ABSTRACT
OBJECTIVES: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions. METHODS: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants. RESULTS: Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process. CONCLUSION: This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.
Subject(s)
Humans , Female , Sarcoma/genetics , Uterine Neoplasms/genetics , Carcinosarcoma/genetics , Brazil , MutationABSTRACT
El síndrome de Li Fraumeni (SLF) es una rara enfermedad hereditaria asociada con un riesgo incrementado de padecer ciertos tumores malignos. Presentamos el caso de una paciente con diagnóstico de SLF con antecedentes de sarcoma de glúteo con metástasis pulmonares y cáncer de mama bilateral metacrónico. Acudió al Servicio de Urgencias por distensión y dolor abdominal. Se objetivó una masa pélvica y se pensó en un probable origen ovárico de la misma. La paciente fue intervenida en el Servicio de Ginecología, y durante la intervención se descartó dicho origen ya que la tumoración dependía del epiplón. El diagnóstico final fue metástasis de sarcoma.
Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various malignant tumors. We present the case of a patient diagnosed LSF with a history of gluteal sarcoma with lung metastases and metachronous bilateral breast cáncer. She came to the emergency department for abdominal bloating and pain. She had a pelvic mass and we had thought probable ovarian dependence. The patient was operated on at the Department of Gynecology, and during the intervention we realized that the tumor depended on the omentum. The final diagnosis was a metastatic of sarcoma.
Subject(s)
Humans , Adult , Female , Peritoneal Neoplasms/surgery , Peritoneal Neoplasms/secondary , Sarcoma/surgery , Sarcoma/secondary , Li-Fraumeni Syndrome/pathology , Omentum/pathology , Peritoneal Neoplasms/genetics , Sarcoma/geneticsABSTRACT
Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prognosis. Sarcomatous change/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we established 4 human CC cell lines (SCK, JCK1, Cho-CK, and Choi-CK). In the present study, we characterized a typical sarcomatoid phenotype of SCK, and classified the other cell lines according to tumor cell differentiation (a poorly differentiated JCK, a moderately differentiated Cho-CK, and a well differentiated Choi-CK cells), both morphologically and immunocytologically. We further analyzed the genetic alterations of two tumor suppressor genes (p53 and FHIT) and the expression of Fas/FasL gene, well known CC-related receptor and its ligand, in these four CC cell lines. The deletion mutation of p53 was found in the sarcomatoid SCK cells. These cells expressed much less Fas/FasL mRNAs than did the other ordinary CC cells. We further characterize the gene expression pattern that is involved in the sarcomatous progression of CC, using cDNA microarrays that contained 18,688 genes. Comparison of the expression patterns between the sarcomatoid SCK cells and the differentiated Choi-CK cells enabled us to identify 260 genes and 247 genes that were significantly over-expressed and under-expressed, respectively. Northern blotting of the 14 randomly selected genes verified the microarray data, including the differential expressions of the LGALS1, TGFBI, CES1, LDHB, UCHL1, ASPH, VDAC1, VIL2, CCND2, S100P, CALB1, MAL2, GPX1, and ANXA8 mRNAs. Immunohistochemistry also revealed in part the differential expressions of these gene proteins. These results suggest that those genetic and gene expression alterations may be relevant to the sarcomatous change/EMT in CC cells.
Subject(s)
Animals , Female , Humans , Mice , Acid Anhydride Hydrolases/genetics , Cell Line, Tumor , Cholangiocarcinoma/genetics , Gene Expression Profiling , Mice, Inbred BALB C , Mutation , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis , Sarcoma/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
Los sarcomas primarios de mama son extremadamente raros y representan menos del 1% de lostumores mamarios comunicados en la literatura. Entre los años 1999 y 2004 se diagnosticaron ennuestra institución 1315 tumores malignos de mama, entre ellos nueve correspondieron a sarcomas primarios:tres angiosarcomas, un leiomiosarcoma, un sarcoma fibromixoide de bajo grado, un dermatofibrosarcoma, unliposarcoma, un osteosarcoma y un tumor maligno de la vaina de los nervios periféricos. Se revisaron los preparadoshistológicos, teñidos con técnicas de rutina y de inmunoperoxidasa, estableciéndose la fracción de crecimiento(FC) y sobre-expresión de proteína p53. Se estudiaron también las historias clínicas de las pacientespara determinar tipos de evolución (favorable y desfavorable). La incidencia observada (0.7%) es similar a lasya publicadas por otros autores. La FC se correlacionó con la evolución, siendo un factor pronóstico desfavorablecuando fue mayor o igual al 30%. La mayoría de los tumores (67%) mostró sobre-expresión de proteína p53(mayor o igual al 20% de tinción nuclear) pero esto no demostró tener una relación directa con la evolución decada neoplasia.
Primary sarcomas of the breast are extremely rare with less than1% of all malignant tumours of the breast reported in literature. At our Institution 1315 malignanttumours of the breast were diagnosed between 1999-2004; nine of them corresponded to primary sarcomas:angiosarcoma (3), leiomyosarcoma (1), low-grade fibromyxoid sarcoma (1), dematofibrosarcoma protuberans (1),liposarcoma (1), osteosarcoma (1), malignant peripheral nerve sheath tumour (1). Histopathological specimensstained with routine techniques and immunoperoxidase were reviewed; proliferation index and p53 over-expressionwere also determined. Patients´ clinical reports were also reviewed to determine prognosis (favorable andunfavorable). The incidence observed (0.7%) is similar to those already published by others authors. Proliferationindex was correlated with type of evolution, being an unfavourable prognosis factor when it was equal ormajor to 30%. Most of the tumours (67%) showed p53 (mayor or equal to 20% of nuclear staining) over-expressionbut this did not show a direct relationship with the evolution of each neoplasm.
Subject(s)
Humans , Female , Adult , Middle Aged , Breast Neoplasms/epidemiology , Sarcoma/epidemiology , Argentina/epidemiology , Biomarkers, Tumor , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Immunohistochemistry , Immunophenotyping , Incidence , Phenotype , Prevalence , Prognosis , Retrospective Studies , Sarcoma/genetics , Sarcoma/pathology , /genetics , /metabolismABSTRACT
Sarcomas de partes moles, como outros tumores humanos, são causados por mutações em genes supressores de tumores e oncogenes. Entre eles alguns, como p53 por exemplo, são freqüentemente detectados na forma mutatada em sarcomas e outros tumores humanos. De outro lado, há várias mutações altamente específicas para determinados sarcomas que podem servir como marcadores diagnósticos de alto valor. Exemplos de mutações de potencial diagnóstico incluem a translocação entre PAX3 e FKHR em rabdomiossarcoma alveolar, a translocação entre EWS e FLI-1 em tumores neuroectodérmicos periféricos primitivos e EWS e ATF-1 e sarcomas de células claras. Todas essas translocações podem ser detectadas por metodologias moleculares e que podem constituir um componente importante de repertório diagnóstico futuro.
Subject(s)
Humans , Child , Adolescent , Adult , Molecular Biology , Mutation/genetics , Sarcoma/diagnosis , Sarcoma/genetics , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/genetics , Genes, Tumor Suppressor/genetics , Genetic Markers , Oncogenes/genetics , Prognosis , Translocation, Genetic/geneticsABSTRACT
Ao longo do processo tumoral, algumas células evadem mecanismos de vigilância intra e extracelular. Essas células adquirem a capacidade de invadir tecidos e colonizar órgãos a distância caracterizando os processos de invasão e metastatização, que caracterizam o câncer. Aqui, revisamos alguns dos elementos que caracterizam o processo de disseminação tumoral, comparando sarcomas, carcinomas e melanomas. Ressaltamos a participação de elementos celulares normais do hospedeiro como moduladores do processo de invasão tumoral. Diferentemente de células tumorais, geralmente heterogêneas e geneticamente menos estáveis, as células do hospedeiro que modulam o processo de disseminação são geneticamente estáveis e fenotipicamente homogêneas. Discutimos a necessidade de se modificar o alvo de estratégias antitumorais, centrado na célula tumoral, ampliando-o para incluir os elementos celulares normais (vasos neoformados) e elementos do sistema imune-agentes moduladores da progressão tumoral.
Subject(s)
Humans , Neoplasm Metastasis/physiopathology , Neovascularization, Pathologic/physiopathology , Neovascularization, Physiologic , Sarcoma/genetics , Sarcoma/physiopathology , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/physiopathology , PrognosisABSTRACT
Family history of cancer and features of the Li-Fraumeni syndrome (LFS) were investigated in 42 patients with soft tissue sarcoma or osteosarcoma in a pediatric hospital in Mexico City, and compared with 42 non-cancer children. Six subjects with cancer were found among 204 first-degree relatives of cancer patients while there were none among 183 first-degree relatives of non-cancer children. In three families, the proband had two affected relatives, and the type of neoplasia as well as the age of onset suggested the clinical diagnosis of LFS. Our results show that 7.1 percent of our pediatric patients with soft tissue sarcoma or osteosarcoma may belong to LFS families. The authors encourage pediatric and adult oncologist to pay more attention to the history of cancer in nuclear families for eventual hereditary cancer syndrome identification and cancer prevention
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Adolescent , Adult , Bone Neoplasms/genetics , Osteosarcoma/genetics , Sarcoma/genetics , Li-Fraumeni Syndrome/genetics , Soft Tissue Neoplasms/geneticsABSTRACT
Pacientes menores de 16 anos, com diagnóstico de sarcoma do tipo desmóide atendidos no Hospital M.D. Anderson da Universidade do Texas pelo período de 1944 e 1975, foram revistos. A mortalidade esperada foi calculada aplicando-se as taxas de mortalidade específicas por idade, raça e sexo dos Estados Unidos sobre a mortalidade pessoa/ano de risco observado. A razäo da mortalidade padronizada - SMR - foi computada. Para o conjunto dos 429 parentes dos 26 casos de sarcoma do tipo desmóide aqui analisados, näo foi encontrado excesso de mortes, observado/esperado= 13/24.7. O risco dos pais terem câncer também näo foi significativo, observado/esperado= 2/1.83. Esses resultados säo indicativos de que as taxas de mortalidade por esse tipo de tumor, tanto para este grupo particular de famílias como para a populaçäo em geral, näo säo os parâmetros adequados para estudar fatores hereditários e ocorrência de tumores desmóides. Sugere-se a comparaçäo de taxas de incidência de tumores benignos em tecidos moles entre os membros da família dos casos com as taxas destes mesmos tumores na populaçäo em geral.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Genetics , Mortality , Sarcoma/genetics , Soft Tissue Neoplasms/genetics , United States , Retrospective StudiesABSTRACT
Foram estudados citogeneticamente o sarcoma dos pulmöes e os sintomas clínicos da síndrome de "Klinefelter's" em um homem branco de 20 anos de idade. Este paciente mostrou linhas múltiplas de células com constituiçäo cromossômica 49,XXYYY, 48,XXYY, 47XXY e 46,XY em sua primeira amostra de sangue. Na segunda amostra recebida um ano depois ele mostrou somente 49,XXYYY e 48,XXYY. Juntamente com este caso estudo, se apresenta uma revisäo da literatura mostrando anomalias constitucionais para certos neoplasmas humanos