Role of pharmacogenetics of drug-metabolizing enzymes in treating osteosarcoma

Hattinger, Claudia Maria; Serra, Massimo

doi:10.1517/17425255.2015.1060220

Cited by 23 publications

(15 citation statements)

References 94 publications

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“…Patients with these polymorphisms had inferior estimated 5-year survival [135]. Other authors have used similar techniques to describe variations in different genes leading to changes in prognosis or resistance to chemotherapy [136, 137]. As this field evolves, new information about a patient’s genetic profile can be used to select the most efficacious therapy, minimize side effects, and better inform prognosis.…”

Section: Clinical Presentation and Management Of Osteosarcomamentioning

confidence: 99%

Review of Osteosarcoma and Current Management

2016

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Osteosarcoma is the most common primary malignancy of bone in children and young adults. This tumor has a very heterogeneous genetic profile and lacks any consistent unifying event that leads to the pathogenesis of osteosarcoma. In this review, some of the important genetic events involved in osteosarcoma will be highlighted. Additionally, the clinical diagnosis of osteosarcoma will be discussed, as well as contemporary chemotherapeutic and surgical management of this tumor. Finally, the review will discuss some of the novel approaches to treating this disease.

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Section: Clinical Presentation and Management Of Osteosarcomamentioning

confidence: 99%

Review of Osteosarcoma and Current Management

2016

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“…16 While earlier candidate gene studies have identified variants associated with prognosis that have not been confirmed, more recent large genome-wide association studies (GWAS) have identified associations between common SNPs and survival in adult cancers of the pancreas, 17 breast, 18-23 ovary 24 and in a rare pediatric cancer, neuroblastoma. [25][26][27] There have also been exploratory pharmacogenomic studies of pediatric Ewing sarcoma and osteosarcoma that have identified SNPs associated with response to treatment and survival, [28][29][30][31] although most await further validation. We performed a GWAS to explore whether germline genetics may contribute to survival in patients with osteosarcoma.…”

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confidence: 99%

Genome‐wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Koster

Panagiotou

Wheeler

et al. 2017

Intl Journal of Cancer

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Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41-2.18, p = 4.84 × 10 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5-2.4; p = 1.3 × 10 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.

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“…The present study showed an association with post-chemotherapy specimens, while Dhaini et al investigated only pre-chemotherapy samples. Moreover, the present results regarding patients' specimens and in vitro assays, demonstrated that chemotherapy upregulates CYP3A4 , which enzyme participates in cisplatin and doxorubicin metabolism [5]. …”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, CYP members can detoxify anticancer drugs used in OS treatment, such as doxorubicin and cisplatin [5]. Thus, CYP members could play a role in both tumorigenesis and treatment response [4].…”

Section: Discussionmentioning

confidence: 99%

“…Although many CYP members detoxify anticancer drugs used in OS treatment, such as ifosfamide, doxorubicin, etoposide and cisplatin [5, 6], the impact of CYP to treatment response and prognosis in OS needs to be further explored and defined [5]. Dhaini et al found a higher frequency of CYP1A2 expression detection in OS biopsy fragments than in most cancers investigated (80%) [7].…”

Section: Introductionmentioning

confidence: 99%

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CYP genes in osteosarcoma: Their role in tumorigenesis, pulmonary metastatic microenvironment and treatment response

et al. 2017

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Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by qRT-PCR in 135 specimens obtained from OS patients, including biopsy (pre-chemotherapy), tumor resected in surgery (post-chemotherapy), adjacent bone to tumor (nonmalignant tissue), pulmonary metastasis and adjacent lung to metastasis (nonmalignant tissue). Normal bone and normal lung tissues were used as control. We also investigated in five OS cell lines the modulation of CYPs expression by cisplatin, doxorubicin and methotrexate. As result, the adjacent lung specimens presented CYP1A2 overexpression compared to the normal lung (p=0.0256). Biopsy specimens presented lower CYP3A4 expression than normal bone (p=0.0314). The overexpression of both CYP1A2 and CYP3A4 in post-chemotherapy specimens were correlated with better event free-survival (p=0.0244) and good response (p=0.0484), respectively. Furthermore, in vitro assays revealed that CYP1A2 was upregulated by doxorubicin (p=0.0034); CYP3A4 was upregulated by cisplatin, doxorubicin and methotrexate (p=0.0004, p=0.0024, p<0.0001, respectively); and CYP3A5 was downregulated by doxorubicin (p=0.0285) and upregulated in time-dependent manner by methotrexate (p=0.0239). In conclusion, our findings suggest that CYP genes play an important role in OS tumorigenesis, at primary and metastatic sites, as well in treatment response.

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Role of pharmacogenetics of drug-metabolizing enzymes in treating osteosarcoma

Abstract: Achieving further insight into pharmacogenetic markers and biological determinants related to treatment response in OS may ultimately lead to individualized treatment regimens, based on a combination of genotype and tumor characteristics of each patient.

Cited by 23 publications

References 94 publications

Review of Osteosarcoma and Current Management

Review of Osteosarcoma and Current Management

Genome‐wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

CYP genes in osteosarcoma: Their role in tumorigenesis, pulmonary metastatic microenvironment and treatment response

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