Genetics of osteosarcoma

Understanding and optimizing osteosarcoma treatment through genetics.
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Genetics of Osteosarcoma

Understanding and optimizing osteosarcoma treatment through genetics.

The GO-consortium

To improve the treatment of osteosarcoma patients, we aim to identify genetic variants that predict or explain treatment efficacy or toxicities in osteosarcoma patients. Our studies consist of three stages:

  • Discovery of new pharmacogenetic associations
  • Validate associations in independent patient cohorts
  • Functionally describe validated associations

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Research groups

Collaboration is essential for genetic association studies. Therefore, these research groups from around the world joined forces within the GO-consortium to reach a common goal: improve treatment of osteosarcoma patients.


The role of pharmacogenetics in the treatment of osteosarcoma

Hanneke I. Vos, Marieke J.H. Coenen, Henk-Jan Guchelaar, and Dunja Maroeska W.M. te Loo

2016, Drug Discovery Today, 21: 1775-86.

In osteosarcoma, large variation is observed in the efficacy and toxicity of chemotherapeutic drugs among similarly treated patients. Treatment optimization using predictive factors or algorithms is of importance, because there has been a lack of improvement of treatment outcome and survival for decades. The outcome of cancer treatment is influenced by the genome, thus studying genetic variants involved in the efficacy and toxicity of the chemotherapeutic drugs used in the treatment of osteosarcoma could be an opportunity to optimize current treatments and improve our understanding of the individual’s drug response in osteosarcoma patients. This review discusses the current insights in the pharmacogenetics of the treatment response of osteosarcoma patients regarding efficacy and toxicity, and implications for future research and treatment.

Replication of a genetic variant in ACYP2 associated with cisplatin-induced hearing loss in patients with osteosarcoma

Hanneke I. Vos, Henk-Jan Guchelaar, Hans Gelderblom, Eveline S.J.M. de Bont, Leontien C.M. Kremer, Anne Marlies Naber, Marina H. Hakobjan, Winette T.A. van der Graaf, Marieke J.H. Coenen, and Dunja Maroeska W.M. te Loo

2016, Pharmacogenetics and Genomics, 26: 243-7.

OBJECTIVE: Irreversible hearing loss is a frequent side effect of the chemotherapeutic agent cisplatin and shows considerable interpatient variability. The variant rs1872328 in the ACYP2 gene was recently identified as a risk factor for the development of cisplatin-induced ototoxicity in children with brain tumors. We aimed to replicate this finding in patients with osteosarcoma.

METHODS: An independent cohort of 156 patients was genotyped for the rs1872328 variant and evaluated for the presence of cisplatin-induced ototoxicity.

RESULTS: A significant association was observed between carriership of the A allele and cisplatin-induced ototoxicity after the end of treatment (P=0.027).

CONCLUSION: This is the first study replicating the association of ACYP2 variant rs1872328 with cisplatin-induced ototoxicity in patients with osteosarcoma who did not receive potentially ototoxic cranial irradiation. Hence, the ACYP2 variant should be considered a predictive pharmacogenetic marker for hearing loss, which may be used to guide therapies for patients treated with cisplatin.

A first step toward personalized medicine in osteosarcoma: pharmacogenetics as predictive marker of outcome after chemotherapy-based treatment

Melanie M. Hagleitner, Marieke J.H. Coenen, Hans Gelderblom, Remco R. Makkinje, Hanneke I. Vos, Eveline S.J.M. de Bont, Winette T.A. van der Graaf, H.W. Bart Schreuder, Uta Flucke, Frank N. van Leeuwen, Peter M. Hoogerbrugge, Henk-Jan Guchelaar, Dunja Maroeska W.M. te Loo

2015, Clinical Cancer Research, 21: 3436-41.

PURPOSE: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.

EXPERIMENTAL DESIGN: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.

RESULTS: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).

CONCLUSIONS: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome.

High-quality genotyping data from formalin-fixed, paraffin-embedded tissue on the drug metabolizing enzymes and transporters plus array

Hanneke I. Vos, Tahar van der Straaten, Marieke J.H. Coenen, Uta Flucke, Dunja Maroeska W.M. te Loo, Henk-Jan Guchelaar

2015, The Journal of Molecular Diagnostics, 17: 4-9.

The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array covers 1936 markers in 231 genes involved in drug metabolism and transport. Blood- and saliva-derived DNA works well on the DMET array, but the utility of DNA from FFPE tissue has not been reported for this array. As the ability to use DNA from FFPE tissue on the array could open the potential for large retrospective sample collections, we examined the performance and reliability of FFPE-derived DNA on the DMET Plus array. Germline DNA isolated from archived normal FFPE tissue blocks stored for 3 to 19 years and matched blood or saliva from 16 patients with osteosarcoma were genotyped on the DMET Plus array. Concordance was assessed by calculating agreement and the kappa-statistic. We observed high call rates for both the blood- or saliva-derived DNA samples (99.4%) and the FFPE-derived DNA samples (98.9%). Moreover, the concordance among the 16 blood- or saliva-derived DNA and FFPE DNA pairs was high (97.4%, kappa = 0.915). This is the first study showing that DNA from normal FFPE tissue provides accurate and reliable genotypes on the DMET Plus array compared with blood- or saliva-derived DNA. This finding provides an opportunity for pharmacogenetic studies in diseases with high mortality rates and prevents a bias in studies where otherwise only alive patients can be included.

Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts

Melanie M. Hagleitner, Marieke J.H. Coenen, Ana Patiño-García, Eveline S.J.M. de Bont, Anna González-Neira, Hanneke I. Vos, Frank N. van Leeuwen, Hans Gelderblom, Peter M. Hoogerbrugge, Henk-Jan Guchelaar, Dunja Maroeska W.M. te Loo

2014, PLoS One, 9: e115869.

Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.