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3.
Artigo em Inglês | MEDLINE | ID: mdl-33236116

RESUMO

CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: To describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases.Design and Setting: Multi-institutional case series from tertiary pediatric oncology centers. PATIENTS: Children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support. OUTCOME MEASURES: Survival, long-term morbidities, germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 female and 7 male); median age at diagnosis was 11 months (range 2-24). Cushing syndrome was the most frequent presentation (n=10). Cushingoid stigmata were absent in seven children (two with raised ACTH; five with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n=7), subtotal resection (n=9), and biopsy (n=1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, nine patients were alive; eight patients died of early medical/surgical complications (n=3), sepsis (n=1), catheter-related complication (n=1), aneurysmal bleeding (n=1), second brain tumor (n=1), and progression (n=1). Surgery was the only intervention for five of nine survivors. Extent of resection, but neither Ki67 labelling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n=8), visual (n=4), and neurodevelopmental (n=3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

4.
Blood Cancer Discov ; 1(1): 96-111, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32793890

RESUMO

Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of childhood death. Prior studies have shown clonal mutations at relapse often arise from relapse-fated subclones that exist at diagnosis. However, the genomic landscape, evolutionary trajectories and mutational mechanisms driving relapse are incompletely understood. In an analysis of 92 cases of relapsed childhood ALL, incorporating multimodal DNA and RNA sequencing, deep digital mutational tracking and xenografting to formally define clonal structure, we identify 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment. CREBBP, NOTCH1, and Ras signaling mutations rose from diagnosis subclones, whereas variants in NCOR2, USH2A and NT5C2 were exclusively observed at relapse. Evolutionary modeling and xenografting demonstrated that relapse-fated clones were minor (50%), major (27%) or multiclonal (18%) at diagnosis. Putative second leukemias, including those with lineage shift, were shown to most commonly represent relapse from an ancestral clone rather than a truly independent second primary leukemia. A subset of leukemias prone to repeated relapse exhibited hypermutation driven by at least three distinct mutational processes, resulting in heightened neoepitope burden and potential vulnerability to immunotherapy. Finally, relapse-driving sequence mutations were detected prior to relapse using deep digital PCR at levels comparable to orthogonal approaches to monitor levels of measurable residual disease. These results provide a genomic framework to anticipate and circumvent relapse by earlier detection and targeting of relapse-fated clones.

6.
Genome Res ; 30(8): 1170-1180, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32817165

RESUMO

De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation [FM]) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: (1) cancer and mutation spectra along with parental ages were similarly distributed; (2) ascertainment criteria like early-onset breast cancer (age 20-35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.

7.
Cancer Genet ; 245: 42-48, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32619790

RESUMO

Gain of function variants in SAMD9 cause MIRAGE syndrome, a rare Mendelian disorder that results in myeloid dysplastic syndrome (MDS), poor immune response, restricted growth, adrenal insufficiency, ambiguous genitalia, feeding difficulties and most often significantly reduced lifespan. In this study, we describe histomorphologic and genetic changes occurring in serial bone marrow measurements in a patient with MIRAGE syndrome and untreated MDS of 9 years. Histomorphological analysis during childhood showed progressive hypocellularity with erythroid and megakaryocytic dysplasia and cytogenetic testing demonstrated monosomy 7. Serial leukemia gene panel testing performed over a seven year period revealed multiple pre-leukemic clones arising at age 7 years followed by sequential mutational events in ETV6 and RUNX1 driving acute myeloid leukemia (AML) at age 9. Comprehensive genotype-phenotype analysis with 28 previously reported patients found the presence of MDS did not impact overall survival, but in silico variant pathogenicity prediction scores for SAMD9 distinguished patients with poor prognosis. Overall, our analysis shows progression of MDS to AML can be monitored by following mutation evolution in leukemia related genes in patients with MIRAGE syndrome, and specific SAMD9 mutations likely influence disease severity and overall survival.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Progressão da Doença , Humanos , Masculino , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Síndrome
8.
Int J Mol Sci ; 21(14)2020 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-32708464

RESUMO

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.

10.
Blood ; 136(5): 524-525, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32730578
11.
Blood ; 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32693409

RESUMO

There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with WT ETV6 with potentially dominate negative effects. Whole transcriptome and whole genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both AML and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by ATAC-seq profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

12.
J Clin Oncol ; 38(24): 2728-2740, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32496904

RESUMO

PURPOSE: To investigate cancer treatment plus pathogenic germline mutations (PGMs) in DNA repair genes (DRGs) for identification of childhood cancer survivors at increased risk of subsequent neoplasms (SNs). METHODS: Whole-genome sequencing was performed on blood-derived DNA from survivors in the St Jude Lifetime Cohort. PGMs were evaluated in 127 genes from 6 major DNA repair pathways. Cumulative doses of chemotherapy and body region-specific radiotherapy (RT) were abstracted from medical records. Relative rates (RRs) and 95% CIs of SNs by mutation status were estimated using multivariable piecewise exponential models. RESULTS: Of 4,402 survivors, 495 (11.2%) developed 1,269 SNs. We identified 538 PGMs in 98 DRGs (POLG, MUTYH, ERCC2, and BRCA2, among others) in 508 (11.5%) survivors. Mutations in homologous recombination (HR) genes were significantly associated with an increased rate of subsequent female breast cancer (RR, 3.7; 95% CI, 1.8 to 7.7), especially among survivors with chest RT ≥ 20 Gy (RR, 4.4; 95% CI, 1.6 to 12.4), or with a cumulative dose of anthracyclines in the second or third tertile (RR, 4.4; 95% CI, 1.7 to 11.4). Mutations in HR genes were also associated with an increased rate of subsequent sarcoma among those who received alkylating agent doses in the third tertile (RR, 14.9; 95% CI, 4.0 to 38.0). Mutations in nucleotide excision repair genes were associated with subsequent thyroid cancer for those treated with neck RT ≥ 30 Gy (RR, 12.9; 95% CI, 1.6 to 46.6) with marginal statistical significance. CONCLUSION: Our study provides novel insights regarding the contribution of genetics, in combination with known treatment-related risks, for the development of SNs. These findings have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of DRGs, which may further inform personalized cancer surveillance and prevention strategies.

13.
Hum Mutat ; 41(9): 1555-1562, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32485079

RESUMO

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.

14.
Blood ; 136(6): 657-668, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530039

RESUMO

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

15.
Int J Mol Sci ; 21(12)2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32560408

RESUMO

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.

16.
Histopathology ; 77(5): 760-768, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32583473

RESUMO

AIMS: Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. METHODS AND RESULTS: Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). CONCLUSION: We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.

17.
JCO Precis Oncol ; 4: 202-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32395682

RESUMO

Purpose: For the advances of pediatric oncology next generation sequencing (NGS) research to equitably benefit all children, a diverse and representative sample of participants is needed. However, little is known about demographic and clinical characteristics that differentiate families who decline enrollment in pediatric oncology NGS research. Methods: Demographic and clinical data were retrospectively extracted for 363 pediatric oncology patients (0-21 years) approached for enrollment on Genomes for Kids (G4K), a study examining the feasibility of comprehensive clinical genomic analysis of tumors and paired normal samples. Demographic and clinical factors that significantly differentiated which families declined were subsequently compared to enrollment in Clinical Implementation of Pharmacogenetics (PG4KDS) for 348 families, a pharmacogenomics study with more explicit therapeutic benefit examining genes affecting drug responses and metabolism. Results: Fifty-three (14.6%) families declined enrollment in G4K. Race/ethnicity was the only variable that significantly differentiated study refusal using multivariate logistic regression, with families of black children more likely to decline enrollment compared to families of non-Hispanic or Hispanic white children. Reasons for declining G4K were generally consistent with other pediatric genomics research, with feeling overwhelmed and insurance discrimination fears most frequently cited. Families of black children were also more likely to decline enrollment in PG4KDS. Thirteen (3.7%) of the 348 families approached for both studies declined PG4KDS. Conclusion: Race/ethnicity differentiated study declination across two different pediatric oncology genomics studies, suggesting enrollment disparities in the context of pediatric oncology genomics research. Genomics research participant samples that do not fully represent racial and ethnic minorities risk further exacerbating health disparities. Additional work is needed to understand the nuances of parental decision making in genomic research and facilitate enrollment of diverse patient populations.

18.
Hum Mol Genet ; 29(R2): R138-R149, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32412586

RESUMO

Wilms' tumor (WT), the most common childhood kidney cancer, develops in association with an underlying germline predisposition in up to 15% of cases. Germline alterations affecting the WT1 gene and epigenetic alterations affecting the 11p15 locus are associated with a selective increase in WT risk. Nevertheless, WT also occurs in the context of more pleiotropic cancer predispositions, such as DICER1, Li-Fraumeni and Bloom syndrome, as well as Fanconi anemia. Recent germline genomic investigations have increased our understanding of the host genetic factors that influence WT risk, with sequencing of rare familial cases and large WT cohorts revealing an expanding array of predisposition genes and associated genetic conditions. Here, we describe evidence implicating WT1, the 11p15 locus, and the recently identified genes CTR9, REST and TRIM28 in WT predisposition. We discuss the clinical features, mode of inheritance and biological aspects of tumorigenesis, when known. Despite these described associations, many cases of familial WT remain unexplained. Continued investigations are needed to fully elucidate the landscape of germline genetic alterations in children with WT. Establishing a genetic diagnosis is imperative for WT families so that individuals harboring a predisposing germline variant can undergo surveillance, which should enable the early detection of tumors and use of less intensive treatments, thereby leading to improved overall outcomes.

19.
Cytotherapy ; 22(5): 276-290, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32238299

RESUMO

BACKGROUND AIMS: Key obstacles in human iNKT cell translational research and immunotherapy include the lack of robust protocols for dependable expansion of human iNKT cells and the paucity of data on phenotypes in post-expanded cells. METHODS: We delineate expansion methods using interleukin (IL)-2, IL-7 and allogeneic feeder cells and anti-CD2/CD3/CD28 stimulation by which to dependably augment Th2 polarization and direct cytotoxicity of human peripheral blood CD3+Vα24+Vß11+ iNKT cells. RESULTS: Gene and protein expression profiling demonstrated augmented Th2 cytokine secretion (IL-4, IL-5, IL-13) in expanded iNKT cells stimulated with anti-CD2/CD3/CD28 antibodies. Cytotoxic effector molecules including granzyme B were increased in expanded iNKT cells after CD2/CD3/CD28 stimulation. Direct cytotoxicity assays using unstimulated expanded iNKT cell effectors revealed α-galactosyl ceramide (α-GalCer)-dependent killing of the T-ALL cell line Jurkat. Moreover, CD2/CD3/CD28 stimulation of expanded iNKT cells augmented their (α-GalCer-independent) killing of Jurkat cells. Co-culture of expanded iNKT cells with stimulated responder cells confirmed contact-dependent inhibition of activated CD4+ and CD8+ responder T cells. DISCUSSION: These data establish a robust protocol to expand and novel pathways to enhance Th2 cytokine secretion and direct cytotoxicity in human iNKT cells, findings with direct implications for autoimmunity, vaccine augmentation and anti-infective immunity, cancer immunotherapy and transplantation.


Assuntos
Antígenos CD2/imunologia , Antígenos CD28/imunologia , Complexo CD3/imunologia , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células T Matadoras Naturais/imunologia , Células Th2/imunologia , Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Doadores de Sangue , Transplante de Células/métodos , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Imunoterapia/métodos , Células Jurkat , Células K562 , Ativação Linfocitária/imunologia
20.
Am Soc Clin Oncol Educ Book ; 40: 1-12, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32213089

RESUMO

Secondary sarcomas are a subset of sarcomas that occur in patients with prior cancer diagnoses and are associated with environmental or genetic factors. Although secondary sarcomas are rare in general, there are predisposing factors that can substantially increase this risk in certain populations. Herein, we review the environmental factors with the strongest association of sarcoma risk, including chemical exposure, certain viruses, cytotoxic and immunosuppressive agents, chronic edema, and radiation exposure. Additionally, the most common genetic disorders that carry a predisposition for sarcoma development will be discussed, including hereditary retinoblastoma (RB), Li-Fraumeni syndrome (LFS), neurofibromatosis type 1 (NF1), and DICER1 syndrome. Although treatment does not generally differ for sporadic versus secondary sarcomas, awareness of the risk factors can alter therapeutic strategies to minimize risk, aid prompt diagnosis by increasing clinical suspicion, and allow for appropriate surveillance and genetic counseling for those patients with cancer predisposition syndromes.


Assuntos
Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Humanos
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