Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors

James N. Ingle, Daniel J. Schaid, Paul E. Goss, Mohan Liu, Taisei Mushiroda, Judy Anne W Chapman, Michiaki Kubo, Gregory D. Jenkins, Anthony Batzler, Lois Shepherd, Joseph Pater, Liewei Wang, Matthew J. Ellis, Vered Stearns, Daniel C. Rohrer, Matthew P. Goetz, Kathleen I. Pritchard, David A. Flockhart, Yusuke Nakamura, Richard M. Weinshilboum

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Abstract

Purpose: We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods: A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results: The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion: This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

Original languageEnglish
Pages (from-to)4674-4682
Number of pages9
JournalJournal of Clinical Oncology
Volume28
Issue number31
DOIs
StatePublished - Nov 1 2010

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Aromatase Inhibitors
Single Nucleotide Polymorphism
Genome
T-Cell Leukemia
Genome-Wide Association Study
Chromosomes, Human, Pair 14
exemestane
Estrogens
Interleukin-17 Receptors
National Cancer Institute (U.S.)
Estrogen Receptor alpha
Response Elements
Terminology
Genes
Estradiol
Genotype
Breast Neoplasms
Cytokines
Research

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Ingle, J. N., Schaid, D. J., Goss, P. E., Liu, M., Mushiroda, T., Chapman, J. A. W., ... Weinshilboum, R. M. (2010). Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. Journal of Clinical Oncology, 28(31), 4674-4682. https://doi.org/10.1200/JCO.2010.28.5064

Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. / Ingle, James N.; Schaid, Daniel J.; Goss, Paul E.; Liu, Mohan; Mushiroda, Taisei; Chapman, Judy Anne W; Kubo, Michiaki; Jenkins, Gregory D.; Batzler, Anthony; Shepherd, Lois; Pater, Joseph; Wang, Liewei; Ellis, Matthew J.; Stearns, Vered; Rohrer, Daniel C.; Goetz, Matthew P.; Pritchard, Kathleen I.; Flockhart, David A.; Nakamura, Yusuke; Weinshilboum, Richard M.

In: Journal of Clinical Oncology, Vol. 28, No. 31, 01.11.2010, p. 4674-4682.

Research output: Contribution to journalArticle

Ingle, JN, Schaid, DJ, Goss, PE, Liu, M, Mushiroda, T, Chapman, JAW, Kubo, M, Jenkins, GD, Batzler, A, Shepherd, L, Pater, J, Wang, L, Ellis, MJ, Stearns, V, Rohrer, DC, Goetz, MP, Pritchard, KI, Flockhart, DA, Nakamura, Y & Weinshilboum, RM 2010, 'Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors', Journal of Clinical Oncology, vol. 28, no. 31, pp. 4674-4682. https://doi.org/10.1200/JCO.2010.28.5064
Ingle, James N. ; Schaid, Daniel J. ; Goss, Paul E. ; Liu, Mohan ; Mushiroda, Taisei ; Chapman, Judy Anne W ; Kubo, Michiaki ; Jenkins, Gregory D. ; Batzler, Anthony ; Shepherd, Lois ; Pater, Joseph ; Wang, Liewei ; Ellis, Matthew J. ; Stearns, Vered ; Rohrer, Daniel C. ; Goetz, Matthew P. ; Pritchard, Kathleen I. ; Flockhart, David A. ; Nakamura, Yusuke ; Weinshilboum, Richard M. / Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 31. pp. 4674-4682.
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AU - Ingle, James N.

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AU - Liu, Mohan

AU - Mushiroda, Taisei

AU - Chapman, Judy Anne W

AU - Kubo, Michiaki

AU - Jenkins, Gregory D.

AU - Batzler, Anthony

AU - Shepherd, Lois

AU - Pater, Joseph

AU - Wang, Liewei

AU - Ellis, Matthew J.

AU - Stearns, Vered

AU - Rohrer, Daniel C.

AU - Goetz, Matthew P.

AU - Pritchard, Kathleen I.

AU - Flockhart, David A.

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AU - Weinshilboum, Richard M.

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N2 - Purpose: We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods: A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results: The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion: This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

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