Osteosarcoma: Genetics of Inherited Susceptibility

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumour that typically occurs in adolescents and young adults. OS incidence has been related to growth and height, age, gender, ethnicity, certain inherited cancer predisposition syndromes, abnormal bone growth and therapeutic radiation. However, most cases are sporadic (not associated with an inherited syndrome) and no specific genetic or environmental predisposing factor has been identified. A common genetic susceptibility locus has not been found.

Germline genetics refers to deoxyribonucleic acid (DNA) sequence changes that are inherited and present in all cells of the body versus an acquired or somatic mutation. Germline candidate gene association studies have identified several common single nucleotide polymorphisms (SNPs) associated with risk of OS, including genes important in growth, cell cycle checkpoint control and tumour immunity. Recently, the first genome‐wide association study was conducted and further expands our understanding of the germline genetics of OS.

Key Concepts:

  • Epidemiologic studies have provided many important clues about the aetiology of OS, including an association with bone growth, which have directed much of the search for candidate genes associated with risk of OS.

  • OS is associated with several rare inherited cancer predisposition syndromes (Li–Fraumeni syndrome, hereditary bilateral retinoblastoma, Bloom, Werner, Rothmund Thomson syndromes, and Diamond–Blackfan anemia) that are caused by highly penetrant germline mutations. These syndromes are not a common cause of OS.

  • Candidate gene association studies have suggested several polymorphisms associated with risk of OS; SNP associations in the following candidate genes have been replicated in two or more studies: IGF2R, FGFR3, MDM2, TGFBR1 and CTLA‐4.

  • An agnostic genome‐wide association study has found two novel loci associated with risk of OS: GRM4 gene and the 2p25.2 chromosomal region.

  • Studies are needed to expand these genetic association findings to more ethnic groups and in larger samples sizes to determine if these are stable associations.

Keywords: Osteosarcoma; germline genetics; epidemiology; SNP; GWAS; inherited susceptibility

Figure 1.

Osteosarcoma incidence by gender in the US based on the Surveillance, Epidemiology, and End Results 9 database, from 1973 to 2004. Rates are per million and are shown for osteosarcomas that are considered a first cancer, excluding cases that occur as a second or later cancer or with Paget's disease of the bone. Data from Mirabello et al..

close

References

Barnette P, Scholl R, Blandford M et al. (2004) High‐throughput detection of glutathione S‐transferase polymorphic alleles in a pediatric cancer population. Cancer Epidemiology Biomarkers and Prevention 13(2): 304–313.

Boria I, Garelli E, Gazda H et al. (2010) The ribosomal basis of Diamond–Blackfan anemia: mutation and database update. Human Mutation 31: 1269–1279.

Calvert G, Randall R, Jones K et al. (2012) At‐risk populations for osteosarcoma: the syndromes and beyond. Sarcoma 2012: 152382.

Contardi E, Palmisano GL, Tazzari PL et al. (2005) CTLA‐4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. International Journal of Cancer 117(4): 538–550.

Griffin K, Kirschner L, Matyakhina L et al. (2004) A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. Journal of Medical Genetics 41(12): 923–931.

Hirschhorn J and Lettre G (2009) Progress in genome‐wide association studies of human height. Hormone Research 71 (Suppl. 2): 5–13.

Hu Y, Pan Y, Li W et al. (2010) Association between TGFBR1*6A and osteosarcoma: a Chinese case‐control study. BMC Cancer 10(1): 169.

Hu Y‐S, Pan Y, Li W‐H et al. (2011) Int7G24A variant of transforming growth factor‐beta receptor 1 is associated with osteosarcoma susceptibility in a Chinese population. Medical Oncology 28(2): 622–625.

Jorgensen TJ, Ruczinski I, Kessing B et al. (2009) Hypothesis‐driven candidate gene association studies: practical design and analytical considerations. American Journal of Epidemiology 170(8): 986–993.

Kansara M and Thomas D (2007) Molecular pathogenesis of osteosarcoma. DNA and Cell Biology 26(1): 1–18.

Koshkina N, Kleinerman E, Li G et al. (2007) Exploratory analysis of Fas gene polymorphisms in pediatric osteosarcoma patients. Journal of Pediatric Hematology/Oncology 29: 815–821.

Liu Y, He Z, Feng D et al. (2011) Cytotoxic T‐lymphocyte antigen‐4 polymorphisms and susceptibility to osteosarcoma. DNA and Cell Biology 30(12): 1051–1055.

Liu Y, Lv B, He Z et al. (2012) Lysyl oxidase polymorphisms and susceptibility to osteosarcoma. PLoS One 7(7): e41610.

Lohmann D (2010) Retinoblastoma. Advances in Experimental Medicine and Biology 685: 220–227.

Lu X, Yang W, Wan Z et al. (2011) Glutathione S‐transferase polymorphisms and bone tumor risk in China. Asian Pacific Journal of Cancer Prevention 12(12): 3357–3360.

Marina N, Gorlick R and Bielack S (2010) Pediatric osteosarcoma. In: Carroll W and Finlay J (eds) Cancer in Children and Adolecents, p. 383–394. Sudbury, MA: Jones and Bartlett.

Miller R (1981) Contrasting epidemiology of childhood osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. Nataional Cancer Institute Monograph 56: 9–15.

Mirabello L, Berndt S, Seratti G et al. (2010) Genetic variation at chromosome 8q24 in osteosarcoma cases and controls. Carcinogenesis 31(8): 1400–1404.

Mirabello L, Pfeiffer R, Murphy G et al. (2011a) Height at diagnosis and birth‐weight as risk factors for osteosarcoma. Cancer Causes Control 22(6): 899–908.

Mirabello L, Richards E, Duong L et al. (2011b) Telomere length and variation in telomere biology genes in individuals with osteosarcoma. International Journal of Molecular Epidemiology and Genetics 2(1): 19–29.

Mirabello L, Troisi R and Savage S (2009a) International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. International Journal of Cancer 125(1): 229–234.

Mirabello L, Troisi R and Savage S (2009b) Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program. Cancer 115(7): 1531–1543.

Mirabello L, Yu K, Berndt S et al. (2011c) A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma. BMC Cancer 11: 209.

Molyneux S, Di Grappa M, Beristain A et al. (2010) Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. Journal of Clinical Investigation 120(9): 3310–3325.

Musselman J, Bergemann T, Ross J et al. (2012) Case‐parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children's Oncology Group (COG) study. International Journal of Molecular Epidemiology and Genetics 3(4): 286–293.

Patio‐Garcia A, Sotillo‐Pieiro E, Modesto C and Sierrases-Maga L (2000) Analysis of the human tumour necrosis factor‐alpha (TNFalpha) gene promoter polymorphisms in children with bone cancer. Journal of Medical Genetics 37: 789–792.

Ruza E, Sotillo E, Sierrasesúmaga L et al. (2003) Analysis of polymorphisms of the vitamin D receptor, estrogen receptor, and collagen Iα1 genes and their relationship with height in children with bone cancer. Journal of Pediatric Hematology/Oncology 25: 780–786.

Salinas‐Souza C, Petrilli A and de Toledo S (2010) Glutathione S‐transferase polymorphisms in osteosarcoma patients. Pharmacogenetics and Genomics 20(8): 507–515.

Sandberg AA and Bridge JA (2003) Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. Cancer Genetics and Cytogenetics 145: 1–30.

Savage SA, Burdett L, Troisi R et al. (2007a) Germ‐line genetic variation of TP53 in osteosarcoma. Pediatric Blood and Cancer 49: 28–33.

Savage S and Mirabello L (2011) Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma 2011: 548151.

Savage SA, Mirabello L, Wang Z et al. (2013) Genome‐wide association study identifies two susceptibility loci for osteosarcoma. Nature Genetics 45(7): 799–803.

Savage SA, Woodson K, Walk E et al. (2007b) Analysis of genes critical for growth regulation identifies insulin‐like growth factor 2 receptor variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiology, Biomarkers and Prevention 16: 1667–1674.

Schneider K, Zelley K, Nichols K and Garber J (1999) Li–Fraumeni syndrome. In: Pagon R, Adam M, Bird T et al. (eds) Gene Reviews, p. 1993–2013. Seattle, WA: University of Washington, Seattle.

Siitonen HA, Sotkasiira J, Biervliet M et al. (2008) The mutation spectrum in RECQL4 diseases. European Journal of Human Genetics 17(2): 151–158.

Skerry T (2008) The role of glutamate in the regulation of bone mass and architecture. Journal of Musculoskeletal and Neuronal Interactions 8(2): 166–173.

Sur I, Tuupanen S, Whitington T et al. (2013) Lessons from functional analysis of genome‐wide association studies. Cancer Research 73(14): 4180–4184.

Toffoli G, Biason P, Russo A et al. (2009) Effect of TP53 Arg72Pro and MDM2 SNP309 polymorphisms on the risk of high‐grade osteosarcoma development and survival. Clinical Cancer Research 15: 3550–3556.

Vlachos A, Rosenberg P, Atsidaftos E et al. (2012) The incidence of neoplasia in Diamond Blackfan Anemia: A report from the Diamond Blackfan anemia registry. Blood 119(16): 3815–3819.

Wang W, Song H, Liu J et al. (2011a) CD86+1057G/A polymorphism and susceptibility to osteosarcoma. DNA and Cell Biology 30(11): 925–929.

Wang W, Wang J, Song H et al. (2011b) Cytotoxic T‐lymphocyte antigen‐4 +49G/A polymorphism is associated with increased risk of osteosarcoma. Genetic Testing and Molecular Biomarkers 15(7–8): 503–506.

Further Reading

Burningham Z, Hashibe M, Spector L and Schiffman JD (2012) The epidemiology of sarcoma. Clinical Sarcoma Research 2(1): 14.

Gorlick R and Khanna C (2010) Osteosarcoma. Journal of Bone and Mineral Research 25(4): 683–691.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mirabello, Lisa(Nov 2013) Osteosarcoma: Genetics of Inherited Susceptibility. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023880]