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Comparative Study
. 2012 Mar;72(4):410-26.
doi: 10.1002/pros.21443. Epub 2011 Jul 11.

Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG

Lingyi Lu  1 , Geraldine Cancel-Tassin, Antoine Valeri, Olivier Cussenot, Ethan M Lange, Kathleen A Cooney, James M Farnham, Nicola J Camp, Lisa A Cannon-Albright, Teuvo L J Tammela, Johanna Schleutker, Josef Hoegel, Kathleen Herkommer, Christiane Maier, Walther Vogel, Fredrik Wiklund, Monica Emanuelsson, Henrik Grönberg, Kathleen E Wiley, Sarah D Isaacs, Patrick C Walsh, Brian T Helfand, Donghui Kan, William J Catalona, Janet L Stanford, Liesel M FitzGerald, Bo Johanneson, Kerry Deutsch, Laura McIntosh, Elaine A Ostrander, Stephen N Thibodeau, Shannon K McDonnell, Scott Hebbring, Daniel J Schaid, Alice S Whittemore, Ingrid Oakley-Girvan, Chih-Lin Hsieh, Isaac Powell, Joan E Bailey-Wilson, Cheryl D Cropp, Claire Simpson, John D Carpten, Daniela Seminara, S Lilly Zheng, Jianfen Xu, Graham G Giles, Gianluca Severi, John L Hopper, Dallas R English, William D Foulkes, Lovise Maehle, Pal Moller, Michael D Badzioch, Steve Edwards, Michelle Guy, Ros Eeles, Douglas Easton, William B Isaacs; International Consortium for Prostate Cancer Genetics
Collaborators, Affiliations
Comparative Study

Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG

Lingyi Lu et al. Prostate. 2012 Mar.

Abstract

Background: In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members.

Methods: In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups.

Results: Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology.

Conclusions: These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.

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Figures

Figure 1
Figure 1
a. Plot of LOD scores for all families by chromosome. b. Chromosomes with LOD scores > 1.86 in all families. c. Chromosomes with LOD Scores > 1.5 in all families.
Figure 1
Figure 1
a. Plot of LOD scores for all families by chromosome. b. Chromosomes with LOD scores > 1.86 in all families. c. Chromosomes with LOD Scores > 1.5 in all families.
Figure 1
Figure 1
a. Plot of LOD scores for all families by chromosome. b. Chromosomes with LOD scores > 1.86 in all families. c. Chromosomes with LOD Scores > 1.5 in all families.
Figure 2
Figure 2
a. Plot of LOD Scores for families with average age at diagnosis under 65. b. Chromosomes with LOD scores ≥ 1.86 in families with young age at diagnosis (<65).
Figure 2
Figure 2
a. Plot of LOD Scores for families with average age at diagnosis under 65. b. Chromosomes with LOD scores ≥ 1.86 in families with young age at diagnosis (<65).
Figure 3
Figure 3
a. Plot of LOD Scores for families with average age at diagnosis ≥ 65. b. Chromosomes with LOD scores ≥ 1.86 in families with average age at diagnosis ≥65.
Figure 3
Figure 3
a. Plot of LOD Scores for families with average age at diagnosis ≥ 65. b. Chromosomes with LOD scores ≥ 1.86 in families with average age at diagnosis ≥65.
Figure 4
Figure 4
a. Plot of LOD Scores for families with more aggressive disease. b. Chromosomes with LOD scores ≥1.86 in families with more aggressive disease.
Figure 4
Figure 4
a. Plot of LOD Scores for families with more aggressive disease. b. Chromosomes with LOD scores ≥1.86 in families with more aggressive disease.
Figure 5
Figure 5
a. Plot of LOD Scores for families with 5 or more affected members. b. Chromosomes with LOD scores ≥ 1.86 in families with 5 or more affected members. c. Chromosome 21 in families with 5 or more affected members. The position of ERG and TMPRSS2, two genes known to undergo common genomic rearrangement leading to gene fusion and activation of ERG (41), is noted.
Figure 5
Figure 5
a. Plot of LOD Scores for families with 5 or more affected members. b. Chromosomes with LOD scores ≥ 1.86 in families with 5 or more affected members. c. Chromosome 21 in families with 5 or more affected members. The position of ERG and TMPRSS2, two genes known to undergo common genomic rearrangement leading to gene fusion and activation of ERG (41), is noted.
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References

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Supplementary concepts