Osteosarcoma complicating familial Paget’s disease

Brenton, D. P.; Isenberg, DA; Bertram, John F.

doi:10.1136/pgmj.56.654.238

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…Osteosarcoma occurs more often in humans with Li-Fraumeni syndrome [127,128,129,130], familial retinoblastoma [131,132,133,134,135,136,137,138,139,140], and Paget’s disease [14,141,142,143,144,145]. It can also occur as a second or later malignancy [131,132,133,134,135,136,137,138,139,140,142].…”

Section: Germline and Somatic Driver Alterationsmentioning

confidence: 99%

Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review

Makielski

Mills

Sarver

et al. 2019

Veterinary Sciences

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Osteosarcoma is the most common primary tumor of bone. Osteosarcomas are rare in humans, but occur more commonly in dogs. A comparative approach to studying osteosarcoma has highlighted many clinical and biologic aspects of the disease that are similar between dogs and humans; however, important species-specific differences are becoming increasingly recognized. In this review, we describe risk factors for the development of osteosarcoma in dogs and humans, including height and body size, genetics, and conditions that increase turnover of bone-forming cells, underscoring the concept that stochastic mutational events associated with cellular replication are likely to be the major molecular drivers of this disease. We also discuss adaptive, cancer-protective traits that have evolved in large, long-lived mammals, and how increasing size and longevity in the absence of natural selection can account for the elevated bone cancer risk in modern domestic dogs.

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Section: Germline and Somatic Driver Alterationsmentioning

confidence: 99%

Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review

Makielski

Mills

Sarver

et al. 2019

Veterinary Sciences

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“…A familial clustering has been rarely described, likely explaining the difficulty to find a common genetic basis. To date, only five families have been reported in the literature in which osteosarcomas had developed in at least two PDB‐affected family members, indicating that there may be a genetic predisposition …”

Section: Introductionmentioning

confidence: 99%

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

Carlo

Pazzaglia

Esposito

et al. 2020

Journal of Bone and Mineral Research

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Paget's disease of bone (PDB) is a late-onset disorder frequently caused by mutations in the SQSTM1 gene, leading to hyperactive osteoclasts and resulting in bone pain, deformities, and fractures. However, some more severe forms of PDB-negative for SQSTM1 mutations-have been described, in which the disease degenerates into bone cancers and shows a poor prognosis. Osteosarcoma is the most frequent and aggressive tumor arising in PDB (OS/PDB), with a 5-year survival rate almost nil, but the underlying molecular mechanism is unknown. Here, we investigated an extended pedigree with 11 individuals affected by early onset and polyostotic PDB, mainly interesting the appendicular skeleton. Interestingly, three members also developed secondary osteosarcoma. We performed exome sequencing and identified a 4-bp deletion in the PFN1 gene, resulting in the degradation of the mutant protein. Copy number screening on 218 PDB individuals of our biobank disclosed that four of them (~2%) carry a germline heterozygous deletion of PFN1. The identification of these subjects, who exhibit a particularly severe form of disease, emphasizes the diagnostic value of this genetic screening to identify PDB individuals predisposed to develop osteosarcoma. In fact, we detected allelic imbalance at PFN1 locus also in 8 of 14 (57%) sporadic OS/PDB, further proving its causative role. in vitro experiments also confirmed PFN1 involvement in this form of PDB. Indeed, CRISPR-Cas9-mediated Pfn1 knockout in pre-osteoclasts resulted into enhanced osteoclast differentiation and resorption, with the formation of large osteoclasts never described before in PDB. In addition, Pfn1 lacking pre-osteoblasts lost their differentiation capability and failed to efficiently mineralize bone. Moreover, they acquired features of malignant transformation, including loss of focal adhesions and increased invasion ability. In conclusion, these findings disclose PFN1 haploinsufficiency as the pathological mechanism in OS/PDB.

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“…There are a few established risk factors for OS apart from early exposure to radiation, Paget's disease, hereditary retinoblastoma, and Li-Fraumeni syndrome (7)(8)(9)(10)(11). The bimodal age-incidence curve with peak rates occurring both in adolescence and in older age suggests 2 separate etiologies.…”

Section: Introductionmentioning

confidence: 99%

Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)

Anfinsen

Devesa

Bray

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Primary bone cancer comprises three major histologic types: osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS). Given the limited knowledge about the etiology of primary bone cancer, we undertook an age-period-cohort (APC) analysis to determine whether incidence varied by birth cohort or calendar period. The purpose was to examine the temporal development of each bone cancer type and generate etiologic hypotheses via the observed birth cohort-related changes.Methods: An APC model was fitted to incidence data for U.S. whites for OS, ES, and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results program, which covers about 10% of the U. S. population, 1976-2005.Results: The incidence of OS decreased between 1976 and 2005 among those aged over 60 years, a decline that occurred among patients with OS as their primary malignancy only. From 1986From -1995From to 1996From -2005, the incidence rate of CS among females of 20 to 69 years rose by about 50%, with rates increasing among consecutive cohorts born during . CS rates among males were stable, as were rates of ES.Conclusion: The risk reduction in OS as a primary malignancy at older ages could possibly be related to diminished exposure over time to bone-seeking radionuclides. The CS increase among females corresponds to birth cohorts with rising exposures to oral contraceptives and menopausal hormonal therapy.Impact: As the estrogen signaling pathway has been shown to stimulate proliferation of normal and malignant chondrocytes, estrogen exposure may increase the risk for CS. Further studies are warranted to clarify its possible etiological significance. Cancer Epidemiol Biomarkers Prev; 20(8); 1770-7. Ó2011 AACR.

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Osteosarcoma complicating familial Paget’s disease

Cited by 10 publications

References 12 publications

Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review

Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)

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