Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
21705454
TITLE
Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients.
ABSTRACT
PURPOSE NlmCategory: OBJECTIVE
Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy.
EXPERIMENTAL DESIGN NlmCategory: METHODS
Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. 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 NlmCategory: RESULTS
Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. 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. 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 (P(per-allele) = 2 × 10(-2)), with a stronger effect in the subset of women with optimally debulked tumors (P(per-allele) = 4 × 10(-3)). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (P(per-allele) = 9 × 10(-3)). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts.
CONCLUSION NlmCategory: CONCLUSIONS
Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. 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. 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 (P(per-allele) = 2 × 10(-2)), with a stronger effect in the subset of women with optimally debulked tumors (P(per-allele) = 4 × 10(-3)). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (P(per-allele) = 9 × 10(-3)). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. 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.
©2011 AACR.
DATE PUBLISHED
2011 Aug 15
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2011/06/28 06:00
pubmed 2011/06/28 06:00
medline 2012/02/04 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Huang RS Huang R Stephanie RS Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Johnatty SE Johnatty Sharon E SE
Gamazon ER Gamazon Eric R ER
Im HK Im Hae Kyung HK
Ziliak D Ziliak Dana D
Duan S Duan Shiwei S
Zhang W Zhang Wei W
Kistner EO Kistner Emily O EO
Chen P Chen Peixian P
Beesley J Beesley Jonathan J
Mi S Mi Shuangli S
O'Donnell PH O'Donnell Peter H PH
Fraiman YS Fraiman Yarden S YS
Das S Das Soma S
Cox NJ Cox Nancy J NJ
Lu Y Lu Yi Y
Macgregor S Macgregor Stuart S
Goode EL Goode Ellen L EL
Vierkant RA Vierkant Robert A RA
Fridley BL Fridley Brooke L BL
Hogdall E Hogdall Estrid E
Kjaer SK Kjaer Susanne K SK
Jensen A Jensen Allan A
Moysich KB Moysich Kirsten B KB
Grasela M Grasela Matthew M
Odunsi K Odunsi Kunle K
Brown R Brown Robert R
Paul J Paul Jim J
Lambrechts D Lambrechts Diether D
Despierre E Despierre Evelyn E
Vergote I Vergote Ignace I
Gross J Gross Jenny J
Karlan BY Karlan Beth Y BY
Defazio A Defazio Anna A
Chenevix-Trench G Chenevix-Trench Georgia G
Australian Ovarian Cancer Study Group
Dolan ME Dolan M Eileen ME
INVESTIGATORS
JOURNAL
VOLUME: 17
ISSUE: 16
TITLE: Clinical cancer research : an official journal of the American Association for Cancer Research
ISOABBREVIATION: Clin Cancer Res
YEAR: 2011
MONTH: Aug
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1557-3265
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Clin Cancer Res
COUNTRY: United States
ISSNLINKING: 1078-0432
NLMUNIQUEID: 9502500
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
P50 CA136393-04 NCI NIH HHS United States
U01 GM061393-06 NIGMS NIH HHS United States
P30 CA014599-34 NCI NIH HHS United States
U01 GM061393 NIGMS NIH HHS United States
K08 GM089941 NIGMS NIH HHS United States
2 T35 HL07764 NHLBI NIH HHS United States
U01 GM061393-04 NIGMS NIH HHS United States
U01 GM061393-07 NIGMS NIH HHS United States
R21 CA139278 NCI NIH HHS United States
P30 CA014599-35 NCI NIH HHS United States
U01 GM061374 NIGMS NIH HHS United States
R01 CA122443 NCI NIH HHS United States
K08GM089941 NIGMS NIH HHS United States
K08 GM089941-02 NIGMS NIH HHS United States
U01 GM061393-05 NIGMS NIH HHS United States
T35 HL007764 NHLBI NIH HHS United States
P50 CA136393 NCI NIH HHS United States
K08 GM089941-01 NIGMS NIH HHS United States
A6689 Cancer Research UK United Kingdom
K12 CA139160 NCI NIH HHS United States
P50 CA125183 NCI NIH HHS United States
C536/A6689 Cancer Research UK United Kingdom
P30 CA14599 NCI NIH HHS United States
R21 CA139278-02 NCI NIH HHS United States
U01GM61393 NIGMS NIH HHS United States
T35 HL007764-15 NHLBI NIH HHS United States
P30 CA014599 NCI NIH HHS United States
R01 CA122443-06 NCI NIH HHS United States
U01GM61374 NIGMS NIH HHS United States
P50 CA125183-04 NCI NIH HHS United States
13086 Cancer Research UK United Kingdom
U01 GM061374-03 NIGMS NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Antineoplastic Agents therapeutic use
Carboplatin therapeutic use
Cell Line therapeutic use
Cell Line, Tumor therapeutic use
Female therapeutic use
Gene Expression Profiling therapeutic use
Gene Expression Regulation, Neoplastic therapeutic use
Genome, Human genetics
Genome-Wide Association Study methods
Humans methods
Kaplan-Meier Estimate methods
Ovarian Neoplasms pathology
Polymorphism, Single Nucleotide pathology
Prognosis pathology
Treatment Outcome pathology
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Antineoplastic Agents
BG3F62OND5 Carboplatin
OTHER ID's
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