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1.  Mapping of the chromosomal amplification 1p21-22 in bladder cancer 
BMC Research Notes  2014;7(1):547.
The aim of the study was to characterize a recurrent amplification at chromosomal region 1p21-22 in bladder cancer.
ArrayCGH (aCGH) was performed to identify DNA copy number variations in 7 clinical samples and 6 bladder cancer cell lines. FISH was used to map the amplicon at 1p21-22 in the cell lines. Gene expression microarrays and qRT-PCR were used to study the expression of putative target genes in the region.
aCGH identified an amplification at 1p21-22 in 10/13 (77%) samples. The minimal region of the amplification was mapped to a region of about 1 Mb in size, containing a total of 11 known genes. The highest amplification was found in SCaBER squamous cell carcinoma cell line. Four genes, TMED5, DR1, RPL5 and EVI5, showed significant overexpression in the SCaBER cell line compared to all the other samples tested. Oncomine database analysis revealed upregulation of DR1 in superficial and infiltrating bladder cancer samples, compared to normal bladder.
In conclusions, we have identified and mapped chromosomal amplification at 1p21-22 in bladder cancer as well as studied the expression of the genes in the region. DR1 was found to be significantly overexpressed in the SCaBER, which is a model of squamous cell carcinoma. However, the overexpression was found also in a published clinical sample cohort of superficial and infiltrating bladder cancers. Further studies with more clinical material are needed to investigate the role of the amplification at 1p21-22.
PMCID: PMC4143550  PMID: 25135188
Gene amplification; Bladder cancer; DR1; aCGH
2.  Responder Analysis of the Effects of Denosumab on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer 
Men with prostate cancer are at risk of experiencing accelerated bone loss and fractures as a result of androgen deprivation therapy (ADT).
We evaluated the effects of denosumab, a fully human monoclonal antibody against RANKL, on preservation of BMD at 3 key skeletal sites (lumbar spine [LS], femoral neck [FN], and total hip [TH]) and the distal radius at 36 months both by responder category and individual responses in a waterfall plot analysis.
Design, Setting, and Participants
This phase 3, randomized, double-blind study of men with non-metastatic prostate cancer receiving ADT investigated the effects of denosumab on bone mineral density (BMD) and fractures. Patients were treated for 36 months.
Subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months. Patients were instructed to take supplemental Calcium and vitamin D.
Primary outcome measure: The percentage change from baseline to month 36 in LS, FN, and TH BMD was measured by dual energy x-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a sub-study of 309 patients.
Results and Limitations
At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78% vs 17%; TH, 48% vs 6%; FN, 48% vs 13%; distal 1/3 radius, 40% vs 7%). The percentage of denosumab patients with bone loss at all 3 key BMD sites at month 36 was 1%, as opposed to 42% in placebo arm. At 36 months 69% of denosumab-treated patients had BMD increases at all three sites (LS, TH or FN) compared with 8% of placebo-treated patients. Lower baseline BMD was associated with higher magnitude lumbar spine, femoral neck, and total hip BMD responses to denosumab.
In men with prostate cancer receiving ADT significantly higher BMD response rates were observed with denosumab vs. placebo.
Trial Registration
This study is registered with with the identifier NCT00089674.
PMCID: PMC3671885  PMID: 22641239
androgen deprivation; bone mineral density; bone loss; antiresorptive therapy; responder analysis
3.  Denosumab and Changes in Bone Turnover Markers During Androgen Deprivation Therapy for Prostate Cancer 
Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a pre-specified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) vs. placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and pre-dose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (<70 years vs. ≥ 70 years), prior duration of ADT (≤6 months vs. >6 months), and baseline BTM (≤ median vs. >median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was −90% in the denosumab group and −3% in the placebo group (p <.0001). The median change in TRAP-5b levels at month 1 was −55% in the denosumab group and −3% in the placebo group (p <.0001). The maximal median change in P1NP was −64% in the denosumab group and −11% in the placebo group, (p <.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.
PMCID: PMC3222788  PMID: 21898590
(5) denosumab; androgen deprivation therapy; bone turnover markers; prostate cancer
4.  Seven novel prostate cancer susceptibility loci identified by a multi-stage genome-wide association study 
Kote-Jarai, Zsofia | Olama, Ali Amin Al | Giles, Graham G. | Severi, Gianluca | Schleutker, Johanna | Weischer, Maren | Canzian, Frederico | Riboli, Elio | Key, Tim | Gronberg, Henrik | Hunter, David J. | Kraft, Peter | Thun, Michael J | Ingles, Sue | Chanock, Stephen | Albanes, Demetrius | Hayes, Richard B | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Pharoah, Paul | Schumacher, Fredrick | Henderson, Brian E. | Stanford, Janet L. | Ostrander, Elaine A. | Sorensen, Karina Dalsgaard | Dörk, Thilo | Andriole, Gerald | Dickinson, Joanne L. | Cybulski, Cezary | Lubinski, Jan | Spurdle, Amanda | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Frank Gardiner, R. A. | Thibodeau, Stephen N. | Schaid, Dan | John, Esther M. | Maier, Christiane | Vogel, Walther | Cooney, Kathleen A. | Park, Jong Y. | Cannon-Albright, Lisa | Brenner, Hermann | Habuchi, Tomonori | Zhang, Hong-Wei | Lu, Yong-Jie | Kaneva, Radka | Muir, Ken | Benlloch, Sara | Leongamornlert, Daniel A. | Saunders, Edward J. | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | O’Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Christmas, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Aritaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Wahlfors, Tiina | Tammela, Teuvo LJ | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Tybjærg-Hansen, Anne | Bojesen, Stig E. | Travis, Ruth | Campa, Daniele | Kaaks, Rudolf | Wiklund, Fredrik | Aly, Markus | Lindstrom, Sara | Diver, W Ryan | Gapstur, Susan | Stern, Mariana C | Corral, Roman | Virtamo, Jarmo | Cox, Angela | Haiman, Christopher A. | Le Marchand, Loic | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Meyer, Andreas | Serth, Jürgen | Yeager, Meredith | Berndt, Sonja I. | Marthick, James R | Patterson, Briony | Wokolorczyk, Dominika | Batra, Jyotsna | Lose, Felicity | McDonnell, Shannon K | Joshi, Amit D. | Shahabi, Ahva | Rinckleb, Antje E. | Ray, Ana | Sellers, Thomas A. | Lin, Huo-Yi | Stephenson, Robert A | Farnham, James | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Easton, Douglas F. | Eeles, Rosalind A.
Nature Genetics  2011;43(8):785-791.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified.
PMCID: PMC3396006  PMID: 21743467
5.  ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer 
Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases vs. sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5–1.2%) in all patient subgroups vs. 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (OR=1.48, 95% CI 1.16–1.87, p=0.001) and prostate cancer patients (OR 1.50, 95% CI 1.13–1.99, p=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8/164, 4.9%) than in controls (13/809, 1.6%; OR 3.14, 95% CI 1.28–7.70, p=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.
PMCID: PMC3404127  PMID: 18337727
ARLTS1; ARL11; prostate cancer; breast cancer; colorectal cancer
6.  Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families 
BMC Medical Genetics  2012;13:46.
Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.
Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.
Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2–3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.
Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2–3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
PMCID: PMC3495053  PMID: 22712434
7.  Overall and worst gleason scores are equally good predictors of prostate cancer progression 
BMC Urology  2011;11:21.
Gleason scoring has experienced several modifications during the past decade. So far, only one study has compared the prognostic abilities of worst (WGS) and overall (OGS) modified Gleason scores after the ISUP 2005 conference. Prostatic needle biopsies are individually paraffin-embedded in 57% of European pathology laboratories, whereas the rest of laboratories embed multiple (2 - 6) biopsies per one paraffin-block. Differences in the processing method can have a far-reaching effect, because reporting of the Gleason score (GS) is different for individually embedded and pooled biopsies, and GS is one of the most important factors when selecting treatment for patients.
The study material consisted of needle biopsies from 236 prostate cancer patients that were endocrine-treated in 1999-2003. Biopsies from left side and right side were embedded separately. Haematoxylin-eosin-stained slides were scanned and analyzed on web-based virtual microscopy. Worst and overall Gleason scores were assessed according to the modified Gleason score schema after analyzing each biopsy separately. The compound Gleason scores (CGS) were obtained from the original pathology reports. Two different grade groupings were used: GS 6 or less vs. 7 vs. 8 or above; and GS 7(3 + 4) or less vs. 7(4 + 3) and 8 vs. 9-10. The prognostic ability of the three scoring methods to predict biochemical progression was compared with Kaplan-Meier survival analysis and univariate and multivariate Cox regression analyses.
The median follow-up time of the patients was 64.5 months (range 0-118). The modified GS criteria led to upgrading of the Gleason sums compared to the original CGS from the pathology reports 1999-2003 (mean 7.0 for CGS, 7.5 for OGS, 7.6 for WGS). In 43 cases WGS was > OGS. In a univariate analysis the relative risks were 2.1 (95%-confidence interval 1.8-2.4) for CGS, 2.5 (2.1-2.8) for OGS, and 2.6 (2.2-2.9) for WGS. In a multivariate analysis, OGS was the only independent prognostic factor.
All of the three Gleason scoring methods are strong predictors of biochemical recurrence. The use of modified Gleason scoring leads to upgrading of GS, but also improves the prognostic value of the scoring. No significant prognostic differences between OGS and WGS could be shown, which may relate to the apparent narrowing of the GS scale from 2-10 to 5-10 due to the recent modifications.
PMCID: PMC3193164  PMID: 21978318
8.  NMD and microRNA expression profiling of the HPCX1 locus reveal MAGEC1 as a candidate prostate cancer predisposition gene 
BMC Cancer  2011;11:327.
Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPCX1 at Xq27-q28, but due to the complex structure of the region, the susceptibility gene has not yet been identified.
In this study, nonsense-mediated mRNA decay (NMD) inhibition was used for the discovery of truncating mutations. Six prostate cancer (PC) patients and their healthy brothers were selected from a group of HPCX1-linked families. Expression analyses were done using Agilent 44 K oligoarrays, and selected genes were screened for mutations by direct sequencing. In addition, microRNA expression levels in the lymphoblastic cells were analyzed to trace variants that might alter miRNA expression and explain partly an inherited genetic predisposion to PC.
Seventeen genes were selected for resequencing based on the NMD array, but no truncating mutations were found. The most interesting variant was MAGEC1 p.Met1?. An association was seen between the variant and unselected PC (OR = 2.35, 95% CI = 1.10-5.02) and HPC (OR = 3.38, 95% CI = 1.10-10.40). miRNA analysis revealed altogether 29 miRNAs with altered expression between the PC cases and controls. miRNA target analysis revealed that 12 of them also had possible target sites in the MAGEC1 gene. These miRNAs were selected for validation process including four miRNAs located in the X chromosome. The expressions of 14 miRNAs were validated in families that contributed to the significant signal differences in Agilent arrays.
Further functional studies are needed to fully understand the possible contribution of these miRNAs and MAGEC1 start codon variant to PC.
PMCID: PMC3162583  PMID: 21810217
9.  PALB2 variants in hereditary and unselected Finnish Prostate cancer cases 
PALB2 1592delT mutation is associated with increased breast cancer and suggestive prostate cancer (PRCA) risk in Finland. In this study we wanted to assess if any other PALB2 variants associate to increased PRCA risk and clinically describe patients with formerly found PALB2 1592delT mutation.
Finnish families with two or more PRCA cases (n = 178) and unselected cases (n = 285) with complete clinical data were initially screened for variants in the coding region and splice sites of PALB2. Potentially interesting variants were verified in additional set of unselected cases (n = 463).
From our clinically defined sample set we identified total of six variants in PALB2. No novel variants among Finnish PRCA cases were found. Clinical characteristics of the variant carriers, including the previously described family carrying PALB2 1592delT, revealed a trend towards aggressive disease, which also applied to a few non-familial cases. Hypersensitivity to mitomycin C (MMC) of lymphoblasts from individuals from the family with 1592delT revealed haploinsufficiency among carriers with altered genotype.
Though any of the detected PALB2 variants do not associate to PRCA in population level in Finland it cannot be ruled out that some of these variants contribute to cancer susceptibility at individual level.
PMCID: PMC2806404  PMID: 20003494
10.  Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance 
Human genetics  2007;121(2):257-267.
Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide. As PCa is a complex, multigenic disease, it has been challenging to establish its genetic basis, with strong risk factors obscured by the genetically heterogeneous patient populations often available for analysis. Worldwide the PCa phenotype has been further complicated based on the frequent inclusion of cases in which prostate specific antigen (PSA)-tests allow early diagnosis of possibly latent disease. Thus, previous segregation analyses have variously suggested that the familial aggregation of PCa follows autosomal dominance, recessive or X-linked inheritance, but remain inconclusive. The objective of this study was to assess the familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during 1988–1993, from the unique, genetically isolated, founder population-based resource of the Finnish Cancer Registry. We performed segregation analysis on two cohorts of 557 early-onset and 989 late-onset families with clinically diagnosed PCa cases, uncomplicated by predictions from PSA screening. We evaluated residual paternal effects, assuming that age at diagnosis followed a logistic distribution after log-transformation. Our results indicate that Mendelian recessive inheritance consistent with the sex-limited X-linked region previously mapped in Finnish families to the HPCX locus best fit the data in each cohort. With a putative high-risk allele frequency qA of 0.09 in the combined analysis, genotype-specific mean ages at diagnosis of 63.6 years for AA and 71.0 years for AB/BB, respectively, were obtained. The significant paternal regressive coefficient was also indicative of a polygenic multifactorial component, suggesting that environmental factors may contribute to the rising incidence of PCa in Finland.
PMCID: PMC1945246  PMID: 17203302
hereditary prostate cancer; Mendelian recessive inheritance; segregation analyses; population-based study; Finland

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