Germline predictors of androgen deprivation therapy response in advanced prostate cancer

Manish Kohli, Shaun M. Riska, Douglas W. Mahoney, High S. Chai, David W. Hillman, David N. Rider, Brian Costello, Rui Qin, Jatinder Lamba, Deepak M. Sahasrabudhe, James R Cerhan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Objective: To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response. Patients and Methods: In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing. Results: At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less. Conclusion: Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.

Original languageEnglish (US)
Pages (from-to)240-246
Number of pages7
JournalMayo Clinic Proceedings
Volume87
Issue number3
DOIs
StatePublished - 2012

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Androgens
Prostatic Neoplasms
Single Nucleotide Polymorphism
Genes
Therapeutics
Genotype
Metabolic Networks and Pathways
Treatment Failure
Proportional Hazards Models
Steroids
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Germline predictors of androgen deprivation therapy response in advanced prostate cancer. / Kohli, Manish; Riska, Shaun M.; Mahoney, Douglas W.; Chai, High S.; Hillman, David W.; Rider, David N.; Costello, Brian; Qin, Rui; Lamba, Jatinder; Sahasrabudhe, Deepak M.; Cerhan, James R.

In: Mayo Clinic Proceedings, Vol. 87, No. 3, 2012, p. 240-246.

Research output: Contribution to journalArticle

Kohli, M, Riska, SM, Mahoney, DW, Chai, HS, Hillman, DW, Rider, DN, Costello, B, Qin, R, Lamba, J, Sahasrabudhe, DM & Cerhan, JR 2012, 'Germline predictors of androgen deprivation therapy response in advanced prostate cancer', Mayo Clinic Proceedings, vol. 87, no. 3, pp. 240-246. https://doi.org/10.1016/j.mayocp.2011.09.009
Kohli, Manish ; Riska, Shaun M. ; Mahoney, Douglas W. ; Chai, High S. ; Hillman, David W. ; Rider, David N. ; Costello, Brian ; Qin, Rui ; Lamba, Jatinder ; Sahasrabudhe, Deepak M. ; Cerhan, James R. / Germline predictors of androgen deprivation therapy response in advanced prostate cancer. In: Mayo Clinic Proceedings. 2012 ; Vol. 87, No. 3. pp. 240-246.
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abstract = "Objective: To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response. Patients and Methods: In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing. Results: At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less. Conclusion: Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.",
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