Preliminary Application of Precision Genomic Medicine Detecting Gene Variation in Patients with Multifocal Osteosarcoma

Orthop Surg. 2016 May;8(2):129-38. doi: 10.1111/os.12249.


Objectives: The purpose of this study was to present our clinical experience of treating multifocal osteosarcoma (MFOS) in our center and gain more insight into the biology of this rare condition; in particular, to address with the help of precision genomic medicine the issue of whether the multiple osteosarcoma (OS) lesions in such patients are multi-centric or originate from one primary lesion and metastasize to other sites. Finally, we aimed to identify particular gene phenotypes and mutations that differentiate MFOS from OS with only one tumor.

Methods: Clinical data of patients with MFOS treated at our center between June 2007 and October 2014 were collected and analyzed retrospectively. High throughput sequencing of the whole exome of normal tissue and multiple lesions had been performed on samples from two patients (HJF and JZ) diagnosed in 2014. To explore the particular gene phenotype and clinical significance of MFOS, these sequencing results were analyzed and compared with those from patients with osteosarcoma in a single site. Seven patients with MFOS (three male and four female; average age 19.71 ± 3.35 years were enrolled in this study. Two of these patients declined treatment and died after 4 and 6 months, respectively. The remaining patients received standard treatment comprising neoadjuvant chemotherapy, surgery and chemotherapy. The chemotherapy regimen was lobaplatin (45 mg/m(2) ), doxorubicin (60 mg/m(2) ) and ifosfamide (12 g/m(2) ). Patients were followed up every 3 months after completing treatment and evaluated by the Enneking and Response Evaluation Criteria in Solid Tumors scoring systems.

Results: Up to the last follow-up on 1 December 2015, three patients were still alive. The event-free survival ranged from 4 to 144 weeks (median, 50.14 weeks), the mean (±SD) being 55.45 ± 45.47 weeks. Overall survival ranged from 16 to 388 weeks (median, 89 weeks; mean ± SD, 118.7 ± 147.7 weeks). The rates of mutation of the targeted drug-related genes were 133.5% ± 3.0% in the proximal tibia lesion and 113.1% ± 1.9% in the distal femur of patient HJF (P < 0.01) and 136.1% ± 10.8% in the proximal tibial lesion and 122.3% ± 5.5% in the proximal humerus of patient JZ (P = 0.0335). Furthermore, there were several anti-oncogenes in the somatic copy number variation lists analyzed from the two patients, especially TP53. However, no kataegis was found.

Conclusions: Early and radical surgery accompanied by appropriate chemotherapy is the optimal means of treating MFOS. These patients may benefit from precision genomic medicine.

Keywords: Copy number variation; Gene mutation; High-throughput sequencing; Multifocal osteosarcoma; Precision medicine.

MeSH terms

  • Adolescent
  • Adult
  • Bone Neoplasms / diagnosis
  • Bone Neoplasms / genetics
  • Bone Neoplasms / therapy*
  • Child
  • Combined Modality Therapy
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • Female
  • Femur
  • Genomics / methods*
  • Humans
  • Humerus
  • Male
  • Mutation*
  • Osteosarcoma / diagnosis
  • Osteosarcoma / genetics
  • Osteosarcoma / therapy*
  • Retrospective Studies
  • Tibia
  • Young Adult


  • DNA, Neoplasm