Prostate-cancer patients over the age of 45 (n=292) were amino acid positions important for the correct biological recruited over the period 1995–2001 from seven univer- function of a protein are conserved across the protein sity hospitals in Japan: Nippon Medical School Hospital family and/or across evolutionary history.
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