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

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. A nested case-control design was used to select patien...

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Bibliographic Details
Published in:	Journal of clinical oncology Vol. 28; no. 31; p. 4674
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States 01.11.2010
Subjects:	Aged Aged, 80 and over Androstadienes - adverse effects Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Aromatase Inhibitors - administration & dosage Aromatase Inhibitors - adverse effects Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Case-Control Studies Chromosome Mapping Chromosomes, Human, Pair 14 Clinical Trials, Phase III as Topic Estrogens - metabolism Female Gene Expression Regulation, Neoplastic Genome-Wide Association Study Genotype Humans Logistic Models Middle Aged Musculoskeletal System - drug effects Neoplasm Staging Nitriles - adverse effects Polymorphism, Single Nucleotide Postmenopause Proto-Oncogene Proteins - genetics Randomized Controlled Trials as Topic Receptors, Interleukin-17 - metabolism Retrospective Studies Severity of Illness Index Triazoles - adverse effects
ISSN:	1527-7755, 1527-7755
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Summary:	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. 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. 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. 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1527-7755 1527-7755
DOI:	10.1200/JCO.2010.28.5064