Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors

University of Toronto, Toronto, Ontario, Canada
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2010; 28(31):4674-82. DOI: 10.1200/JCO.2010.28.5064
Source: PubMed


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.

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Available from: Richard Weinshilboum
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    • "By reviewing the pertinent literature we found that all but one of these polymorphisms (rs2369049-TCL1A), the underlying studies were largely negative[39,40]. As for rs2369049, however, two studies detected an association with exemestane toxicity but in opposite direction[39,41]. "
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    ABSTRACT: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher’s exact test. Statistical analyses revealed that 13 out of the 41 (32 %) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy. All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.
    Preview · Article · Dec 2016 · Journal of Translational Medicine
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    • "They scanned 551,395 single nucleotide polymorphisms (SNPs) and identified four variants close to T-cell leukemia 1A (TCL1A) gene, which were found to be associated with musculoskeletal toxicity risk. Interestingly, the subsequent in vitro analysis revealed altered estrogen response for the above TCL1A variants compared to the wild alleles and the imputed SNP rs11849538 created a new estrogen response element.11 The gene encoding TCL1A protein, belonging to the TCL1 family is expressed in activated T lymphocytes and B lymphocytes. "
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    ABSTRACT: Introduction: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. Methods: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. Results: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. Conclusion: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians.
    Full-text · Article · Jun 2014 · BioImpacts
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    • "Severe musculoskeletal pain has been reported in up to half of women treated with aromatase inhibitors contributing to a treatment discontinuation rate of about 10% (Crew et al., 2007; Henry et al., 2008; Ingle et al., 2010). Ingle et al. found four single nucleotide polymorphisms (SNPs) mapping to the T-cell leukemia 1A (TCL1A) gene were associated with the development of musculoskeletal adverse events in patients receiving adjuvant aromatase inhibitors (Ingle et al., 2010). Subsequent functional studies revealed that TCL1A was induced by estrogen with higher levels of expression in cells with the variant alleles for these SNPs. "
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    ABSTRACT: Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized control trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed.
    Full-text · Article · Apr 2014 · Frontiers in Genetics
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