Unraveling syndrome-driven osteosarcoma: genetic insights and therapeutic frontiers

Abstract

Osteosarcoma is a highly malignant bone tumor, and a subset of cases is closely associated with hereditary syndromes. These syndrome-related osteosarcomas exhibit unique clinical features, molecular mechanisms, and therapeutic challenges. This review summarizes the current understanding of specific types of syndrome-related osteosarcomas, including those associated with Rothmund-Thomson syndrome, Li-Fraumeni syndrome, secondary osteosarcoma in retinoblastoma survivors, Werner syndrome, and Bloom syndrome. These syndromes are typically characterized by specific gene mutations or chromosomal instability, significantly increasing the risk of osteosarcoma development. However, the rarity and heterogeneity of syndrome-related osteosarcomas pose significant challenges for diagnosis and treatment, including difficulties in early detection, incomplete elucidation of molecular mechanisms, and limitations of conventional therapeutic approaches. This article aims to systematically review the clinical characteristics, molecular mechanisms, and therapeutic challenges of these syndromes, providing a comprehensive reference for clinicians and directions for future research.

Introduction

Osteosarcoma, the most common primary malignant bone tumor in children and adolescents, is closely associated with various hereditary syndromes in terms of its pathogenesis. Studies indicate that approximately 28% of osteosarcoma patients carry highly penetrant pathogenic or likely pathogenic germline mutations, with TP53 mutations leading to Li-Fraumeni syndrome being the most prevalent, accounting for a significant proportion of syndrome-related osteosarcomas [1]. Additionally, hereditary retinoblastoma syndrome, Werner syndrome, Bloom syndrome, and Diamond-Blackfan anemia are also linked to osteosarcoma susceptibility [2]. These syndrome-related osteosarcomas often exhibit distinct clinical features, such as earlier onset in Li-Fraumeni syndrome -related cases (median diagnosis age of 16 years) and a higher incidence of secondary malignancies (e.g., breast cancer, soft tissue sarcomas) [3].

At the molecular level, driver mutations in syndrome-related osteosarcomas involve multiple signaling pathways. TP53 mutations lead to increased genomic instability, while RB1 loss promotes tumorigenesis through dysregulation of the cell cycle [4]. Mutations in DNA helicase genes, such as RECQL4, impair DNA damage repair, exacerbating genomic aberrations [5]. Furthermore, non-coding RNAs (e.g., miR-21, miR-34a) contribute to tumor progression by regulating MAPK and PI3K/Akt pathways [6]. Notably, CD133+ tumor stem cells in syndrome-related osteosarcomas exhibit enhanced metastatic and drug-resistant properties, potentially linked to Wnt/β-catenin pathway activation [7].

In addition to large-scale chromosomal rearrangements, osteosarcoma exhibits another hallmark of genomic instability at the sub-chromosomal level: a profound dependency on the Alternative Lengthening of Telomeres (ALT) mechanism for telomere maintenance. Unlike the majority of cancers which reactivate telomerase, osteosarcoma is one of the few tumor types where ALT is prevalently activated [8]. This reliance is mechanistically linked to the dysfunction of RecQ-family DNA helicases, which are crucial regulators of telomere homeostasis and homologous recombination. Specifically, the helicases RECQL4, WRN, and BLM play non-redundant roles in suppressing aberrant recombination at telomeres and resolving ALT-associated DNA structures, such as telomeric D-loops and stalled replication forks [9, 10].

The critical in vivo evidence for this link stems from the dramatically elevated osteosarcoma susceptibility observed in patients with germline RecQ helicase deficiency syndromes: Rothmund-Thomson, Werner, and Bloom [11]. The prevailing model posits that loss of functional RECQL4, WRN, or BLM leads to the accumulation of unresolved, replication-stressed telomeric DNA, which in turn acts as a substrate for aberrant homologous recombination. This creates a permissive genomic environment that precipitates ALT activation [10]. Consequently, in sporadic osteosarcomas, somatic alterations or dysregulation of these helicases may serve as a key permissive event, enabling cancer cells to exploit the ALT pathway to achieve replicative immortality. This ALT dependency, coupled with catastrophic chromosomal instability, defines the unique genomic landscape of osteosarcoma and presents a potential therapeutic vulnerability.

Therapeutically, syndrome-related osteosarcomas present multiple challenges. Conventional chemotherapy regimens (e.g., doxorubicin combined with cisplatin) have limited efficacy due to variations in patients’ sensitivity to DNA-damaging agents [12]. For instance, LFS patients face a significantly elevated risk of secondary tumors following radiotherapy or alkylating agent-based chemotherapy [13]. In recent years, targeted therapies (e.g., cabozantinib, sorafenib) and immune checkpoint inhibitors (e.g., pembrolizumab) have shown promise in specific subgroups, but their application requires individualized selection based on germline mutation profiles [14]. Additionally, drug development targeting molecules such as RECQL4 offers new avenues for future treatments.

In summary, the unique genetic background and clinical complexity of syndrome-related osteosarcomas necessitate multidisciplinary collaboration, integrating genetic testing, risk stratification, and personalized treatment strategies to improve patient outcomes. Future research should focus on elucidating the molecular mechanisms of driver mutations and their interactions with the tumor microenvironment, as well as exploring precise interventions for genetic predispositions. This review is the first to compare osteosarcomas associated with five rare syndromes, integrate the latest advancements in targeted therapy, and emphasize common molecular pathways, which is different from previous reviews that focused on a single syndrome.

Syndromes and osteosarcoma

Rothmund-Thomson syndrome and osteosarcoma

Clinical characteristics (Table 1)

Table 1.

Clinical characteristics of syndrome-related osteosarcoma

Syndrome	Gene Mutation	Age of Onset	Tumor Location	Key Clinical Features
Rothmund-Thomson Syndrome	RECQL4	6–10 years	Multifocal or bilateral	Poikiloderma, growth retardation, cataracts [References 16, 17, 19]
Li-Fraumeni Syndrome	TP53	Median 16 years	Long bones	Early onset, multiple malignancies (e.g., breast cancer, brain tumors) [References 3, 3]
Retinoblastoma	RB1	10–20 years	Craniofacial or long bones	Radiation-induced, aggressive growth [References 20, 21]
Werner Syndrome	WRN	30–50 years	Pelvis, spine	Premature aging (cataracts, skin sclerosis), late onset [References 22, 23]
Bloom Syndrome	BLM	Adolescence	Long bones	Short stature, photosensitive rashes, immunodeficiency [References 1, 24]

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genetic disorder characterized by poikiloderma, skeletal abnormalities, and cancer predisposition, particularly to osteosarcoma (OS). However, the risk of osteosarcoma is almost exclusively associated with Type II RTS (RECQL4 mutations, skeletal defects), whereas Type I carries a low risk. Clinical observations indicate that RTS patients typically develop erythema and photosensitivity in childhood, progressing to characteristic reticulated pigmentation and atrophy (poikiloderma) [15]. Approximately 30% of RTS patients develop osteosarcoma, with an earlier onset compared to sporadic cases (average diagnosis age of 6–10 years) [16]. Notably, RTS-related osteosarcomas often present as multifocal or bilateral, with a higher risk of recurrence [17]. Case reports indicate that some patients develop a second primary osteosarcoma in the contralateral limb within a decade of curing the initial tumor, underscoring the importance of long-term monitoring [18]. Additional systemic manifestations, such as growth retardation, cataracts, and sparse hair, aid in the early identification of high-risk individuals [19].

RECQL4 gene mutations and pathogenesis (Table 2)

Table 2.

Germline mutations associated with Syndrome-Related Osteosarcoma

Syndrome	Mutated Gene	Protein Function	Risk of OS in syndrome carriers	Key References
Rothmund-Thomson Syndrome	RECQL4	DNA helicase, repair	30%	[11, 16, 25, 27]
Li-Fraumeni Syndrome	TP53	Tumor suppression, genomic stability	38%	[1, 31–33]
Retinoblastoma	RB1	Cell cycle regulation	36.2%	[34–36]
Werner Syndrome	WRN	DNA helicase, telomere maintenance	8%	[23, 37–39]
Bloom Syndrome	BLM	DNA helicase, homologous recombination	＜2%	[40–43]

The molecular basis of RTS is primarily attributed to biallelic pathogenic mutations in the RECQL4 gene [25]. RECQL4 encodes a DNA helicase involved in DNA replication, repair, and telomere maintenance [26]. Functional studies demonstrate that RECQL4 loss leads to genomic instability, including chromosomal breaks and copy number variations, thereby promoting tumorigenesis [27]. In RTS-related osteosarcomas, RECQL4 mutations often result in complete loss of protein function, leading to defects in cell cycle regulation (e.g., G1/S checkpoint deficiencies) and resistance to apoptosis [28]. Additionally, somatic TP53 mutations frequently coexist in RTS-related osteosarcomas, suggesting synergistic roles of RECQL4 and p53 pathways in tumor development [29]. Animal models further confirm that RECQL4-deficient mice are prone to osteosarcoma, with tumor tissues exhibiting aberrant Wnt/β-catenin pathway activation [30]. These findings provide a molecular basis for the high osteosarcoma susceptibility in RTS patients.

Treatment and prognosis (Table 3)

Table 3.

Treatment challenges and emerging therapeutic options

Syndrome	Standard Drug Therapy	Challenges	Emerging therapeutic Options	References
Rothmund-Thomson Syndrome	Doxorubicin + Cisplatin	High chemotherapy toxicity, myelosuppression	Cabozantinib, Pazopanib	[15, 44, 45]
Li-Fraumeni Syndrome	Anthracyclines + Cisplatin	Concurrent malignancies	TP53 activators, Cabozantinib	[13, 47]
Retinoblastoma	Anthracyclines + Cisplatin	Risk of repeated radiation exposure	Local therapy, Immunotherapy	[14, 48, 49]
Werner Syndrome	Doxorubicin + Cisplatin	Poor chemotherapy tolerance, cardiovascular risks	RECQL4 inhibitors, Pembrolizumab	[50, 51]
Bloom Syndrome	Anthracyclines + Cisplatin	High toxicity to DNA-damaging drugs	RecQ helicase-targeted therapies	[40, 41]

The treatment of RTS-related osteosarcoma faces dual challenges: patients’ poor tolerance to the toxicity of conventional chemotherapy (e.g., increased risks of myelosuppression and mucositis) [44] and the more aggressive biological behavior of the tumors. Clinical data indicate that, despite the use of doxorubicin-based EURAMOS-1/COSS protocols, the 5-year survival rate for RTS patients remains lower than that for sporadic osteosarcoma (approximately 50–60% vs. 70%) [15]. Surgical resection remains the cornerstone of local control, but the balance between wide excision and limb preservation is critical. In recent years, targeted therapies (e.g., cabozantinib and pazopanib) have shown potential in suppressing tumor growth in RECQL4-deficient models, though their clinical efficacy requires further validation [45]. Given the elevated risk of secondary malignancies (e.g., breast cancer, skin cancer) in RTS patients, multidisciplinary follow-up, including regular imaging screening and genetic counseling, is recommended post-osteosarcoma treatment [46]. Early genetic diagnosis and personalized treatment strategies are key to improving prognosis.

Li-Fraumeni syndrome and osteosarcoma

Molecular mechanisms of TP53 mutations (Table 2)

The TP53 gene, a critical tumor suppressor, plays a central role in Li-Fraumeni syndrome (LFS)-related osteosarcoma [31]. The p53 protein, encoded by TP53, maintains genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair [52]. Germline TP53 mutations in LFS patients (e.g., missense, nonsense, or splice-site mutations) result in loss of p53 function, leading to genomic instability and tumorigenesis [32]. Studies show that TP53 mutation frequency is significantly higher in osteosarcoma than in other sarcoma subtypes, often accompanied by loss of heterozygosity (i.e., the “second hit” model) [53]. Additionally, TP53 mutations promote osteosarcoma cell invasion by activating the MEK-ERK pathway and synergize with mutations in NOTCH1 and FOS to drive tumor progression [54]. Notably, certain TP53 mutations (e.g., p.Arg267Trp) may exacerbate phenotypic heterogeneity by disrupting interactions with CCAR2, impairing p53’s transcriptional regulatory functions [55]. Of particular relevance in certain populations, such as in Southern Brazil, is the founder TP53 R337H mutation. This specific variant is strongly associated with a very high incidence of pediatric adrenocortical carcinoma and a significantly increased risk of childhood osteosarcoma [56].

Osteosarcoma is characterized by profound genomic instability, which contributes to its aggressive behavior and evolution. This instability is frequently driven by catastrophic events such as chromothripsis, a process wherein dozens to hundreds of clustered genomic rearrangements occur in a single catastrophic episode. Critically, seminal studies have established that loss of TP53 function is a fundamental prerequisite for cells to undergo and survive chromothripsis [57, 58]. The underlying mechanism involves the survival of cells with mitotic errors (e.g., micronuclei formation) that, in a TP53-wildtype context, would be eliminated by apoptosis [57]. In TP53-deficient cells, however, the encapsulated chromosomal DNA within micronuclei undergoes pulverization and error-prone repair, leading to the complex rearrangements hallmark of chromothripsis. In osteosarcoma, where TP53 pathway inactivation is near-universal, this mechanism provides a rapid ‘evolutionary leap’ by simultaneously amplifying oncogenes and deleting tumor suppressors, thereby fueling tumor progression and heterogeneity [53].

Clinical characteristics and familial inheritance patterns (Table 1)

LFS-related osteosarcoma is characterized by early onset and familial clustering, with approximately 28% of osteosarcoma patients carrying highly penetrant cancer susceptibility gene variants, predominantly TP53 mutations [1]. Clinically, it manifests in childhood or adolescence (median diagnosis age of 16 years) and is often accompanied by other LFS-associated tumors (e.g., breast cancer, brain tumors) [3]. The inheritance pattern is autosomal dominant, but phenotypic heterogeneity is pronounced, with family members potentially presenting different tumor types or ages of onset [59]. Case reports indicate that some patients present with osteosarcoma as the initial manifestation, with LFS diagnosed only after subsequent malignancies (e.g., breast cancer, glioma) [60]. Moreover, LFS patients have a significantly elevated risk of second primary malignancies; for example, a study reported a 17-year-old osteosarcoma survivor developing HER2-positive breast cancer 10 years later, with genetic testing confirming a TP53 germline mutation [61].

Treatment strategies and monitoring (Table 3)

The treatment of LFS-related osteosarcoma must balance tumor eradication with minimizing the risk of secondary cancers [9]. Current standard protocols involve surgery combined with anthracycline-based chemotherapy (e.g., doxorubicin). Radiotherapy is absolutely contraindicated in patients with confirmed or clinically suspected Li-Fraumeni syndrome. This is due to the profoundly elevated risk of radiation-induced secondary malignancies, which is a hallmark of TP53-deficient cells. Functional restoration strategies targeting TP53 mutations (e.g., p53 activators) are under investigation, while targeted therapies (e.g., cabozantinib, sorafenib) have shown promise in clinical trials [47]. Monitoring involves a multidisciplinary follow-up approach, including whole-body MRI, 68 Ga-DOTATATE PET/CT, and cascade screening for TP53 mutation carriers within families [62]. International guidelines recommend lifelong annual screening for LFS patients, covering high-risk organs such as the breast, brain, and hematopoietic system. Genetic counseling is critical, particularly for young patients or those with a family history of multiple primary cancers, to assess the need for germline testing and develop individualized risk management plans.

Secondary osteosarcoma in retinoblastoma survivors

RB1 gene mutations and secondary tumor risk (Table 2)

The risk of secondary osteosarcoma in retinoblastoma (Rb) survivors is closely linked to germline mutations in the RB1 gene [34]. Studies show that patients with RB1 mutations are not only susceptible to retinoblastoma but also have a significantly elevated risk of osteosarcoma. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle, and its loss leads to genomic instability and tumor predisposition [63]. In vitro studies demonstrate that mesenchymal stem cells with heterozygous RB1 mutations exhibit reduced RB1 expression, alongside altered expression of other tumor suppressors (e.g., TP53) [35]. Additionally, RB1 mutations may promote osteosarcoma development by enhancing the activity of oncogenes such as MET [45]. These findings underscore the central role of RB1 in osteosarcoma pathogenesis and provide a foundation for genetic counseling.

pRB directly binds to the master osteogenic transcription factor RUNX2 via its pocket domain, and this interaction is critical for recruiting RUNX2 to target gene promoters and activating the transcriptional program essential for terminal osteogenic differentiation [64, 65]. Loss of RB1 function disrupts this pRB-RUNX2 complex, leading to dysregulated RUNX2 activity. The consequence is not a simple loss of RUNX2 function but a differentiation block: osteoprogenitor cells enter the osteoblastic lineage but fail to exit the cell cycle and complete maturation. These proliferating, undifferentiated cells accumulate, particularly in areas of active bone growth such as the metaphyses of long bones, ultimately leading to tumor formation [66, 67]. Therefore, the disruption of the pRB-RUNX2 interaction and the resulting differentiation block constitute a key tissue-specific mechanism linking the general cell cycle defect caused by RB1 loss to the development of osteosarcoma.

Radiotherapy and secondary osteosarcoma (Table 1)

Radiotherapy, a key treatment for retinoblastoma, is a well-established risk factor for secondary osteosarcoma [68]. Studies indicate that Rb patients receiving external beam radiotherapy have a 35-year cumulative incidence of secondary osteosarcoma of up to 32.6%, predominantly in craniofacial bones (e.g., mandible, skull base) within the radiation field [20, 69]. The mechanisms underlying radiotherapy-induced osteosarcoma include direct DNA damage, increased genomic instability, and alterations in the local microenvironment [70]. Notably, neither age at radiotherapy (e.g., < 12 months) nor bilateral irradiation significantly increases the risk, but radiation dose and field size correlate closely with the latency period (median 16.9 years) [71]. Clinically, radiotherapy-induced osteosarcomas often exhibit aggressive growth and may be associated with secondary RB1 mutations [21], suggesting a synergistic role of radiotherapy and genetic predisposition in tumorigenesis.

Clinical management and prevention (Table 3)

Long-term management of Rb survivors requires a multidisciplinary approach to minimize the risk of secondary osteosarcoma. Radiotherapy should be avoided in hereditary Rb patients, particularly infants, with chemotherapy or local treatments (e.g., brachytherapy) prioritized [48]. For patients who have received radiotherapy, lifelong follow-up is recommended, including annual clinical evaluations and imaging surveillance (e.g., Tc-99 m bone scans or MRI) to detect asymptomatic lesions early [72]. Studies show that early osteosarcomas detected via routine bone scans have a 5-year survival rate of up to 86%, significantly higher than cases diagnosed after symptom onset [49]. Additionally, RB1 gene testing is recommended for all Rb patients, with mutation carriers offered genetic counseling, including family screening and individualized tumor risk assessments. For patients developing osteosarcoma, treatment mirrors that of primary osteosarcoma (neoadjuvant chemotherapy + wide resection + adjuvant chemotherapy), but repeated radiotherapy exposure should be avoided to reduce the risk of secondary malignancies.

Werner syndrome and osteosarcoma

WRN gene mutations and premature aging features (Table 2)

Werner syndrome (WS), a rare autosomal recessive disorder, is caused by mutations in the WRN gene (located at 8p12), which encodes a member of the RecQ DNA helicase family [73]. The WRN protein plays a critical role in DNA repair, telomere maintenance, and genomic stability [37]. Mutations lead to loss of WRN protein function, resulting in premature aging features, including cataracts, skin sclerosis, osteoporosis, diabetes, and atherosclerosis appearing after adolescence [38]. Notably, WS patients have a significantly elevated cancer risk, particularly for soft tissue sarcomas and osteosarcoma, directly linked to genomic instability caused by DNA repair defects [16]. Studies suggest that WRN loss accelerates cellular senescence and promotes tumorigenesis, potentially through telomere dysfunction and mitochondrial metabolic abnormalities [74]. Additionally, WRN mutations may enhance osteosarcoma susceptibility by affecting p53 pathways and homologous recombination repair [39].

Clinical features of osteosarcoma (Table 1)

Osteosarcoma in WS patients exhibits distinct clinical and molecular characteristics. Compared to sporadic osteosarcoma, WS-related osteosarcoma has a later onset (typically 30–50 years) [22] and frequently affects sites other than long bones, such as the pelvis or spine [23]. At the molecular level, these tumors frequently harbor secondary mutations in tumor suppressor genes (e.g., TP53, RB1), which synergize with WRN defects to drive malignant transformation [45]. Genomic analyses also reveal high-frequency copy number variations (e.g., MYC amplification) and driver mutations in NOTCH1 and FOS [54]. Furthermore, CD133+ tumor stem cells are more active in WS patients, potentially contributing to increased invasiveness and drug resistance [75]. These features pose significant challenges for the diagnosis and treatment of WS-related osteosarcoma.

Treatment challenges and prognosis (Table 3)

The treatment of WS-associated osteosarcoma is complicated by patients’ systemic conditions and molecular defects. Cardiovascular risk is the core manifestation of the premature aging phenotype of Werner syndrome, which is characterized by extensive, premature, and dangerous accelerated atherosclerosis, especially coronary artery disease, and characteristic severe peripheral artery disease. Therefore, Werner syndrome with osteosarcoma is poorly tolerated by chemotherapy. [50]. Moreover, WRN defects impair DNA repair, potentially reducing radiotherapy efficacy while elevating the risk of secondary malignancies [70]. Clinical data indicate that the 5-year survival rate for WS patients with osteosarcoma is less than 30%, significantly lower than that for sporadic osteosarcoma (approximately 60–70%) [51]. To optimize prognosis, individualized treatment plans and multidisciplinary follow-up (including imaging and genetic counseling) are recommended to monitor secondary tumor risks.

Bloom syndrome and osteosarcoma

BLM gene mutations and molecular mechanisms (Table 2)

Bloom syndrome (BS) is an autosomal recessive disorder caused by mutations in the BLM gene, which encodes a member of the RecQ helicase family critical for maintaining genomic stability [40]. BLM mutations lead to increased genomic instability and significantly elevated cancer susceptibility [41]. The BLM protein, a DNA helicase, is involved in DNA replication, recombination, and repair, particularly in homologous recombination repair (HRR) pathways [76]. BLM defects result in an inability to dissolve Holliday junctions, thereby increasing the incidence of chromosome breaks and sister chromatid exchanges [42]. In osteosarcoma, BLM mutations may promote oncogenic mutation accumulation by disrupting DNA damage response mechanisms [16]. Additionally, mutations in other RecQ helicase family members (e.g., WRN, RECQL4) are also associated with osteosarcoma, highlighting the family’s critical role in tumorigenesis [39].

Clinical characteristics and diagnosis (Table 1)

Patients with Bloom syndrome-related osteosarcoma typically exhibit BS’s hallmark clinical features, including short stature, photosensitive rashes, immunodeficiency, and characteristic facial morphology (e.g., narrow face, small mandible) [24]. These patients develop osteosarcoma at a younger age and may have concurrent malignancies (e.g., leukemia, lymphoma) [1]. Diagnosis relies on conventional imaging and histopathological examinations, with genetic testing to confirm BLM gene and biallelic mutations being essential for BS confirmation [77]. Notably, some patients are initially misdiagnosed with other RecQ helicase-related syndromes (e.g., Rothmund-Thomson syndrome), underscoring the importance of genetic testing for differential diagnosis [19].

Conclusion

Syndrome-related osteosarcomas, due to their unique clinical characteristics and molecular mechanisms, represent a critical focus in osteosarcoma research. These tumors are closely associated with hereditary syndromes such as Li-Fraumeni syndrome and hereditary retinoblastoma syndrome and others, with pathogenesis involving complex gene mutations and signaling pathway aberrations. Early diagnosis and personalized treatment are pivotal for improving patient outcomes. Although studies have confirmed the central role of TP53, RB1, and other gene mutations in syndrome-related osteosarcomas, discrepancies exist across studies regarding the pathogenicity of specific genes. Future research should integrate multi-omics data with clinical phenotypes to more precisely elucidate the pathogenic mechanisms of these genes.

Therapeutically, the efficacy of conventional chemotherapy and surgery is limited, while targeted therapies and immunotherapies remain in exploratory stages. Inhibitors targeting specific signaling pathways (e.g., mTOR, CDK4/6) may be effective, but patient responses vary significantly. Additionally, genetic counseling and regular monitoring are crucial for reducing incidence and improving early detection rates in high-risk populations. However, optimizing surveillance protocols requires further evidence-based support. Through multidisciplinary collaboration (e.g., genetics, oncology, imaging), combined with precision medicine and personalized treatment strategies, significant improvements in patient survival and quality of life are anticipated in the future [78].

Abbreviations

BS

Bloom Syndrome

COSS

Cooperative Osteosarcoma Study

EURAMOS-1

European and American Osteosarcoma Study Group 1

HRR

Homologous Recombination Repair

LFS

Li-Fraumeni Syndrome

MAPK

Mitogen-Activated Protein Kinase

OS

Osteosarcoma

PET/CT

Positron Emission Tomography/Computed Tomography

PI3K/Akt

Phosphatidylinositol 3-Kinase/Protein Kinase B

pRB

Retinoblastoma Protein

Rb

Retinoblastoma

RTS

Rothmund-Thomson Syndrome

WS

Werner Syndrome

Biographies

Yang Zhou

is a senior researcher in the Department of Bone and Soft Tissue Oncology at Cancer Hospital Chinese Academy of Medical Sciences Shenzhen Center, Shenzhen, China, with 17 years of experience in bone and soft tissue sarcomas, specializing in osteosarcoma, soft tissue sarcoma, and their surgical management.

Wen Wang

is the Laboratory Supervisor (Molecular Pathology) in the Department of Pathology at the same institution, with 13 years of experience in tumor molecular pathology, focusing on molecular pathology techniques and laboratory quality management, with expertise in genetic analysis of rare cancers.

Jin Qiu

is a resident physician in the Department of Bone and Soft Tissue Oncology, focusing on molecular and clinical aspects of bone and soft tissue tumors.

Jingyang Huang

is an attending physician in the same department, focusing on clinical management of bone and soft tissue tumors.

Laihua Fu

is a researcher in the same department, with expertise in surgical treatment of osteosarcoma and soft tissue sarcomas.

Songfeng Xu

is a researcher in the same department, specializing in surgical management of osteosarcoma and bone metastases.

Authors’ contributions

Yang Zhou conceptualized the study, conducted the literature review, drafted the initial manuscript, and contributed equally as co-first author. Wen Wang provided expertise in genetic analysis, compiled genetic data, critically revised the manuscript, and contributed equally as co-first author. Jin Qiu and Jingyang Huang performed data collection, analyzed molecular mechanisms, and contributed to writing the clinical characteristics sections. Laihua Fu provided expertise in genetic analysis and compiled genetic data. Songfeng Xu analyzed therapeutic data and prepared the tables. Yang Zhou supervised the study and approved the final version. All authors read and approved the final manuscript.

Funding

Shenzhen Health and Wellness Elite Talent Cultivation Project 2024XKG070.

Data availability

Data sharing not applicable as no datasets were generated.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.