Download Compelling evidence for a prostate cancer gene at 22q12.3 by the

Human Molecular Genetics, 2007, Vol. 16, No. 11
doi:10.1093/hmg/ddm075
Advance Access published on May 3, 2007
1271–1278
Compelling evidence for a prostate cancer gene
at 22q12.3 by the International Consortium for
Prostate Cancer Genetics
Nicola J. Camp1,*, Lisa A. Cannon-Albright1, James M. Farnham1, Agnes B. Baffoe-Bonnie2,3,4,
Asha George2,3, Isaac Powell2,5, Joan E. Bailey-Wilson2,4, John D. Carpten2,6,
Graham G. Giles7,8, John L. Hopper7,9, Gianluca Severi7,8, Dallas R. English7,9,
William D. Foulkes7,10, Lovise Maehle7,11, Pal Moller7,11, Ros Eeles7,12, Douglas Easton7,13,
Michael D. Badzioch7,14, Alice S. Whittemore15,16,17, Ingrid Oakley-Girvan15,17,
Chih-Lin Hsieh15,18, Latchezar Dimitrov19, Jianfeng Xu19, Janet L. Stanford20,21,
Bo Johanneson20,22, Kerry Deutsch20,23, Laura McIntosh20,21, Elaine A. Ostrander20,22,
Kathleen E. Wiley24, Sarah D. Isaacs24, Patrick C. Walsh24, Stephen N. Thibodeau25,
Shannon K. McDonnell25, Scott Hebbring25, Daniel J. Schaid25, Ethan M. Lange26,27,
Kathleen A. Cooney26,28, Teuvo L.J. Tammela29, Johanna Schleutker29, Thomas Paiss30,31,
Christiane Maier30,32, Henrik Grönberg33,35, Fredrik Wiklund33,35, Monica Emanuelsson33,34
and William B. Isaacs24 for the International Consortium for Prostate Cancer Genetics
1
University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, 391,
Chipeta Way, Suite D, Salt Lake City, UT 84108, USA, 2African American Hereditary Prostate Cancer ICPCG Group,
3
Fox Chase Cancer Center, Philadelphia, PA, USA, 4National Human Genome Research Institute, NIH, Bethesda, MD,
USA, 5Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA, 6Translational Genomics Research
Institute, Genetic Basis of Human Disease Research Division, Phoenix, AZ, USA, 7ACTANE Consortium ICPCG Group,
8
Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia, 9Centre for Molecular, Environmental,
Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia,
10
Department of Oncology, McGill University, Montreal, Quebec, Canada, 11The Norwegian Radium Hospital, Oslo,
Norway, 12Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK, 13Cancer Research UK
Genetic Epidemiology Unit, Cambridge, UK, 14Division of Medical Genetics, University of Washington Medical Center,
Seattle, WA, USA, 15BC/CA/HI ICPCG Group, 16Department of Health Research and Policy, 17Stanford Comprehensive
Cancer Center, Stanford School of Medicine, CA, USA, 18Department of Urology and Department of Biochemistry and
Molecular Biology, University of Southern California, CA, USA, 19Data Coordinating Center for the ICPCG and Center for
Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, 20FHCRC ICPCG Group,
21
Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, Seattle, WA, USA, 22Cancer
Genetics Branch, National Institutes of Health, Bethesda, MD, USA, 23Institute for Systems Biology, Seattle, WA, USA,
24
Johns Hopkins University ICPCG group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore,
MD, USA, 25Mayo Clinic ICPCG Group and Mayo Clinic, Rochester, MN, USA, 26University of Michigan ICPCG Group,
27
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, 28University of Michigan, Ann Arbor,
MI, USA, 29University of Tampere ICPCG group and Tampere University Hospital, University of Tampere, Tampere,
Finland, 30University of Ulm ICPCG group, 31Department of Urology, 32Institute of Human Genetics, University of
Ulm, Germany, 33University of Umeå ICPCG group, 34Oncologic Centre, Umeå University, Umeå, Sweden and
35
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
*To whom correspondence should be addressed. Tel: +1 8015879351; Fax: +1 8015816052; Email: [email protected]
# The Author 2007. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected]
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Human Molecular Genetics, 2007, Vol. 16, No. 11
Received January 28, 2007; Revised and Accepted March 20, 2007
Previously, an analysis of 14 extended, high-risk Utah pedigrees localized in the chromosome 22q linkage
region to 3.2 Mb at 22q12.3-13.1 (flanked on each side by three recombinants) contained 31 annotated
genes. In this large, multi-centered, collaborative study, we performed statistical recombinant mapping in
54 pedigrees selected to be informative for recombinant mapping from nine member groups of the
International Consortium for Prostate Cancer Genetics (ICPCG). These 54 pedigrees included the 14 extended
pedigrees from Utah and 40 pedigrees from eight other ICPCG member groups. The additional 40 pedigrees
were selected from a total pool of 1213 such that each pedigree was required to contain both at least four
prostate cancer (PRCA) cases and exhibit evidence for linkage to the chromosome 22q region. The recombinant events in these 40 independent pedigrees confirmed the previously proposed region. Further, when all
54 pedigrees were considered, the three-recombinant consensus region was narrowed down by more than a
megabase to 2.2 Mb at chromosome 22q12.3 flanked by D22S281 and D22S683. This narrower region eliminated 20 annotated genes from that previously proposed, leaving only 11 genes. This region at 22q12.3 is
the most consistently identified and smallest linkage region for PRCA. This collaborative study by the
ICPCG illustrates the value of consortium efforts and the continued utility of linkage analysis using informative pedigrees to localize genes for complex diseases.
INTRODUCTION
The International Consortium for Prostate Cancer Genetics
(ICPCG) was created to foster collaborative efforts towards
gene identification through powerful, combined analyses
using linkage data in pedigrees. Currently, the ICPCG brings
together genome-wide linkage data from 11 international prostate cancer [PRCA (MIM 176807)] research groups comprising 1310 pedigrees. The initial ICPCG genome-wide linkage
scan for PRCA identified chromosome 22q with the strongest
linkage evidence [log of the odds (LOD) score of 3.57] with a
1-LOD support interval from 35 to 47 cM (1). This combined
linkage analysis used a strict definition for PRCA and particular linkage techniques which, in some cases, imposed restrictions on pedigree structure. Several of the individual groups’
linkage studies, which often differed in disease definition
and linkage method, also reported linkage evidence to the
22q region with varying degrees of significance (2 –9). This
makes chromosome 22q the most consistently identified
linkage region for PRCA genes.
Localization efforts are challenging, in particular due to
genetic heterogeneity; statistical noise from unlinked pedigrees and phenocopy PRCA cases can misleadingly shift
linkage evidence. One approach for localization is therefore
to focus on only those pedigrees that are unlikely to represent
mere chance clustering and that contribute most to the overall
linkage signal. That is, multi-case pedigrees that exhibit at
least nominally significant linkage evidence to a region of
interest. The disadvantage of this approach is that only a
few such pedigrees may exist in a single collection.
However, such an approach may be possible in an international collaborative setting, such as the ICPCG.
Camp et al. (10) performed recombinant mapping in
14 high-risk, extended Utah pedigrees selected from their previous genome-wide linkage study (7) to localize the 22q
region to 3.2 Mb at 22q12.3-13.1 containing 31 known
genes. In the present collaborative study, we describe further
localization of the region using data from an additional
40 pedigrees each with multiple PRCA cases and at least
nominally significant evidence for linkage to the chromosome
22q region.
RESULTS
From the total of 1213 ICPCG pedigrees, 40 were identified
with at least four confirmed PRCA cases and a pedigreespecific LOD score indicating at least nominal evidence for
linkage to the chromosome 22q region. Recombinant
mapping was performed for each of these 40 pedigrees,
which entails using the LOD graphs to identify the recombinant positions and identify the shared, linked, segregating haplotype. Figure 1 shows an example of an LOD graph for a
single pedigree (Michigan pedigree 6196). A single recombinant has occurred between D22S315 at 22.88 cM (where the
LOD score is .1.0) and D22S539 at 14.68 cM (where the
LOD score is ,20.5). The true position of the recombinant
could lie anywhere between these two markers. We use the
outermost marker to define the recombinant position. This is
the conservative approach because it can only over-estimate
the shared chromosomal segment and hence the resulting consensus region. As shown in Figure 1, the most conservative
estimation for the position of the recombination in
Michigan-6196 is at D22S539. The linked haplotype is therefore recorded from D22S539 to the q-terminus. We performed
this for each pedigree and overlaid the haplotype segments to
identify the consensus region across all pedigrees. In particular, the consensus region flanked by three recombinants on
each side is akin to a 99% credible interval (see Materials
and Methods section).
Figure 2 shows the results from the recombinant mapping.
The non-recombinant chromosomal segments, both for the
additional 40 ICPCG pedigrees and for the 14 Utah pedigrees,
which initially localized the region are shown (10). The previously described three-recombinant region was at chromosome 22q12.3-13.1 and stretched from D22S281 at 38.55 cM
Human Molecular Genetics, 2007, Vol. 16, No. 11
1273
Figure 1. Log of the odds score graph for Michigan pedigree 6196. Arrow indicates the estimated position of the recombinant event.
(32 666 708 bp) to D22S1045 at 44.75 cM (35 866 231 bp).
In the 40 pedigrees in the current study, the three-recombinant
region is flanked by D22S280 at 37.03 cM (31 295 286 bp)
and D22S283 at 41.63 cM (35 080 651 bp). Considering all
54 pedigrees together, the consensus one-recombinant region
remains between D22S1265 at 39.06 cM (33 719 908 bp)
and D22S277 at 40.82 cM (34 601 466 bp). The consensus
three-recombinant region is narrowed to 2.2 Mb at 22q12.3
between D22S281 at 38.55 cM (32 666 708 bp) and D22S683
at 41.23 cM (34 843 637 bp). This represents a reduction
of 30%, or 1 022 594 bp, from that reported previously, and
eliminates 20 genes.
Analysis of these 40 ICPCG pedigrees not only corroborates
the region previously described, but provides a more precise
definition of the 22q region containing the hypothesized
susceptibility variant(s). Figure 3 shows the location of the
11 known genes within the 2.2 Mb consensus three-recombinant
region at chromosome 22q12.3 (ISX, HMG2L1, TOM1,
HMOX1, MCM5, RASD2, MB, LOC284912, APOL6, APOL5
and RBM9).
DISCUSSION
We have analyzed 40 ICPCG pedigrees, each with at least four
PRCA cases confirmed by medical record or death certificate
and with pedigree-specific linkage evidence to the region to
further localize the PRCA linkage evidence on 22q. Together
with the 14 high-risk Utah pedigrees that were used
to perform the initial localization, the total collection of
54 pedigrees contributes 55 defining recombinant events that
taken together provide identification of a consensus region
with no conflicts. The one-recombinant consensus region is
an 881 538 bp interval containing 11 genes. More conservatively, if we consider the putative 22q12.3 PRCA locus as the
larger three-recombinant region, the physical size is 2.2 Mb,
but contains no additional known genes. In particular, the two
additional telomeric recombinants provided by ICPCG pedigrees analyzed here narrowed the previously proposed (10)
three-recombinant region by over 1 Mb, removing 20 genes
from the region. No further narrowing was achieved on the centromeric end of the region; however, there is a gene desert in this
direction and no genes lie centromeric of D22S1265.
This study illustrates the utility of statistical recombinant
mapping to localize linkage regions. In this particular study,
the 1-LOD support interval from the collaborative genomewide scan was a 12 cM (approximately 8 Mb) region (1).
However, the three-recombinant consensus region using the
same data (without Utah) in a pedigree-specific manner is a
4.6 cM (3.8 Mb) region. Note that this region size is smaller
than the genomic search resolution of any individual group’s
map. This ‘fine-mapping’ is achieved simply by virtue of the
use of different marker maps by the different groups. Incorporating the Utah pedigrees with their fine-mapping markers, the
region becomes 2.7 cM (2.2 Mb). If fine-mapping markers
were to be added to select ICPCG pedigrees, there would be
potential to narrow the region even more.
The individual pedigree-based strategy for localization
seems to have been largely overlooked for mapping complex
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Human Molecular Genetics, 2007, Vol. 16, No. 11
Figure 2. Recombinant map for all 54 pedigrees within the previously defined 1-LOD support interval (35–47 cM) (1). Solid vertical lines indicate the nonrecombinant chromosomal segment that is segregated in the pedigree. Pedigrees to the left of the dashed line are the 14 Utah pedigrees used in the initial localization efforts (10). Pedigrees to the right of the dashed line are the 40 additional ICPCG pedigrees. Grey, horizontal hashed arrows indicate the three left and
right recombinant events that defines the three-recombinant region for the 14 Utah pedigrees. Black horizontal arrows indicate the three left and right recombinant events that define the ICPCG three-recombinant region. The grey, vertical rectangle against the y-axis indicates the three-recombinant region for the 14 Utah
pedigrees. The black, vertical rectangle against the y-axis indicates the three-recombinant region for the ICPCG.
disease genes but, through consortia efforts, it may prove beneficial in localizing linkage regions and moving towards successful gene identification. The key undoubtedly lies in the
ability to identify multiple, informative localization pedigrees
to provide the statistical recombinant events. The requisite
properties of such pedigrees include a significant excess of
disease to avoid studying pedigrees which are merely chance
clustering of disease and good evidence for segregation of
the region of interest with the disease. Here we focused on
only those pedigrees that contained at least four PRCA cases
and that had a nominally significant pedigree-specific LOD
score (LOD 0.588; P 0.05). We considered these were
reasonably strict criteria, which were satisfied by 40 pedigrees
from the total resource of 1213 (3%). In addition to disease
clustering and linkage evidence, another valuable characteristic for a localization pedigree is having a large number of
meioses (gained via large numbers of generations and/or
large sibships). It is clear that the more meioses contained in
a pedigree, the more opportunities to observe recombinant
events, although the disadvantage with a large number of generations is the increased likelihood of intra-familial genetic
heterogeneity. In fact, the proportionately larger number of
meioses in the high-risk Utah pedigrees is likely the reason
that a single research group was able to perform the initial
localization effectively (10). On average 1.5 times more
recombinant events were observed across chromosome 22 in
the Utah pedigrees than in the pedigrees from other groups.
The fundamental advantage of the ICPCG is that through
collaborative efforts, the consortium creates a large pool of
pedigrees from which homogeneous subsets can be selected
for specific purposes, such as in the current study or in the
ICPCG aggressive disease analysis (11). But more than this,
it also brings together a diversity of ethnicities and origins,
ranging from Northern European pedigrees from Finland to
African American pedigrees in the AAHPC. Inspecting
results across this spectrum may be informative. In the
current study, Table 2 indicates the proportion of powerful
pedigrees (with greater than or equal to four PRCA) that
were found to be linked (LOD 0.588) to the chromosome
22q12 region. The proportion of informative linked pedigrees
calculated across all groups was 0.07 (40/538), but proportions
ranged from 0.00 (0/37) in German pedigrees collected at
University of Ulm to 0.16 (7/45) in the University of
Michigan resource. However, even these two extremes are
Human Molecular Genetics, 2007, Vol. 16, No. 11
1275
Figure 3. Schematic representation of the physical 22q12.3 region from 32.6 to 34.9 Mb. Light grey, mid-grey and dark-grey horizontal lines indicate the one-,
two- and three-recombinant regions across the combined 54 pedigrees. Black horizontal lines indicate the position of known genes across the whole region. There
is a gene-desert on the centromeric side of the region. The names of each gene are written to the left or right.
not statistically different than the global estimate across all
pedigrees (P . 0.05). Thus, while the underlying gene at
chromosome 22q12 may only account for ,10% of pedigrees,
it does seem reasonably consistent across populations.
Multiple studies have suggested that a PRCA susceptibility
gene resides in the chromosome 22q12 region (1–9). Through
analysis of 54 selected pedigrees we have used recombinant
mapping to narrow the consensus three-recombinant region to
2.2 Mb at 22q12.3 between D22S281 and D22S683. There
remains only a small probability (P , 0.007) that the putative
disease gene lies outside this region. In addition, we have established that the 881 538 bp interval, between D22S1265 and
D22S277 remains the consensus one-recombinant region,
which is most likely to contain the 22q PRCA predisposition
gene. This collaborative study from the ICPCG illustrates the
strength of the consortium and indicates the continued utility
of linkage analysis in informative pedigrees to localize genes
for complex diseases.
MATERIALS AND METHODS
component from the ICPCG, the remaining consortium total
is 1213 pedigrees with genomic search linkage data. Here
we concentrate on the additional localization information
found using these 1213 pedigrees. All linkage results presented for the pedigrees are based on a strict PRCA definition
(confirmed by medical record or death certificate) and parametric multipoint LOD scores calculated using the
Genehunter-Plus software (13), and utilizing the ‘Smith’
model (14) which was used in the original ICPCG genomewide linkage scan that indicated the linkage to the region on
22q (1). This model assumes a sex-limited, dominant gene
with a disease allele frequency of 0.003 and a 15% phenocopy
rate. Unaffected men under 75 and women are of unknown
phenotype. In unaffected men over 75, a penetrance for
carriers of 63% was assumed, while the risk for non-carriers
was 16%. Linkage evidence was calculated at a 1 cM resolution across the chromosome for each pedigree. The genetic
markers available for each group and the consensus map
used are shown in Table 1. The research protocols and
informed consent procedures were approved by each group’s
institutional review board.
Linkage analyses
The ICPCG comprises 1310 pedigrees with genomic search
data: 1233 pedigrees from 10 groups (referred to as
ACTANE, BC/CA/HI, Johns Hopkins University, Mayo
Clinic, Fred Hutchinson Cancer Research Center (FHCRC),
University of Michigan, University of Tampere – Finland, University of Ulm –Germany, University of Umeå – Sweden and
University of Utah) that are described in detail elsewhere
(12) and 77 pedigrees from the African American Hereditary
Prostate Cancer (AAHPC) group (9). For the chromosome
22 region, the initial localization efforts were carried out as
an independent study of high-risk Utah pedigrees without
limitations on pedigree structure (10). Removing the Utah
Selection of localization pedigrees
Table 2 shows pertinent characteristics of the pedigrees from
the 10 ICPCG groups. Localization pedigrees were chosen
to be those with at least four confirmed PRCA cases and
with LOD 0.588 (P 0.05) within the 1-LOD support interval (35 –47 cM) previously described by the ICPCG genomewide linkage scan (1). These represent the criteria used in the
initial localization of Camp et al. (10). A total of 40 pedigrees
satisfied these criteria, comprising 5 pedigrees from the AAHPC
group, 1 pedigree from the ACTANE group, 1 pedigree from
the BC/CA/HI group, 14 pedigrees from Johns Hopkins, 5
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Human Molecular Genetics, 2007, Vol. 16, No. 11
Table 1. Chromosome marker maps by group
Marker
cMa
bpb
D22S420
D22S427
D22S446
D22S539
D22S686
D22S257
D22S345c
ATTT019c
D22S315c
D22S1154
D22S310
D22S1144
D22S1163
D22S689
D22S531
D22S273c
D22S1686
D22S280
D22S1172
D22S281
D22S685
D22S1265
D22S424
D22S277c
D22S683c
D22S283c
D22S692
D22S1177
D22S1045
D22S445
D22S1156
D22S423
D22S1179
D22S274
D22S928
D22S1169
2.96
5.80
14.09
14.68
15.46
16.80
19.09
19.67
22.88
24.38
24.38
29.41
30.54
32.92
34.49
36.03
36.74
37.03
37.45
38.55
38.79
39.06
39.85
40.82
41.23
41.63
42.27
43.51
44.75
45.22
46.24
49.14
50.03
56.47
57.28
68.82
16 239 281
16 971 317
20 349 111
20 587 780
21 398 516
21 898 429
22 818 587
23 051 479
24 345 840
24 947 527
24 958 223
26 012 933
26 248 651
27 186 340
29 029 219
30 582 056
31 295 286
31 539 372
32 004 392
32 666 708
32 925 479
33 719 908
34 029 013
34 601 446
34 843 637
35 080 651
35 455 491
35 593 050
35 866 231
35 895 844
36 711 579
38 712 132
41 922 461
43 647 780
43 853 966
47 788 060
Cytogenetic band AAHPC ACTANE BC/CA/HI JHU Mayo FHCRC Michigan Tampere Ulm Umeå Utah
22q11.1
22q11.21
22q11.21
22q11.22
22q11.22
22q11.23
22q11.23
22q11.23
22q12.1
22q12.1
22q12.1
22q12.1
22q12.1
22q12.1
22q12.2
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q12.3
22q13.1
22q13.1
22q13.1
22q13.1
22q13.2
22q13.31
22q13.31
22q13.32
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a
deCODE genetic position.
Physical bp position for start site of genetic marker from UCSC Genome Browser March 2006 human reference sequence (NCBI Build 36.1; http://
genome.ucsc.edu/).
c
Interpolated cM positions using physical bp position and cM for flanking markers.
b
from Mayo Clinic, 6 from the FHCRC, 7 from the University of
Michigan and 1 from the University of Umeå in Sweden.
Statistical recombinant mapping and
consensus regions
For each pedigree with an LOD 0.588, the multipoint LOD
graph was used to estimate the position of recombinant events.
A sharp decrease in LOD (.0.5 LOD units) was used to indicate loss in sharing (recombination). To remain conservative,
we report the outermost possible position of each recombinant.
For each pedigree, the non-recombinant chromosomal segments are overlaid to create the consensus region. The
minimal one-recombinant consensus region is the region
defined by one recombinant at each side. Similarly, two- and
three-recombinant consensus regions can be defined. In particular, we focus on the three-recombinant consensus region
because, even if we consider a phenocopy PRCA rate as
high as 15%, the probability that the gene lies outside of the
region is very low (P ¼ 0.007). That is, the putative mutation
will lie outside of the region only if all three boundary recombination events were observed, by chance, in phenocopy
PRCA cases, on either or both sides of the region, which is
simply 2 (0.15)3 2 (0.15)6 ¼ 0.007. Hence, the threerecombinant consensus region is akin to a 99% credible interval. The same probabilities for the one- and two-recombinant
regions are 0.28 and 0.04, respectively. Of course, this
credible interval is clearly influenced by the ‘sporadic’ rate
considered. It should be noted, however, that the meaning of
sporadic in this situation is the probability that a confirmed
PRCA case which shares a segregating haplotype in a linked
pedigree with a least three other confirmed PRCA cases, is,
in fact, merely a phenocopy.
ACKNOWLEDGEMENTS
We would like to express our gratitude to the many families
who participated in the many studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG).
The ICPCG, including the consortium’s Data Coordinating
References are given for each research group where details on ascertainment can be found.
Men affected with PRCA confirmed by either medical records or death certificate.
c
In the ACTANE pedigree, one parent was born in Africa, and in the FHCRC and Michigan collections 1of 6 and 1 of 7 of the informative pedigrees were African American, respectively.
b
a
0.06
0.07
0.05
0.06
0.09
0.16
0.16
0.00
0.00
0.03
0.07
5
1c
1
6c
14
5
7c
0
0
1
40
77
14
20
109
160
31
45
8
37
37
538
77
64
98
254
188
157
176
10
139
50
1213
AAHPC (9)
ACTANE (15)
BC/CA/HI (16)
FHCRC (2)
Johns Hopkins University (3)
Mayo Clinic (5)
University of Michigan (4)
University of Tampere –Finland (17)
University of Ulm–Germany (18)
University of Umeå–Sweden (19)
Total
Number of pedigrees
with greater than or equal
to four PRCA cases and
LOD 0.588 at chr 22q12
Number of pedigrees
with greater than or
equal to four PRCA casesb
Total pedigrees
Groupa
Table 2. Pedigree characteristics
Center (DCC), is made possible by a grant from the National
Institutes of Health U01 CA89600 (to W.B.I.). N.J.C. was supported in part by USPHS CA98364. Additional support to participating groups, or members within groups, is as follows:
AAHPC Group: The authors would like to express their
gratitude to the AAHPC study families and study participants
for their continued involvement in this research. We specifically name, C. Ahaghotu, J. Bennett, W. Boykin, G. Hoke,
T. Mason, C. Pettaway, S. Vijayakumar, S. Weinrich,
M. Franklin, P. Roberson, J. Frost, E. Johnson, L. FaisonSmith, C. Meegan, M. Johnson, L. Kososki, C. Jones and
R. Mejia. We would also like to thank the members of the
National Human Genome Center (NHGC) at Howard University namely R. Kittles, G.M. Dunston, P. Furbert-Harris and
C. Royal. We would also like to acknowledge the contribution
of the National Human Genome Research Institute (NHGRI)
and TGen genotyping staff including E. Gillanders and
C. Robbins. The AAHPC study would not have been possible
without F. Collins (Director of NHGRI) and J. Trent (Director
of TGen). This research was funded primarily through the NIH
Center for Minority and Health Disparities (1-HG-75418).
A.B.B-B and A.G. also received support from USPHS
CA-06927 and an appropriation from the Commonwealth of
Pennsylvania. This research was also supported in part by
the Intramural Research Program of the NIH (NHGRI) and
USPHS RR03048 from the National Center for Research Institute and USPHS RR03048 from the National Center for
Research Resources. ACTANE Group: Genotyping and statistical analysis for this study, and recruitment of UK families,
was supported by Cancer Research UK (CR-UK). Additional
support was provided by The Prostate Cancer Research Foundation, The Times Christmas Appeal and the Institute of
Cancer Research. Genotyping was conducted in the ‘Jean
Rook Gene Cloning Laboratory’ which is supported by
BREAKTHROUGH Breast Cancer—Charity No. 328323.
The funds for the ABI 377 used in this study were generously
provided by the legacy of the late Marion Silcock. We
thank S. Seal and A. Hall for kindly storing and logging the
samples that were provided. D.F.E. is a Principal Research
Fellow of CR-UK. Funding in Australia was obtained from
The Cancer Council Victoria, The National Health and
Medical Research Council (grants 940934, 251533, 209057,
126402, 396407), Tattersall’s and The Whitten Foundation.
We would like to acknowledge the work of the study coordinator
M. Staples and the Research Team B. McCudden, J. Connal,
R. Thorowgood, C. Costa, M. Kevan and S. Palmer, and to
J. Karpowicz for DNA extractions. The Texas study of familial
prostate cancer was initiated by the Department of Epidemiology, M.D. Anderson Cancer Center. M.B. was supported by
an NCI Post-doctoral Fellowship in Cancer Prevention (R25).
We would also like to specifically thank the following
members of ACTANE: S. Edwards, M. Guy, Q. Hope,
S. Bullock, S. Bryant, S. Mulholland, S. Jugurnauth,
N. Garcia, A. Ardern-Jones, A. Hall, L. O’Brien, B. Gehr-Swain,
R. Wilkinson, D. Dearnaley, The UKGPCS Collaborators,
British Association of Urological Surgeons’ Section of Oncology (UK Sutton); Chris Evans (UK Cambridge); M. Southey
(Australia); N. Hamel, S. Narod, J. Simard (Canada); C. Amos
(TX, USA); N. Wessel, T. Andersen (Norway); D.T. Bishop
(EU Biomed). BC/CA/HI Group: USPHS CA67044.
Proportion of pedigrees
with greater than or equal
to four PRCA cases that
are linked to chr 22q12
Human Molecular Genetics, 2007, Vol. 16, No. 11
1277
1278
Human Molecular Genetics, 2007, Vol. 16, No. 11
FHCRC Group: USPHS CA80122 (to J.L.S.) which supports
the family collection; USPHS CA78836 (to E.A.O). E.A.O
was supported in part by the NHGRI. JHU Group: Genotyping
for the JHU, University of Michigan, University of Tampere,
and University of Umeå groups’ pedigrees was provided by
NHGRI and TGen genotyping staff including E. Gillanders,
M.P. Jones, D. Gildea, E. Riedesel, J. Albertus, D. Freas-Lutz,
C. Markey, J. Carpten and J. Trent. Mayo Clinic Group:
USPHS CA72818. Michigan Group: USPHS CA079596.
University of Tampere Group: The Competitive Research
Funding of the Pirkanmaa Hospital District, Reino Lahtikari
Foundation, Finnish Cancer Organisations, Sigrid Juselius Foundation and Academy of Finland grant 211123. University of
Ulm Group: Deutsche Krebshilfe, grant number 70-3111-V03.
University of Umea Group: Work was supported by the
Swedish Cancer Society and a Spear grant from the Umeå University Hospital, Umeå, Sweden. University of Utah Group:
Data collection was supported by USPHS CA90752 (to
L.A.C.-A.) and by the Utah Cancer Registry, which is funded
by Contract no. N01-PC-35141 from the National Cancer Institute’s Surveillance, Epidemiology and End-Results Program
with additional support from the Utah State Department of
Heath and the University of Utah. Partial support for all datasets
within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute and also by the
USPHS M01-RR00064 from the National Center for Research
Resources. Genotyping services were provided by the Center
for Inherited Disease Research (N01-HG-65403). DCC: The
study is partially supported by USPHS CA106523 (to J.X.),
USPHS CA95052 (to J.X.) and Department of Defense grant
PC051264 (to J.X.).
Conflict of Interest statement. There are no conflicts of interest
to declare.
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