Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases

L. M. Fitzgerald, S. Zhao, A. Leonardson, M. S. Geybels, S. Kolb, D. W. Lin, J. L. Wright, R. Eeles, Z. Kote-Jarai, K. Govindasami, G. G. Giles, M. C. Southey, J. Schleutker, T. L. Tammela, C. Sipeky, K. L. Penney, M. J. Stampfer, H. Gronberg, F. Wiklund, P. Stattin & 5 others J. Hugosson, D. M. Karyadi, E. A. Ostrander, Z. Feng, J. L. Stanford

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Original languageEnglish
Pages (from-to)228-237
Number of pages10
JournalProstate Cancer and Prostatic Diseases
Volume21
Issue number2
DOIs
Publication statusPublished - 1 Jun 2018
Externally publishedYes

Cite this

Fitzgerald, L. M. ; Zhao, S. ; Leonardson, A. ; Geybels, M. S. ; Kolb, S. ; Lin, D. W. ; Wright, J. L. ; Eeles, R. ; Kote-Jarai, Z. ; Govindasami, K. ; Giles, G. G. ; Southey, M. C. ; Schleutker, J. ; Tammela, T. L. ; Sipeky, C. ; Penney, K. L. ; Stampfer, M. J. ; Gronberg, H. ; Wiklund, F. ; Stattin, P. ; Hugosson, J. ; Karyadi, D. M. ; Ostrander, E. A. ; Feng, Z. ; Stanford, J. L. / Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality : An analysis of 12,082 prostate cancer cases. In: Prostate Cancer and Prostatic Diseases. 2018 ; Vol. 21, No. 2. pp. 228-237.
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title = "Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases",
abstract = "Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95{\%} confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.",
author = "Fitzgerald, {L. M.} and S. Zhao and A. Leonardson and Geybels, {M. S.} and S. Kolb and Lin, {D. W.} and Wright, {J. L.} and R. Eeles and Z. Kote-Jarai and K. Govindasami and Giles, {G. G.} and Southey, {M. C.} and J. Schleutker and Tammela, {T. L.} and C. Sipeky and Penney, {K. L.} and Stampfer, {M. J.} and H. Gronberg and F. Wiklund and P. Stattin and J. Hugosson and Karyadi, {D. M.} and Ostrander, {E. A.} and Z. Feng and Stanford, {J. L.}",
year = "2018",
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Fitzgerald, LM, Zhao, S, Leonardson, A, Geybels, MS, Kolb, S, Lin, DW, Wright, JL, Eeles, R, Kote-Jarai, Z, Govindasami, K, Giles, GG, Southey, MC, Schleutker, J, Tammela, TL, Sipeky, C, Penney, KL, Stampfer, MJ, Gronberg, H, Wiklund, F, Stattin, P, Hugosson, J, Karyadi, DM, Ostrander, EA, Feng, Z & Stanford, JL 2018, 'Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases' Prostate Cancer and Prostatic Diseases, vol. 21, no. 2, pp. 228-237. https://doi.org/10.1038/s41391-017-0029-2

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality : An analysis of 12,082 prostate cancer cases. / Fitzgerald, L. M.; Zhao, S.; Leonardson, A.; Geybels, M. S.; Kolb, S.; Lin, D. W.; Wright, J. L.; Eeles, R.; Kote-Jarai, Z.; Govindasami, K.; Giles, G. G.; Southey, M. C.; Schleutker, J.; Tammela, T. L.; Sipeky, C.; Penney, K. L.; Stampfer, M. J.; Gronberg, H.; Wiklund, F.; Stattin, P.; Hugosson, J.; Karyadi, D. M.; Ostrander, E. A.; Feng, Z.; Stanford, J. L.

In: Prostate Cancer and Prostatic Diseases, Vol. 21, No. 2, 01.06.2018, p. 228-237.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality

T2 - An analysis of 12,082 prostate cancer cases

AU - Fitzgerald, L. M.

AU - Zhao, S.

AU - Leonardson, A.

AU - Geybels, M. S.

AU - Kolb, S.

AU - Lin, D. W.

AU - Wright, J. L.

AU - Eeles, R.

AU - Kote-Jarai, Z.

AU - Govindasami, K.

AU - Giles, G. G.

AU - Southey, M. C.

AU - Schleutker, J.

AU - Tammela, T. L.

AU - Sipeky, C.

AU - Penney, K. L.

AU - Stampfer, M. J.

AU - Gronberg, H.

AU - Wiklund, F.

AU - Stattin, P.

AU - Hugosson, J.

AU - Karyadi, D. M.

AU - Ostrander, E. A.

AU - Feng, Z.

AU - Stanford, J. L.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

AB - Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

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U2 - 10.1038/s41391-017-0029-2

DO - 10.1038/s41391-017-0029-2

M3 - Article

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SP - 228

EP - 237

JO - Prostate Cancer and Prostatic Diseases

JF - Prostate Cancer and Prostatic Diseases

SN - 1365-7852

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ER -