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  • Review Article
  • Published:

Germline and somatic genetics of osteosarcoma — connecting aetiology, biology and therapy

Key Points

  • Osteosarcoma treatment and outcomes have not changed substantially over the past 30 years

  • Osteosarcoma is associated with growth and certain inherited cancer predisposition syndromes

  • The somatic genome of osteosarcoma is complex and highly heterogeneous within tumours and among patients

  • Numerous biological pathways that are essential to cell growth, apoptosis and bone development are important in osteosarcoma biology

  • Studies incorporating germline and somatic genetics with osteosarcoma biology are required to identify novel therapeutic targets

Abstract

Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma.

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Figure 1: Osteosarcoma epidemiology.
Figure 2: Connections among osteosarcoma aetiology, biology and treatment.

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Acknowledgements

The authors' work is supported by the intramural research programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health.

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D.M.G., L.M. and S.A.S. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Sharon A. Savage.

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Glossary

Aneuploid

An abnormal number of chromosomes in a cell.

Metaphysis

The part of bone that contains the growth plate.

Periosteal reaction

The production of bone by the membrane covering bone in response to injury, such as in the case of infection or cancer. This reaction can sometimes be seen on X-rays.

Osteomyelitis

Infection or inflammation of the bone.

Tumour grade

Low grade, or well-differentiated tumours, look and typically act more like normal cells. By contrast, high grade or poorly differentiated cancers do not look like normal cells nor do they behave like the tissue of origin.

Neoadjuvant chemotherapy

Chemotherapy administered before cancer surgery.

Adjuvant chemotherapy

Chemotherapy administered after cancer surgery.

Single-nucleotide polymorphisms

(SNPs). The most common type of genetic variation in DNA, which results when a single nucleotide is replaced with another.

Age-standardized incidence rates

Incidence can vary based on age; therefore, age-standardized incidence rates take into account variation of age when comparing two different populations.

Paget's disease of bone

A disease of bone remodelling (increased bone breakdown and increased bone formation) that is a known risk factor for osteosarcoma.

Ecological

An observational study that uses data measured at the group level and not the individual level.

Case–control

Describes a study that categorizes people with and without disease (cases and controls, respectively), and then retrospectively identifies potential exposures in both groups to create odds ratios.

Alkylating agent

A class of chemotherapy drug that adds alkyl groups to DNA. Examples include ifosfamide and cyclophosphamide.

Candidate-gene studies

A study approach that focuses on determining whether variants in specific genes are associated with disease, based on a priori hypotheses.

Genome-wide association studies

(GWAS). Approaches used to identify genetic variants across the genome that are associated with disease.

Next-generation sequencing

A high-throughput sequencing technique that enables the rapid generation of sequencing data.

Osteoblast

A cell formed from a mesenchymal stem cell that is responsible for bone production.

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Gianferante, D., Mirabello, L. & Savage, S. Germline and somatic genetics of osteosarcoma — connecting aetiology, biology and therapy. Nat Rev Endocrinol 13, 480–491 (2017). https://doi.org/10.1038/nrendo.2017.16

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