Whole-exome analysis in osteosarcoma to identify a personalized therapy.

Caterina Chiappetta,Francesca Lessi,Massimiliano Mancini,Claudio Di Cristofano,Carlo Della Rocca,Vincenzo Petrozza,Chiara Puggioni,Veronica De Gregorio,Prospero Civita,Paolo Aretini,Sara Franceschi,Chiara M Mazzanti,Raffaella Carletti,Antonio G Naccarato

doi:10.18632/oncotarget.19010

Caterina Chiappetta, Francesca Lessi + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.19010

Copy DOI

Abstract

Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy.We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors.These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile.

Highlights

Osteosarcoma is the most common nonhaematological primary malignant tumor of the bone, it arises from mesenchymal cells that produce osteoid and immature bone and affects mainly the extremities of adolescents and young adults [1,2].The 5-years survival rate for patients with osteosarcoma without evidence of metastasis is 60% to 65%, whereas it is only 20% to 28% for osteosarcoma patients with metastases at the time of diagnosis [3]
Sequence coverage and mutation analysis. This analysis provided a vast new reservoir of data and, after filtering the data, within our discovery set of eight osteosarcomas, 5 responder and 3 non-responder, we identified 18,275 somatic variations in 8,247 genes
It is essential to find useful biomarkers and to detect the potential targets for new drugs, to increase overall survival of these patients. This could be done only if we better understand the complex biology of this tumor and the molecular pathways that lead to the development of metastases and resistance to therapy

Summary

Introduction

Osteosarcoma is the most common nonhaematological primary malignant tumor of the bone, it arises from mesenchymal cells that produce osteoid and immature bone and affects mainly the extremities of adolescents and young adults [1,2].The 5-years survival rate for patients with osteosarcoma without evidence of metastasis is 60% to 65%, whereas it is only 20% to 28% for osteosarcoma patients with metastases at the time of diagnosis [3]. Treatment of high grade osteosarcoma is based on a multidisciplinary approach that includes neoadjuvant chemotherapy, surgical excision of the primary tumor and www.impactjournals.com/oncotarget metastasis excision; evaluation of response to therapy in the surgical specimen is crucial to eventually schedule a postoperative chemotherapy [4]. The survival rate has improved considerably after the introduction of neoadjuvant chemotherapy and surgery, metastatic or recurrent disease still occurs and the survival rate of patients is mainly linked to the resistance to therapy and to the development of metastasis [7]. In patients with metastatic osteosarcoma treated with neoadjuvant therapy, the “Responder” status shows improved survival (82% at 5-years) compared to “Non-Responder” (70% at 5-years) [8,9]. Even the osteosarcoma karyotype is considered complex and only mutations of tumor suppressors genes TP53 and RB1 are commonly associated with the development of osteosarcoma [12]

Objectives

Methods

Results

Conclusion