Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors

Nina Mononen, Eija H. Seppälä, Priya Duggal, Ville Autio, Tarja Ikonen, Pekka Ellonen, Juha Saharinen, Janna Saarela, Mauno Vihinen, Teuvo L.J. Tammela, Olli Kallioniemi, Joan E. Bailey-Wilson, Johanna Schleutker

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Abstract

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T1-T2) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 −34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3−252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.
Original languageEnglish
Pages (from-to)743-747
Number of pages5
JournalCancer Research
Volume66
Issue number2
DOIs
Publication statusPublished - 2006
MoE publication typeA1 Journal article-refereed

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Androgens
Single Nucleotide Polymorphism
Prostatic Neoplasms
Odds Ratio
Confidence Intervals
Genes
Population Control
Alleles
DNA
Neoplasms

Cite this

Mononen, Nina ; Seppälä, Eija H. ; Duggal, Priya ; Autio, Ville ; Ikonen, Tarja ; Ellonen, Pekka ; Saharinen, Juha ; Saarela, Janna ; Vihinen, Mauno ; Tammela, Teuvo L.J. ; Kallioniemi, Olli ; Bailey-Wilson, Joan E. ; Schleutker, Johanna. / Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors. In: Cancer Research. 2006 ; Vol. 66, No. 2. pp. 743-747.
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title = "Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors",
abstract = "Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95{\%} confidence interval (95{\%} CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T1-T2) and low-grade (WHO grade 1) tumors (OR, 5.42; 95{\%} CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 −34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95{\%} CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3−252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95{\%} CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.",
author = "Nina Mononen and Sepp{\"a}l{\"a}, {Eija H.} and Priya Duggal and Ville Autio and Tarja Ikonen and Pekka Ellonen and Juha Saharinen and Janna Saarela and Mauno Vihinen and Tammela, {Teuvo L.J.} and Olli Kallioniemi and Bailey-Wilson, {Joan E.} and Johanna Schleutker",
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Mononen, N, Seppälä, EH, Duggal, P, Autio, V, Ikonen, T, Ellonen, P, Saharinen, J, Saarela, J, Vihinen, M, Tammela, TLJ, Kallioniemi, O, Bailey-Wilson, JE & Schleutker, J 2006, 'Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors', Cancer Research, vol. 66, no. 2, pp. 743-747. https://doi.org/10.1158/0008-5472.CAN-05-1723

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors. / Mononen, Nina; Seppälä, Eija H.; Duggal, Priya; Autio, Ville; Ikonen, Tarja; Ellonen, Pekka; Saharinen, Juha; Saarela, Janna; Vihinen, Mauno; Tammela, Teuvo L.J.; Kallioniemi, Olli; Bailey-Wilson, Joan E.; Schleutker, Johanna.

In: Cancer Research, Vol. 66, No. 2, 2006, p. 743-747.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors

AU - Mononen, Nina

AU - Seppälä, Eija H.

AU - Duggal, Priya

AU - Autio, Ville

AU - Ikonen, Tarja

AU - Ellonen, Pekka

AU - Saharinen, Juha

AU - Saarela, Janna

AU - Vihinen, Mauno

AU - Tammela, Teuvo L.J.

AU - Kallioniemi, Olli

AU - Bailey-Wilson, Joan E.

AU - Schleutker, Johanna

PY - 2006

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N2 - Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T1-T2) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 −34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3−252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

AB - Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T1-T2) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 −34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3−252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

U2 - 10.1158/0008-5472.CAN-05-1723

DO - 10.1158/0008-5472.CAN-05-1723

M3 - Article

VL - 66

SP - 743

EP - 747

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 2

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