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


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.


CONCLUSIONS
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.
Ingle
James N
JN
Mayo Clinic, Rochester, MN 55905, USA. ingle.james@mayo.edu
Schaid
Daniel J
DJ
Goss
Paul E
PE
Liu
Mohan
M
Mushiroda
Taisei
T
Chapman
Judy-Anne W
JA
Kubo
Michiaki
M
Jenkins
Gregory D
GD
Batzler
Anthony
A
Shepherd
Lois
L
Pater
Joseph
J
Wang
Liewei
L
Ellis
Matthew J
MJ
Stearns
Vered
V
Rohrer
Daniel C
DC
Goetz
Matthew P
MP
Pritchard
Kathleen I
KI
Flockhart
David A
DA
Nakamura
Yusuke
Y
Weinshilboum
Richard M
RM
D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D000730:Androstadienes / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D017326:Clinical Trials, Phase III as Topic; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009141:Musculoskeletal System / Q000187:drug effects*; D009367:Neoplasm Staging; D009570:Nitriles / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014230:Triazoles / Q000009:adverse effects
D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004967:Estrogens; C109985:IL17RA protein, human; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D053722:Receptors, Interleukin-17; C090851:TCL1A protein, human; D014230:Triazoles; D000077384:Anastrozole; C056516:exemestane