[CANCER RESEARCH 60, 6479 – 6481, November 15, 2000]
`
`Two Percent of Finnish Prostate Cancer Patients Have a Germ-line Mutation in the
`Hormone-binding Domain of the Androgen Receptor Gene1
`
`Nina Mononen, Kirsi Syrja¨koski, Mika Matikainen, Teuvo L. J. Tammela, Johanna Schleutker, Olli-P. Kallioniemi,
`Jan Trapman, and Pasi A. Koivisto2
`Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital [N. M., K. S., M. M., J. S., O-P. K., P. A. K.];
`Department of Clinical Genetics, Tampere University Hospital [P. A. K.]; and Division of Urology, Tampere University Hospital and Medical School, University of Tampere
`[T. L. J. T.], 33521 Tampere, Finland; Laboratory of Cancer Genetics, National Center for Human Genome Research, NIH, Bethesda, Maryland 20892-4470 [J. S., O-P. K.]; and
`Department of Pathology, Erasmus University, 3000 Rotterdam, the Netherlands [J. T.]
`
`ABSTRACT
`
`Mutations of the androgen receptor (AR) gene have been reported in
`prostate cancer, usually from tumor tissue specimens from late-stage,
`androgen-independent cancer. Occasionally, germ-line mutations have
`been found, but a link between AR mutations and predisposition to human
`prostate cancer has not been firmly established. Recently, two independ-
`ent studies reported the same germ-line mutation at codon 726 in exon E
`(CGC to CTC) in two apparently unrelated Finnish prostate cancer
`patients. This arginine to leucine substitution was reported to alter the
`transactivational specificity of the AR protein. In the present study, the
`R726L mutation was analyzed by allele-specific oligohybridization in
`DNA specimens from 418 consecutive prostate cancer patients who re-
`ported a negative family history (sporadic group) and from 106 patients
`with a positive family history (hereditary group). The population fre-
`quency of the R726L mutation in blood donors was 3 of 900 (0.33%). In
`contrast, eight (1.91%) mutations (odds ratio 5 5.8; P 5 0.006) were
`found in the sporadic group, and two (1.89%) mutations were found in the
`hereditary group (odds ratio 5 5.8; P 5 0.09). Suggestive evidence of the
`segregation of the mutation with prostate cancer was seen in these two
`families. The present study indicates that the R726L substitution in the
`AR may confer an up to 6-fold increased risk of prostate cancer and may
`contribute to cancer development in up to 2% of Finnish prostate cancer
`patients. These results warrant additional large-scale studies of the sig-
`nificance of rare mutations and polymorphisms in candidate genes along
`the androgen signaling pathway as risk factors for prostate cancer.
`
`INTRODUCTION
`
`In many Western countries, prostate cancer is the most common
`malignancy among men, who have a cumulative lifetime risk of 1 in 10
`or greater (1). Prostate cancer is believed to arise as a result of an
`interplay of genetic factors, endogenous hormones, and environmental
`influences, with the strongest known risk factors being age, ethnic origin,
`and positive family history (2–7). Male relatives of prostate cancer
`patients have a 2–5-fold elevated risk of cancer. Up to 5–10% of all
`prostate cancers may result from an inherited predisposition. Up to seven
`genetic predisposition loci for prostate cancer have been found in genetic
`linkage studies (8–14). These include three predisposition loci on chro-
`mosome 1: (a) HPC1 (8) at 1q24–q25; (b) HPC2 at 1q42 (9); and (c) a
`putative prostate-brain tumor (CAPB) locus at 1p36 (10). Other chromo-
`somal regions suggested to harbor prostate cancer susceptibility loci
`include Xq27–q28 (HPCX; Ref. 11), 11p (12), 16q (13), and 20q13 (14).
`All of these loci are suspected to harbor rare gene mutations conferring a
`
`Received 3/27/00; accepted 9/15/00.
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must therefore be hereby marked advertisement in accordance with
`18 U.S.C. Section 1734 solely to indicate this fact.
`1 Supported by the Medical Research Fund of Tampere University Hospital, the Sigrid
`Juselius Foundation, the Lahtikari Foundation, the Finnish Cancer Institute (P. A. K.),
`Duodecim (Finnish College of Physicians; P. A. K.), the Dutch Cancer Society (J. T.),
`Pirkanmaa Cancer Society, and Maud Kuistila Foundation. The prostate cancer family
`collection was supported in part by a contract from the National Human Genome Research
`Institute, NIH (NO1-HG-55389).
`2 To whom requests for reprints should be addressed, at Laboratory of Cancer Genet-
`ics, Tampere University Hospital, P. O. Box 2000, FIN-33521 Tampere, Finland. Phone:
`358-3-2474128; Fax: 358-3-2474168; E-mail: blpako@uta.fi.
`
`high risk for prostate cancer development. Other genetic features sug-
`gested to be involved in prostate cancer include mutations in the BRCA1
`(15) and BRCA2 genes (16), as well as common polymorphisms of a
`number of candidate genes, such as 5-a reductase, vitamin D receptor,
`and the AR3 gene (17–19).
`Because AR protein is a key mediator of growth signaling in the
`prostate, many investigators have considered AR as a candidate pros-
`tate cancer susceptibility gene. The AR gene contains two polymor-
`phic trinucleotide repeat regions in exon A: (a) a CAG repeat (coding
`for polyglutamine); and (b) a GGC repeat (polyglycine). The length of
`the CAG repeat sequence is inversely correlated with the transactiva-
`tional activity of the AR. Irvine et al. (20) proposed that men with
`short CAG repeats would have an increased risk of prostate cancer.
`Subsequently, Giovannucci et al. (21) and Stanford et al. (22) con-
`ducted a case-control study and found an association between a low
`number of AR gene CAG repeats and an increased risk of prostate
`cancer. In particular, short CAG repeat sequence was strongly asso-
`ciated with cancers characterized by extraprostatic extension, distant
`metastases, or poor histological differentiation. However, not all au-
`thors have been able to confirm these findings (23, 24).
`Numerous specific mutations of the AR gene have also been reported
`in human prostate cancer patients (see the Androgen Receptor Gene
`Mutations Database4). Many of these mutations occur in regions of the
`gene coding for the ligand- or DNA-binding domains of the AR, and
`functional studies have indicated that such mutations often alter the
`specificity of the transcriptional response of the AR to androgens, anti-
`androgens, and other steroids. In many cases, the mutations have only
`been studied from the tumor tissue, with the highest prevalence of AR
`mutations reported in metastases of patients with hormone-refractory
`disease (25, 26). The germ-line origin of such mutations has been estab-
`lished in only two reports (27, 28), but the role of such mutations in the
`genetic predisposition to prostate cancer has not been firmly established.
`Elo et al. (27) described an R726L germ-line mutation of the AR
`gene in a prostate cancer patient from Northern Finland. We recently
`found the same mutation in another Finnish prostate cancer patient
`when screening for AR mutations by single-strand conformational
`polymorphism in six patients whose cancers appeared during finas-
`teride treatment for benign prostatic hyperplasia (29). The R726L
`mutation affects the hormone-binding region in exon E and was
`reported to lead to activation of the AR not only by dihydrotestoster-
`one and testosterone but also by estradiol (27). The fact that this
`mutation has not been found in any published study of the AR gene
`suggests that it may represent a unique Finnish mutation. Here we
`analyzed the frequency of the R726L mutation in over 1400 speci-
`mens from blood donors, consecutive prostate cancer patients with no
`family history of prostate cancer, and patients with a positive family
`history of prostate cancer to explore the frequency of this mutation in
`the Finnish population, as well as its association with prostate cancer.
`
`3 The abbreviations used are: AR, androgen receptor; ASO, allele-specific oligonu-
`cleotide; OR, odds ratio; TAUH, Tampere University Hospital.
`4 http://www.mcgill.ca/androgendb.
`
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`AVENTIS EXHIBIT 2105
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`AR R726L MUTATION IN PROSTATE CANCER
`
`Table 1 R726L mutation in Finnish prostate cancer patients and families
`
`No. of
`mutations (%)
`
`Total no. of
`AR alleles
`
`Controls
`Sporadic
`Familial
`
`3 (0.33)
`8 (1.91)
`2 (1.89)
`
`900
`418
`106
`
`p
`
`0.006
`0.09
`
`OR
`
`1.0
`5.8
`5.8
`
`95% Confidence
`interval
`
`1.5–22.1
`0.95–34.8
`
`MATERIALS AND METHODS
`
`Patients. We collected blood samples from 418 consecutive sporadic pros-
`tate cancer patients at TAUH between 1996 and 1999, 106 patients with a
`positive family history of prostate cancer from the whole of Finland, and 778
`healthy blood donors (656 men and 122 women) from the Tampere region.
`During the sample collection, 559 new prostate carcinomas were diagnosed
`at TAUH. Twenty-five percent of the patients were excluded from the present
`study because of a positive family history for prostate cancer or their refusal to
`participate in the study. One hundred and six prostate cancer families with two
`or more affected cases were identified through referrals from physicians,
`family questionnaires sent to patients, and newspaper, radio, and television
`advertisements. A sample from one randomly chosen affected case from each
`family was screened for the R726L mutation.
`Written informed consent was obtained from all patients and their family
`members, and research protocols were approved by the Ethical Committee of
`TAUH. Diagnoses of all prostate cancer patients were confirmed through
`medical records or the Finnish Cancer Registry. The patients’ family histories
`for malignancies were documented from family questionnaires completed by
`the patients. Prostate cancer was considered “sporadic” when the patient
`reported no first- or second-degree relatives with prostate cancer.
`The population frequency of the R726L mutation was established by ana-
`lyzing DNA specimens from 778 anonymous, unselected healthy blood donors
`from the Tampere region (656 men and 122 women). Together, these speci-
`mens allowed us to scan for the allele frequency of the R726L mutation on 900
`X chromosomes.
`ASO Hybridization to Detect R726L. Genomic DNA was amplified
`using primers 59-CCCAACAGGGAGTCAGACTTA-39 and 59-CCTGGAGT-
`TGACATTGGTGA-39. One hundred ng of DNA was amplified by 35 cycles
`of PCR in reactions containing 200 nM of both primers, 200 mM of each
`deoxynucleotide triphosphate, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.75 mM
`MgCl2, 0.001% (w/v) gelatin, and 2.5 units of AmpliTaqGold DNA poly-
`merase (Perkin-Elmer, Norwalk, CT). After an initial denaturation step of 10
`min at 95°C, the cycle parameters were as follows: 95°C for 30 s, 57°C for 1
`min, and 72°C for 1 min, with a 5-min extension at 72°C after the last cycle.
`Mutation detection was done using ASO hybridization as described by Fried-
`man et al. (30) with the following exceptions: (a) filters were prewet and wells
`were washed with 0.4 M Tris-HCl (pH 7.5); (b) probes were end-labeled with
`32P at 37°C fo r 3 h byterminal deoxynucleotidyl transferase (Amersham Life
`Science Inc., Cleveland, OH); and (c) hybridizations were performed at 54°C.
`ASOs used in hybridizations were 59-AGGCTTCCGCAACTTACA-39 (wild
`type) and 59-AGGCTTCCTCAACTTACA-39 (mutation). A mutation positive
`control as well as a negative control of the PCR reaction was included in each
`ASO hybridization. All samples with R726L mutation as well as 42 randomly
`chosen samples negative for mutation were sequenced with ABI PRISM 310
`Genetic Analyzer (Perkin-Elmer) as recommended by the manufacturer. Prim-
`ers used in sequencing were the same as those used for PCR.
`Analysis for CAG Repeats in the AR. To explore whether the R726L
`mutation had a common origin, we analyzed the length of the AR CAG repeat
`in all mutation carriers. If the R726L mutation represented an ancient founder
`mutation, one would expect to find that neighboring genetic markers on the X
`chromosome, such as the CAG repeat, would also be shared between the
`mutation carriers. The distribution of CAG repeats in the R726L carriers was
`compared with CAG repeats of 811 Finnish blood donors.5 The fragment
`containing the CAG repeat was amplified by PCR using previously published
`primers (20), with the exception that the other inner primer was labeled with
`59-6 – 6-carboxyfluorescein. Electrophoresis was performed using the ABI 310
`
`5 N. Mononen, M. Matikainen, J. Schleutker, P. A. Koivisto, T. L. J. Tammela, and
`O-P. Kallioniemi. The AR CAG repeat and its relationship to prostate cancer, manuscript
`in preparation.
`
`6480
`
`Genetic Analyzer (Perkin-Elmer) according to the manufacturer’s instructions.
`Run results were analyzed by use of the Genescan 2.1 and Genotyper 2.0
`(Perkin-Elmer) computer programs.
`Statistical Analyses. Statistical analyses were performed using GraphPad
`InStat version 2.04a (GraphPad Software, San Diego, CA). Correlations were
`made with the two-tailed Fisher’s exact test, x2 test, and x2 test for linear trend.
`Comparison of the ages was made using the two-tailed Student’s t test. In
`addition, the OR and 95% confidence intervals were calculated.
`
`RESULTS
`
`Germ-line R726L AR mutation was found in 8 of 418 (1.91%)
`consecutive prostate cancer patients collected at TAUH between 1996
`and 1999 (Table 1). All of these patients reported a negative family
`history for prostate cancer. On the basis of the analysis of blood
`donors from the same hospital region, the carrier frequency of R726L
`was established as 3 of 900 people (0.33%), which is significantly less
`than the frequency of the R726L mutation among the prostate cancer
`patients (OR 5 5.8; P 5 0.006).
`The R726L mutation was also found in 2 of the 106 patients
`(1.89%) with a positive family history for prostate cancer (OR 5 5.8;
`P 5 0.09). Analysis of additional affected and unaffected cases from
`these two families indicated that the mutation was systematically
`present in all affected cases, whereas unaffected male individuals
`were not carriers.
`Because the R726L mutation was also found in eight prostate
`cancer patients who reported no family history of prostate cancer, we
`constructed extended pedigrees from their families based on family
`questionnaires sent to the patients. Two of these patients turned out to
`have a maternal relative with prostate cancer.
`Clinical features of the R726L mutation-positive prostate can-
`cers were compared with those of noncarriers (Table 2). There
`were no significant differences in tumor stage, metastasis stage, or
`tumor grade between these groups. The average age at prostate
`cancer diagnosis was slightly lower in patients harboring the
`R726L mutation (65.5 6 7.0 years; range, 59 –79 years) as com-
`pared with the rest of the prostate cancer patients (68.4 6 8.3
`years; range, 48 –92 years), but this difference was not statistically
`significant (P 5 0.25).
`To explore whether the R726L mutations shared the same origin,
`we studied the distribution of the adjacent AR CAG repeat in the 13
`mutation carriers. Strong evidence of linkage disequilibrium was
`observed between the two different loci at the same gene. Eleven
`cases (85%) had 26 CAG repeats, and the remaining two cases had 25
`and 27 repeats. As compared with the distribution of the CAG repeat
`lengths in the general Finnish population, the CAG repeat length of 26
`is rather long. In the unselected Finnish population, the average CAG
`repeat length is 21.6 6 2.6.5 Only 2.7% of men have 26 CAG repeats,
`
`Table 2 Tumor characteristics of the R726L mutation carriers compared to sporadic
`prostate cancer patients
`
`R726L mutation
`n 5 13 (%)
`
`No. mutations
`n 5 410 (%)
`
`Tumor-stage
`1 1 2
`3 1 4
`Metastasis-stage
`0
`1
`Unknown
`WHO grade
`I
`II
`III
`a Fischer’s exact test.
`b x2 test.
`c x2 test for linear trend.
`
`6 (46)
`7 (54)
`
`7 (54)
`3 (23)
`3 (23)
`
`3 (23)
`6 (46)
`4 (31)
`
`225 (55)
`185 (45)
`
`281 (69)
`62 (15)
`67 (16)
`
`100 (24)
`238 (58)
`72 (18)
`
`P
`0.58a
`
`0.53b
`
`0.46c
`
`
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`
`AR R726L MUTATION IN PROSTATE CANCER
`
`a significant difference as compared with R726L mutation carriers
`(OR 5 197.3; 95% confidence interval, 41.2–943.8; P , 0.0001). The
`two mutation-positive cases with 25 and 27 CAG repeats could represent
`new mutations in this unstable trinucleotide tract. This strong linkage
`disequilibrium between the two markers, as well as the homogeneous
`distribution of CAG repeat lengths in the cases, suggests that the R726L
`mutation originates from a single ancestral event. Two repeat lengths (25
`and 27 nucleotides) that differed in the mutation carriers may represent
`the inherent instability of the trinucleotide repeats, especially over many,
`perhaps dozens, of generations.
`
`DISCUSSION
`
`In this study, we report a comprehensive analysis of the frequency and
`significance of the R726L germ-line mutation of the AR gene in Finnish
`prostate cancer patients. Several findings substantiate the hypothesis that
`the R726L mutation contributes to the development of prostate cancer.
`First, the mutation was seen in approximately 2% of the samples
`from the prostate cancer patients, whereas the population frequency of
`this allele in blood donors was 0.3%. The results suggest an almost
`6-fold overrepresentation of the R726L mutation in the prostate can-
`cer cases as compared with ethnically and geographically matched
`population controls. Second, the mutation was found in two patients
`with a positive family history for prostate cancer. Family members of
`the mutation-positive cases were also screened for the R726L muta-
`tion, and the R726L mutation was shared between the prostate cancer
`patients. Third, the R726L germ-line mutation in the coding region of
`the AR gene changes an evolutionarily exceptionally well-conserved
`amino acid in the protein (from a positively charged amino acid to a
`nonpolar amino acid). In addition, there is prior evidence that the
`R726L mutation may change the functional characteristics of the AR
`protein. Elo et al. (27) demonstrated that the R726L mutation did not
`alter the ligand binding specificity of the AR protein, but its transac-
`tivational activity in the presence of estradiol was increased. Although
`estradiol itself is unlikely to be the target of the mutant receptor, this
`finding suggests that the transactivational response of the mutated AR
`gene is altered in response to the ligands. This, in turn, may explain
`its association with prostate cancer. Additional studies are needed to
`establish the exact biological significance of the R726L mutation.
`Eighty-five percent of the R726L mutation carriers had 26 CAG
`repeats in the AR gene. The average AR CAG repeat length in the Finnish
`population is 22, with a wide range from 8 to 30. The population
`frequency of the 26 CAG repeat length is only 2.7%,5 suggesting that
`there is a strong linkage disequilibrium between the R726L mutation and
`the CAG repeat within the AR gene. The 25 and 27 AR CAG repeats seen
`in two mutation carriers may be explained by the instability of the CAG
`repeats (20–24). Together, the results suggest that the R726L mutation
`carriers originate from a single ancestral founder.
`In conclusion, we have demonstrated an up to 6-fold increased fre-
`quency of the AR R726L germ-line mutation in sporadic as well as
`family-positive prostate cancers. Additional studies are required to elu-
`cidate the potential role of the R726L mutation as a marker of genetic
`predisposition for prostate cancer or as a modifier locus. These kinds of
`infrequent but potentially cancer-associated variants of the AR gene
`provide an example of the importance of rare disease-associated single-
`nucleotide polymorphisms that are often overlooked in single-nucleotide
`polymorphism-based genetic studies. The role of such events along the
`AR signaling pathway deserves further study in prostate cancer.
`
`ACKNOWLEDGMENTS
`
`We are grateful to the participating subjects and their families. We thank
`Kaisa Vaherto for help with data collection and pedigree files and Minna
`Sjo¨blom for technical assistance.
`
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`Two Percent of Finnish Prostate Cancer Patients Have a
`Germ-line Mutation in the Hormone-binding Domain of the
`Androgen Receptor Gene
`(cid:160)
`Nina Mononen, Kirsi Syrjäkoski, Mika Matikainen, et al.
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