Abstract
Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund–Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li–Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three criteria must be met for a diagnosis of Li–Fraumeni syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A first-degree relative with any cancer diagnosed when younger than 45 years; (3) Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the development and progression of osteosarcoma. Osteosarcoma has also been associated with solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Ollier’s disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic prostheses and sites of prior internal fixation. Ionizing radiation is a well-documented etiologic factor. Osteosarcoma has also been associated with the use of intravenous radium and Thorotrast. Exposure to alkylating agents may also contribute to its development ,and it is apparently independent of the administration of radiotherapy.
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References
Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LA, Smith MAS, Gurney JG, et al., eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute; 1999. Available at: http://seer.cancer.gov/publications/childhood/bone.pdf; Accessed August 2008.
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2001 Incidence and Mortality. Atlanta, GA: Centers for Disease Control and Prevention and National Cancer Institute; 2004.
Jaffe N. Malignant bone tumors in children: incidence and etiologic considerations. In: Jaffe N, ed. Solid Tumors in Childhood. Littleton, MA: PSG Publishing Co; 1979:1-10.
Miller RW, Boice JD Jr, Curtis RE. Bone cancer. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press; 1996:971-983.
Dahlin DC, Unni KK, eds. Bone Tumors: General Aspects and Data on 8,542 Cases. 4th ed. Springfield, IL: Charles C. Thomas; 1986.
Hartford CM, Wodowski KS, Rao BN, et al. Osteosarcoma among children aged 5 years or younger: the St Jude Children’s Research Hospital experience. J Pediatr Hematol Oncol. 2006;28:43-47.
Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer. 2008;112:416-432.
Tjalma RA. Canine bone sarcoma: estimation of relative risk as a function of body size. J Natl Cancer Inst. 1966;3:1137-1150.
Mascarenhas L, Siegel S, Spector L, et al. Malignant bone tumors. In: Bleyer A, O’Leary M, Barr R, et al., eds. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975–2000 (NIH Pub. No. 06-5767). Bethesda, MD: National Cancer Institute; 2006:97–110. Available at: http://seer.cancer.gov/publications/aya/8_bone.pdf; Accessed January 2009.
Price CH. Primary bone-forming tumours and their relationship to skeletal growth. J Bone Joint Surg Br. 1958;36:1137-1150.
Buckley JD, Pendergrass TW, Buckley CM, et al. Epidemiology of osteosarcoma and Ewing’s sarcoma in childhood: a study of 305 cases by the Children’s Cancer Group. Cancer. 1998;83:1440-1448.
Cotterill SJ, Wright CM, Pearce MS, et al. Stature of young people with malignant bone tumors. Pediatr Blood Cancer. 2004;42:59-63.
Longhi A, Pasini A, Cicognani A, et al. Height as a risk factor for osteosarcoma. J Pediatr Hematol Oncol. 2005;27:314-318.
Troisi R, Masters MN, Joshipura K, et al. Perinatal factors, growth and development, and osteosarcoma risk. Br J Cancer. 2006;95:1603-1607.
Operskalski EA, Preston-Martin S, Henderson BE, et al. A case-control study of osteosarcoma in young persons. Am J Epidemiol. 1987;126:118-126.
dos Santos Aguiar S, de Jesus Girotto Zambaldi L, dos Santos AM, et al. Comparative genomic hybridization analysis of abnormalities in chromosome 21 in childhood osteosarcoma. Cancer Genet Cytogenet. 2007;175:35-40.
Ottaviani G, Jaffe N. Clinical and pathological study of two siblings with osteosarcoma. Med Pediatr Oncol. 2002;38:62-64.
Harmon TP, Morton KS. Osteogenic sarcoma in four siblings. J Bone Joint Surg Br. 1966;48:493-498.
Robbins R. Familial osteosarcoma. Fifth reported occurrence. JAMA. 1967;202:1055.
Epstein LI, Bixler D, Bennett JE. An incident of familial cancer, including 3 cases of ostogenic sarcoma. Cancer. 1970;25:889-891.
Swaney JJ. Familial osteogenic sarcoma. Clin Orthop. 1973;97:64-68.
Miller CW, McLaughlin RE. Osteosarcoma in siblings. Report of two cases. J Bone Joint Surg Am. 1977;59:261-262.
Mulvihill JJ, Gralnick HR, Whang-Peng J, et al. Multiple childhood osteosarcomas in an American Indian family with erythroid macrocytosis and skeletal anomalies. Cancer. 1977;40:3115-3122.
Colyer RA. Osteogenic sarcoma in siblings. Johns Hopkins Med J. 1979;145:131-135.
Hillmann A, Ozaki T, Winkelmann W. Familial occurrence of osteosarcoma. A case report and review of the literature. J Cancer Res Clin Oncol. 2000;126:497-502.
Chin KR, Mankin HJ, Gebhardt MC. Primary osteosarcoma of the distal femur in two consecutive brothers. Clin Orthop Relat Res. 2001;382:191-196.
Norrdin RW, Powers BE, Torgersen JL, et al. Characterization of osteosarcoma cells from two sibling large-breed dogs. Am J Vet Res. 1989;50:1971-1975.
Glass AG, Fraumeni JF Jr. Epidemiology of bone cancer in children. J Natl Cancer Inst. 1970;44:187-199.
Longhi A, Benassi MS, Molendini L, et al. Osteosarcoma in blood relatives. Oncol Rep. 2001;8:131-136.
Ji J, Hemminki K. Familial risk for histology-specific bone cancers: an updated study in Sweden. Eur J Cancer. 2006;42:2343-2349.
Nishida J, Abe M, Shiraishi H, et al. Familial occurrence of telangiectatic osteosarcoma: cousin cases. J Pediatr Orthop. 1994;14:119-122.
Hansen MF. Genetic and molecular aspects of osteosarcoma. J Musculoskelet Neuronal Interact. 2002;2:554-560.
Patiño-García A, Piñeiro ES, Díez MZ, et al. Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas. J Pediatr Hematol Oncol. 2003;25:362-367.
Levesque AA, Eastman A. p53-based cancer therapies: is defective p53 the Achilles heel of the tumor? Carcinogenesis. 2007;28:13-20.
Kaseta MK, Khaldi L, Gomatos IP, et al. Prognostic value of bax, bcl-2, and p53 staining in primary osteosarcoma. J Surg Oncol. 2008;97:259-266.
Gebhardt MC. Molecular biology of sarcomas. Orthop Clin North Am. 1996;27:421-429.
Jensen RD, Miller RW. Retinoblastoma: epidemiologic characteristics. N Engl J Med. 1971;285:307-311.
Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986;53:661-671.
Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Soft Tissue and Bone. Lyon: IARC Press; 2002.
Le Vu B, de Vathaire F, Shamsaldin A, et al. Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J Cancer. 1998;77:370-377.
McIntyre JF, Smith-Sorensen B, Friend SH, et al. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol. 1994;12:925-930.
Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med. 1969;71:747-752.
Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362.
Plon SE, Malkin D. Childhood cancer and heredity. In: Pizzo PA, Poplack DG, eds. Principles and Practices of Pediatric Oncology. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2006:14-37.
Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Cancer. 1990;250:1233-1238.
Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li–Fraumeni families. Cancer Res. 1994;54:1298-1304.
Frebourg T, Barbier N, Yan Y, et al. Germ-line p53 mutations in 15 families with Li–Fraumeni syndrome. Am J Hum Genet. 1995;56:608-615.
Kitao S, Shimamoto A, Goto M, et al. Mutations in RECQL4 cause a subset of cases of Rothmund–Thomson syndrome. Nat Genet. 1999;22:82-84.
Sim FH, Devries EM, Miser JS, et al. Case report 760: Osteoblastic osteosarcoma (grade 4) with Rothmund–Thomson syndrome. Skeletal Radiol. 1992;21:543-545.
Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund–Thomson syndrome patients. Am J Med Genet. 2001;102:11-17.
Hicks MJ, Roth JR, Kozinetz CA, et al. Clinicopathologic features of osteosarcoma in patients with Rothmund–Thomson syndrome. J Clin Oncol. 2007;25:370-375.
Beghini A, Larizza L. Rothmund–Thomson syndrome (RTS). Atlas Genet Cytogenet Oncol Haematol. Milan, Italy; 2001. http://atlasgeneticsoncology.org/Kprones/RothmundID10021.html; Accessed January 2009.
German J. Bloom’s syndrome: XX – The first 100 cancers. Cancer Genet Cytogenet. 1997;93:100-106.
Goto M, Miller RW, Ishikawa Y, et al. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev. 1996;5:239-246.
Ishikawa Y, Miller RW, Machinami R, et al. Atypical osteosarcomas in Werner Syndrome (adult progeria). Jpn J Cancer Res. 2000;91:1345-1349.
Marcove RC, Miké V, Hajeck JV, et al. Osteogenic sarcoma under the age of twenty one. A review of one hundred and forty-five operative cases. J Bone Joint Surg Am. 1970;52:411-423.
McKenna RJ, Schwinn CP, Soonh KY, et al. Sarcomata of osteogenic series (osteosarcoma, fibrosarcoma, chondrosarcoma, parosteal osteosarcoma, and sarcomata arising in abnormal bone): an analysis of 552 cases. J Bone Joint Surg Am. 1966;48-A:1-26.
Rockwell MA, Enneking WF. Osteosarcoma developing in solitary enchondroma of the tibia. J Bone Joint Surg Am. 1971;53:341-344.
Huvos AG, Higinbotham NL, Miller TR. Bone sarcomas arising in fibrous dysplasia. J Bone Joint Surg Am. 1972;54:1047-1056.
Braddock GT, Hadlow VD. Osteosarcoma in enchondromatosis (Ollier’s disease). Report of a case. J Bone Joint Surg Br. 1966;48:145-149.
Johnston RM, Miles JS. Sarcomas arising from chronic osteomyelitic sinuses. A report of two cases. J Bone Joint Surg Am. 1973;55:162-168.
Sim FH, Cupps RE, Dahlin DC, et al. Postradiation sarcoma of bone. J Bone Joint Surg Am. 1972;54:1479-1489.
Huvos A. Bone Tumors: Diagnosis, Treatment, and Prognosis. 2nd ed. Philadelphia, PA: Saunders; 1991.
Inskip PD, Ries LAG, Cohen RJ, et al. New malignancies following childhood cancer. In: Curtis RE, Freedman DM, Ron E, et al., eds. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973–2000 (NIH Publ. No. 05-5302). Bethesda, MD: National Cancer Institute; 2006. Available at: http://seer.cancer.gov/publications/mpmono/Ch18_Childhood.pdf; Accessed August 2008.
Kalra S, Grimer RJ, Spooner D, et al. Radiation-induced sarcomas of bone: factors that affect outcome. J Bone Joint Surg Br. 2007;89:808-813.
Spiess H, Mays CW. Bone cancers induced by 224 Ra (Th X) in children and adults. Health Phys. 1970;19:713-729.
Shaheen M, Deheshi BM, Riad S, et al. Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res. 2006;450:76-81.
Loutit JF. Malignancy from radium. Br J Cancer. 1970;24:195-207.
Aub JC, Evans RD, Hempelmann LH, et al. The late effects of internally-deposited radioactive materials in man. Medicine. 1952;31:221-329.
Harrist TJ, Schiller AL, Trelstad RL, et al. Thorotrast-associated sarcoma of bone: a case report and review of the literature. Cancer. 1979;44:2049-2058.
Yamamoto T, Wakabayashi T. Bone tumors among the atomic bomb survivors of Hiroshima and Nagasaki. Acta Pathol Jpn. 1969;19:201-212.
Shigematsu I. Health effects of atomic bomb radiation. Rinsho Byori. 1994;42:313-319.
Harvey RT, Donald PJ, Weinstein GS. Osteogenic sarcoma of the maxillary alveolus occurring five years following the Chernobyl nuclear accident. Am J Otolaryngol. 1996;17:210-214.
Finkelstein MM, Kreiger N. Radium in drinking water and risk of bone cancer in Ontario youths: a second study and combined analysis. Occup Environ Med. 1996;53:305-311.
Newton WA Jr, Meadows AT, Shimada H, et al. Bone sarcomas as second malignant neoplasms following childhood cancer. Cancer. 1991;67:193-201.
Henderson TO, Whitton J, Stovall M, et al. Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2007;99:300-308.
Zilioli E, Ottaviani C. Osteosarcoma: concetti attuali di patologia e nuove prospettive terapeutiche. Nota I: aspetti bioimmulogici della neoplasia. Chir Ital. 1978;30:953-961.
Zilioli E, Ottaviani C. Osteosarcoma: concetti attuali di patologia e nuove prospettive terapeutiche. Nota II: criteri prognostici e terapia. Chir Ital. 1978;30:975-991.
Finkel MP, Jinkins PB, Tolle J, et al. Serial radiography of virus-induced osteosarcomas in mice. Radiology. 1966;87:333-339.
Finkel MP, Biskis BO, Farrell C. Pathogenic effects of extracts of human osteosarcomas in hamsters and mice. Arch Pathol. 1967;84:425-428.
Finkel MP, Biskis BO, Farrell C. Osteosarcomas appearing in Syrian hamsters after treatment with extracts of human osteosarcomas. Proc Natl Acad Sci USA. 1968;60:1223-1230.
Finkel MP, Biskis BO, Farrell C. Nonmalignant and malignant changes in hamsters inoculated with extracts of human osteosarcomas. Radiology. 1969;92:1546-1552.
Reilly CA Jr, Pritchard DJ, Biskis BO, et al. Immunologic evidence suggesting a viral etiology of human osteosarcoma. Cancer. 1972;30:603-609.
Finkel MP, Reilly CA Jr, Biskis BO. Pathogenesis of radiation and virus-induced bone tumors. Recent Results Cancer Res. 1976;54:92-103.
Eilber FR, Morton DL. Sarcoma-specific antigens: detection by complement fixation with serum from sarcoma patients. J Natl Cancer Inst. 1970;44:651-656.
Shah KV. SV40 and human cancer: a review of recent data. Int J Cancer. 2007;120:215-223.
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Ottaviani, G., Jaffe, N. (2009). The Etiology of Osteosarcoma. In: Jaffe, N., Bruland, O., Bielack, S. (eds) Pediatric and Adolescent Osteosarcoma. Cancer Treatment and Research, vol 152. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0284-9_2
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