Fine-mapping the putative chromosome 17q21–22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis

Lange, Ethan M.; Robbins, Christiane M.; Gillanders, Elizabeth M.; Zheng, S. Lilly; Xu, Jianfeng; Wang, Yunfei; White, Kirsten A.; Chang, Bao Li; Ho, Lindsey A.; Trent, Jeffrey M.; Carpten, John D.; Isaacs, William B.; Cooney, Kathleen A.

doi:10.1007/s00439-006-0274-2

Cited by 29 publications

(22 citation statements)

References 19 publications

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“…33 We have previously reported genome-wide linkage analysis of hereditary PrCa in 69 highly aggregated Finnish families, 34 where we replicated a previously reported linkage to HPC9 on 17q21-q22 35,36 and identified a novel locus on 2q37.2. Here we describe a secondary analysis of these data using OSA to condition on linkage to either or both linkage peaks to attempt to identify additional loci linked to this disease.…”

Section: Introductionsupporting

confidence: 77%

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

et al. 2012

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Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (DLOD ¼ 3.193, empirical P ¼ 0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD ¼ 2.541, DLOD ¼ 1.651, P ¼ 0.03) and 22q11.1-q11.21 (OSA LOD ¼ 2.395, DLOD ¼ 2.36, P ¼ 0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.

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Section: Introductionsupporting

confidence: 77%

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

et al. 2012

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“…Because the average age at diagnosis for prostate cancer was f65 years old before PSA screening, we used this as one of the age cut-points. This age at diagnosis cut-point has been commonly used in the literature to define early and late prostate cancer diagnoses (19,20). The effects of age at diagnosis were explored further by using the ages of 60 and 70 as cut-points.…”

Section: Methodsmentioning

confidence: 99%

A Common 8q24 Variant in Prostate and Breast Cancer from a Large Nested Case-Control Study

Schumacher¹,

et al. 2007

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Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 Â 10 À13

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“…The initial linkage peak was identified in a scan of 175 hereditary pedigrees and was replicated by the International Consortium for Prostate Cancer Genetics, a large collaborative group with more than 2,000 hereditary PC families 39,40. Fine mapping of the region narrowed the focus to chromosome 17q21-22, a region with more than 200 genes in the minimal recombination region 41. With this smaller region identified, the group evaluated the coding sequence of 202 candidate genes in search of potential PC susceptibility alleles or genes 36.…”

Section: Initial Findingsmentioning

confidence: 95%

Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

Decker¹,

Ostrander²

2014

PGPM

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Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk.

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Fine-mapping the putative chromosome 17q21–22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis

Cited by 29 publications

References 19 publications

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

A Common 8q24 Variant in Prostate and Breast Cancer from a Large Nested Case-Control Study

Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

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