Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients

R. Stephanie Huang, Sharon E. Johnatty, Eric R. Gamazon, Hae Kyung Im, Dana Ziliak, Shiwei Duan, Wei Zhang, Emily O. Kistner, Peixian Chen, Jonathan Beesley, Shuangli Mi, Peter H. O'Donnell, Yarden S. Fraiman, Soma Das, Nancy J. Cox, Yi Lu, Stuart MacGregor, Ellen L Goode, Robert A. Vierkant, Brooke L. FridleyEstrid Hogdall, Susanne K. Kjaer, Allan Jensen, Kirsten B. Moysich, Matthew Grasela, Kunle Odunsi, Robert Brown, Jim Paul, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Jenny Gross, Beth Y. Karlan, Anna DeFazio, Georgia Chenevix-Trench, M. Eileen Dolan

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Abstract

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10-2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10-3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10-3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect.

Original languageEnglish (US)
Pages (from-to)5490-5500
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number16
DOIs
StatePublished - Aug 15 2011

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Platinum
Ovarian Neoplasms
Single Nucleotide Polymorphism
Carboplatin
Genome-Wide Association Study
Alleles
Disease-Free Survival
Genome
HapMap Project
Cell Line
Neoplasms
Atlases
Paclitaxel
Genetic Markers
Research Design
Gene Expression
Drug Therapy
Messenger RNA
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. / Huang, R. Stephanie; Johnatty, Sharon E.; Gamazon, Eric R.; Im, Hae Kyung; Ziliak, Dana; Duan, Shiwei; Zhang, Wei; Kistner, Emily O.; Chen, Peixian; Beesley, Jonathan; Mi, Shuangli; O'Donnell, Peter H.; Fraiman, Yarden S.; Das, Soma; Cox, Nancy J.; Lu, Yi; MacGregor, Stuart; Goode, Ellen L; Vierkant, Robert A.; Fridley, Brooke L.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Moysich, Kirsten B.; Grasela, Matthew; Odunsi, Kunle; Brown, Robert; Paul, Jim; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Gross, Jenny; Karlan, Beth Y.; DeFazio, Anna; Chenevix-Trench, Georgia; Dolan, M. Eileen.

In: Clinical Cancer Research, Vol. 17, No. 16, 15.08.2011, p. 5490-5500.

Research output: Contribution to journalArticle

Huang, RS, Johnatty, SE, Gamazon, ER, Im, HK, Ziliak, D, Duan, S, Zhang, W, Kistner, EO, Chen, P, Beesley, J, Mi, S, O'Donnell, PH, Fraiman, YS, Das, S, Cox, NJ, Lu, Y, MacGregor, S, Goode, EL, Vierkant, RA, Fridley, BL, Hogdall, E, Kjaer, SK, Jensen, A, Moysich, KB, Grasela, M, Odunsi, K, Brown, R, Paul, J, Lambrechts, D, Despierre, E, Vergote, I, Gross, J, Karlan, BY, DeFazio, A, Chenevix-Trench, G & Dolan, ME 2011, 'Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients', Clinical Cancer Research, vol. 17, no. 16, pp. 5490-5500. https://doi.org/10.1158/1078-0432.CCR-11-0724
Huang, R. Stephanie ; Johnatty, Sharon E. ; Gamazon, Eric R. ; Im, Hae Kyung ; Ziliak, Dana ; Duan, Shiwei ; Zhang, Wei ; Kistner, Emily O. ; Chen, Peixian ; Beesley, Jonathan ; Mi, Shuangli ; O'Donnell, Peter H. ; Fraiman, Yarden S. ; Das, Soma ; Cox, Nancy J. ; Lu, Yi ; MacGregor, Stuart ; Goode, Ellen L ; Vierkant, Robert A. ; Fridley, Brooke L. ; Hogdall, Estrid ; Kjaer, Susanne K. ; Jensen, Allan ; Moysich, Kirsten B. ; Grasela, Matthew ; Odunsi, Kunle ; Brown, Robert ; Paul, Jim ; Lambrechts, Diether ; Despierre, Evelyn ; Vergote, Ignace ; Gross, Jenny ; Karlan, Beth Y. ; DeFazio, Anna ; Chenevix-Trench, Georgia ; Dolan, M. Eileen. / Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 16. pp. 5490-5500.
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abstract = "Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10-2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10-3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10-3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect.",
author = "Huang, {R. Stephanie} and Johnatty, {Sharon E.} and Gamazon, {Eric R.} and Im, {Hae Kyung} and Dana Ziliak and Shiwei Duan and Wei Zhang and Kistner, {Emily O.} and Peixian Chen and Jonathan Beesley and Shuangli Mi and O'Donnell, {Peter H.} and Fraiman, {Yarden S.} and Soma Das and Cox, {Nancy J.} and Yi Lu and Stuart MacGregor and Goode, {Ellen L} and Vierkant, {Robert A.} and Fridley, {Brooke L.} and Estrid Hogdall and Kjaer, {Susanne K.} and Allan Jensen and Moysich, {Kirsten B.} and Matthew Grasela and Kunle Odunsi and Robert Brown and Jim Paul and Diether Lambrechts and Evelyn Despierre and Ignace Vergote and Jenny Gross and Karlan, {Beth Y.} and Anna DeFazio and Georgia Chenevix-Trench and Dolan, {M. Eileen}",
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T1 - Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients

AU - Huang, R. Stephanie

AU - Johnatty, Sharon E.

AU - Gamazon, Eric R.

AU - Im, Hae Kyung

AU - Ziliak, Dana

AU - Duan, Shiwei

AU - Zhang, Wei

AU - Kistner, Emily O.

AU - Chen, Peixian

AU - Beesley, Jonathan

AU - Mi, Shuangli

AU - O'Donnell, Peter H.

AU - Fraiman, Yarden S.

AU - Das, Soma

AU - Cox, Nancy J.

AU - Lu, Yi

AU - MacGregor, Stuart

AU - Goode, Ellen L

AU - Vierkant, Robert A.

AU - Fridley, Brooke L.

AU - Hogdall, Estrid

AU - Kjaer, Susanne K.

AU - Jensen, Allan

AU - Moysich, Kirsten B.

AU - Grasela, Matthew

AU - Odunsi, Kunle

AU - Brown, Robert

AU - Paul, Jim

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Vergote, Ignace

AU - Gross, Jenny

AU - Karlan, Beth Y.

AU - DeFazio, Anna

AU - Chenevix-Trench, Georgia

AU - Dolan, M. Eileen

PY - 2011/8/15

Y1 - 2011/8/15

N2 - Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10-2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10-3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10-3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect.

AB - Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10-2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10-3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10-3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect.

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