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1.
Anticancer Res ; 40(7): 3811-3818, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620620

RESUMO

BACKGROUND/AIM: The objective of this study was to determine the molecular and clinicopathological features, as well as the prognosis of patients with endometrial cancer (EC) having prior malignancy (second primary EC: SPEC) compared with those without a history of prior malignancy (first primary EC: FPEC). MATERIALS AND METHODS: We enrolled 294 FPEC patients and 32 SPEC patients who had undergone surgical resection with curative intent. EC was divided into four groups according to Cancer Genome Atlas Research Network (TCGA) classification. RESULTS: SPEC patients having greater than a 10-year interval from prior malignancy had risk factors including type II histology, deeper myometrial invasion, cervical invasion, and copy number high (CNH) phenotype compared with patients having less than a 10-year interval (p=0.007, p=0.002, p=0.015 and p=0.001). CONCLUSION: SPEC patients having greater than a 10-year interval from prior malignancy possessed numerous high-risk factors for EC.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Idoso , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/cirurgia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imuno-Histoquímica , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/cirurgia , Prognóstico
2.
Int J Hematol ; 112(4): 524-534, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32588395

RESUMO

Programmed death 1 ligand (PD-L1) is an immunomodulatory molecule expressed by cancer cells, and it has been widely demonstrated to inhibit host antitumor responses. The aim of the present study was to identify clinicopathological features associated with PD-L1 expression in the secondary solid cancers of patients after allogeneic hematopoietic stem cell transplantation. In this database of 530 patients who received allo-HSCT between 1990 and 2017, 15 developed solid cancers with a median interval of 3487 days after transplantation. Three patients had 2 different solid cancers. Eighteen solid cancer cases were identified. A multivariate analysis showed that chronic graft-versus-host disease (GVHD) was associated with an increased risk of solid cancer. The presence of chronic GVHD was observed in 8 out of 18 cases at the diagnosis of secondary malignancies. PD-L1 expression levels in cancers were significantly higher in patients with active chronic GVHD than in those without chronic GVHD (P = 0.020). Five cases of cancer that developed in the involved organs of chronic GVHD showed 30% or higher PD-L1 positivity. The present results revealed distinct PD-L1 expression in the secondary solid cancers of post-transplant patients with chronic GVHD.


Assuntos
Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Expressão Gênica , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Transplante Homólogo , Adulto Jovem
3.
Int J Clin Oncol ; 25(9): 1644-1652, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32430733

RESUMO

BACKGROUND: Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection. METHODS: Patient's clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan-Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated. RESULTS: In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively). CONCLUSIONS: Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Segunda Neoplasia Primária/patologia , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
4.
Eur J Cancer ; 133: 47-55, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434110

RESUMO

BACKGROUND: Patients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy. METHODS: From 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma. RESULTS: SPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3-11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0-11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5-13.8] vs. IR 3.2 [95% CI: 1.0-7.5]; p < 0.05). In the subgroup without previous radiotherapy SPM were only observed in patients with regular penetrance variants (IR 6.3 [95% CI: 3.0-11.5]). Carriers of incomplete penetrance variants developed similar tumour entities as those with regular penetrance. CONCLUSIONS: Patients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.


Assuntos
Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Neoplasias da Retina/genética , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/genética , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/terapia , Retinoblastoma/epidemiologia , Retinoblastoma/terapia , Adulto Jovem
5.
Hematology ; 25(1): 176-180, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32345147

RESUMO

Objectives: Multiple myeloma (MM) often develops as a secondary primary malignancy (SPM). The retinoblastoma susceptibility gene (RB1) was the first tumour suppressor gene to be identified. We pooled and analyzed available data to compare the incidence of RB1 gene deletions and other cytogenetic abnormalities in patients with MM alone or as an SPM.Methods: We conducted a retrospective study of 475 patients. The experimental group comprised 18 patients with MM as an SPM, and the control group comprised 457 MM patients. We analyzed the baseline information in both groups, and used the odds ratio (OR), 95% confidence interval (CI), and forest plot to determine the incidence of SPMs with and without cytogenetic abnormalities.Results: The incidence of RB1 gene deletion was higher in the experimental group. There was no significant difference in other cytogenetic abnormalities.Conclusions: RB1 gene deletions appear to be associated with MM that develops as an SPM.


Assuntos
Aberrações Cromossômicas , Mieloma Múltiplo/genética , Segunda Neoplasia Primária/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Nat Commun ; 11(1): 1894, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313009

RESUMO

Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Segunda Neoplasia Primária/genética , Neoplasias Uveais/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Dosagem de Genes , Técnicas de Silenciamento de Genes , Humanos , Linfócitos , Linfócitos do Interstício Tumoral/patologia , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mutação , Segunda Neoplasia Primária/imunologia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Prognóstico , Análise de Sequência de DNA , Transcriptoma , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/imunologia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia
7.
Diagn Pathol ; 15(1): 24, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32169099

RESUMO

BACKGROUND: Malignant eccrine spiradenoma is one of the rarest sweat-gland tumors. Here, we describe a rare case of low grade malignant eccrine spiradenoma located at the vulva. CASE PRESENTATION: The vulvar lesion was described as a mass measured 3.5 cm and located in the dermis and subcutis with no attachment to the epidermis. The neoplasm was arranged in ragged sheets or solid nodules sometimes with focal necrosis. The tumor cells had hyperchromatism, pleomorphism, and prominent nucleoli with high mitotic index and KI-67 estimated at 70-80%. CONCLUSIONS: It's only the fifth case of malignant eccrine spiradenoma localized at the vulva. This is the first time that an HPV genotyping was made in this type of lesion with no HPV found while the p16 expression was diffuse. Moreover, it's the first time that a p53 mutation is detected by sequencing in this location.


Assuntos
Acrospiroma/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Proteína Supressora de Tumor p53/genética , Neoplasias Vulvares/patologia , Acrospiroma/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Papillomaviridae , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias Vulvares/genética
8.
PLoS One ; 15(2): e0228887, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040538

RESUMO

BACKGROUND: Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes. METHODS: We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets. RESULTS: The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004). CONCLUSIONS: Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.


Assuntos
Segunda Neoplasia Primária/genética , Proteínas de Ligação a Telômeros/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Sobreviventes de Câncer , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Humanos , Incidência , Íntrons , Estudos Longitudinais , Masculino , Segunda Neoplasia Primária/epidemiologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Fatores de Risco , Homeostase do Telômero/genética , Neoplasias da Glândula Tireoide/epidemiologia
10.
Ann Hematol ; 99(3): 487-500, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006151

RESUMO

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.


Assuntos
Proteína de Ligação a CREB/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Factuais , Neoplasias Hematológicas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária , Proteínas de Fusão Oncogênica/genética , Inibidores da Topoisomerase II/administração & dosagem , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Medição de Risco
11.
Pathologe ; 41(1): 70-72, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-31938820

RESUMO

A 37-year-old patient presented with B symptoms. On examination, hypodense liver lesions, multiple enlarged and partly confluent lymph nodes in the upper abdomen and retroperitoneum, as well as disseminated splenic and pulmonary foci were detected. Biopsies of a tumor in the coecum and the liver led to the diagnosis of an adenocarcinoma of the colon. In molecular pathology, microsatellite instability was detected. The post-neoadjuvant surgical specimen showed an unusual morphology and the question arose whether a second tumor should be considered.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias do Colo/diagnóstico , Neoplasias Hepáticas/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Adenocarcinoma/genética , Adulto , Neoplasias do Colo/genética , Humanos , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Terapia Neoadjuvante , Segunda Neoplasia Primária/genética
12.
J Cutan Pathol ; 47(1): 12-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31449665

RESUMO

The association of syringocystadenoma papilliferum (SCAP) with verrucous carcinoma (VC) of the skin in the same lesion is a rare, but well-documented event. Although human papillomaviruses (HPV) have been proposed to have an etiologic role in the development of the verrucous proliferations associated with SCAP, most of the immunohistochemical and molecular studies have failed to show the presence of their genomic material in these lesions. We report a series of four cases of SCAP associated with VC in anogenital lesions. In two of the cases, we demonstrated the presence of the BRAF V600E mutation by polymerase chain reaction and immunohistochemistry, both in the glandular and in the squamous component. No HPV-related histopathologic changes were found, nor could the presence of viral DNA be showed.


Assuntos
Carcinoma Verrucoso , Mutação de Sentido Incorreto , Segunda Neoplasia Primária , Proteínas Proto-Oncogênicas B-raf , Neoplasias das Glândulas Sudoríparas , Adenomas Tubulares de Glândulas Sudoríparas , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Carcinoma Verrucoso/genética , Carcinoma Verrucoso/metabolismo , Carcinoma Verrucoso/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/metabolismo , Neoplasias das Glândulas Sudoríparas/patologia , Adenomas Tubulares de Glândulas Sudoríparas/genética , Adenomas Tubulares de Glândulas Sudoríparas/metabolismo , Adenomas Tubulares de Glândulas Sudoríparas/patologia
13.
Int J Surg Pathol ; 28(2): 225-228, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31559875

RESUMO

Pleomorphic myxoid liposarcoma is an extremely rare, clinically aggressive subtype of liposarcoma that has been primarily reported in young patients. In this article, we report a case of a pleomorphic myxoid liposarcoma that presented as a second primary neoplasm in a 34-year-old man with history of primary mediastinal large B-cell lymphoma. During the clinical workup, the patient was diagnosed with a germline TP53 gene mutation and Li-Fraumeni syndrome. The tumor, a 2.9 × 2.3 × 2.0 cm well-demarcated and solid mass, was centered in the anterior chest wall soft tissue. Histologically, most of the tumor displayed abundantly myxoid stroma, low cellularity of mostly bland spindle cells, delicate branching capillaries, and lipoblasts; these areas transitioned to small areas whose features were reminiscent of pleomorphic liposarcoma. As assessed by fluorescence in situ hybridization, the tumor showed no DDIT3 (CHOP) (12q13) rearrangements or MDM2 gene amplification. Clinically, the tumor progressed with multiple recurrences and metastasis to the humerus bone. To our knowledge, this is the first case of pleomorphic myxoid liposarcoma diagnosed in an adult with Li-Fraumeni syndrome.


Assuntos
Síndrome de Li-Fraumeni/complicações , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Adulto , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Neoplasias do Mediastino/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
14.
J Pediatr Hematol Oncol ; 42(4): e258-e261, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31343482

RESUMO

T-cell therapy-related acute lymphoblastic leukemia (T-t-ALL) is a rare condition associated with previous cytotoxic therapy for another disease. Here we report T-t-ALL with inv(11)(q21q23), which involves KMT2A and MAML2, a transcriptional coactivator of NOTCH proteins, that occurred after chemotherapy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. This case describes the youngest patient with T-t-ALL harboring inv(11)(q21q23) and is the first independent report following an initial series also occurring in children. Our results lend further support to the observation that the KMT2A-MAML2 fusion gene resulting from inv(11)(q21q23) is likely a recurrent cytogenetic abnormality in T-t-ALL and appears to be associated with pediatric cases.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 11 , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transativadores/genética , Pré-Escolar , Humanos , Masculino , Segunda Neoplasia Primária/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia
15.
J Pediatr Hematol Oncol ; 42(4): 302-306, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30499911

RESUMO

We report on a 16-year-old Japanese boy in whom an esophageal squamous cell carcinoma (ESCC) developed 12 years after allogeneic hematopoietic stem cell transplantation was performed for aplastic anemia. A high frequency of microsatellite instability was detected in samples of ESCC. Moreover, the detection of pathogenic variants, including single nucleotide substitution of TP53 (c.346C>T) and BRCA2 (c.6952C>T) and splicing of KDM6A (c.1194+2T>G), suggest that the development of ESCC in the patient was triggered by impairment of checkpoint and repair for DNA damage and epigenetic modification through accumulation of gene mutations induced by chronic graft-versus-host disease and prolonged administration of tacrolimus.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Transplante de Células-Tronco Hematopoéticas , Instabilidade de Microssatélites , Segunda Neoplasia Primária , Mutação Puntual , Adolescente , Aloenxertos , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Anemia Aplástica/terapia , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Masculino , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Leukemia ; 34(3): 811-820, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31719678

RESUMO

Therapy-related myeloid neoplasms (tMN) following successful treatment of acute myeloid leukemia (AML) are rare and poorly characterized. To evaluate the presence of a common ancestral clone, we performed whole-exome sequencing of 25 patients at AML diagnosis, tMN diagnosis (tMDS: 13; tAML: 12), and matched remission samples, identifying 607 mutations affecting 504 different genes (46 recurrently mutated). Number of mutations was higher in tAML vs. tMDS cases (median 19 vs 13 mutations, p = 0.05). Focusing on 24 genes commonly mutated in hematological malignancies, 19/25 (76%) patients were found to share mutations between AML and tMN, mostly affecting epigenetic modifiers (21/32; 66%), splicing factors (6/32; 19%), and chromatin modifiers (3/32; 9%). Analysis of remission samples identified 13 persisting mutations in 10/22 patients, affecting DNMT3A (n = 6), TET2 (n = 5), IDH1 and SRSF2 (n = 1, each). Comparison of cytogenetics revealed that 9/12 patients with a normal karyotype (NK) in AML harbored aberrations in tMN, four aberrant AML cases presented with NK in tMN, four other patients showed unrelated cytogenetic aberrations. Our study provides novel insights into the pathogenesis of tMN, hypothesizing the presence of a common ancestral clone in AML and tMN. Mutations mostly affected epigenetic modifiers, which have previously been linked to clonal hematopoiesis.


Assuntos
Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Segunda Neoplasia Primária/complicações , Segunda Neoplasia Primária/genética , Adulto , Idoso , Cromatina/metabolismo , Aberrações Cromossômicas , Exoma , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Indução de Remissão , Resultado do Tratamento
17.
Cancer Res ; 80(2): 347-353, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31719099

RESUMO

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families = 189; single primary cancer (SPC) = 771; and MPC = 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC = 102 and MPC = 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1-2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. SIGNIFICANCE: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.See related article by Shin et al., p. 354.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Modelos Genéticos , Segunda Neoplasia Primária/genética , Penetrância , Adolescente , Adulto , Criança , Pré-Escolar , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Aconselhamento Genético/métodos , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Lactente , Recém-Nascido , Síndrome de Li-Fraumeni/diagnóstico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Valor Preditivo dos Testes , Medição de Risco/métodos , Software , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Adulto Jovem
18.
Am J Clin Oncol ; 43(4): 263-269, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876540

RESUMO

BACKGROUND: Early onset colorectal cancer in persons younger than 50 years is increasingly common. Clinical and molecular characterizations reveal a distinctive disease. Thirty percent of patients have mutations of hereditary cancer syndromes, especially Lynch syndrome. A recent analysis, testing germline DNA for mutations in 25 cancer susceptibility genes, showed that some patients younger than 50 years had mutations of high-penetrance colorectal cancer genes such as APC (adenopolyposis coli). Others had mutations in high-penetrance or moderate-penetrance genes not traditionally associated with colorectal cancer, such as ATM (ataxia telangiectasia mutated), whereas still others had low penetrance colorectal cancer genes. In the current study, we examined the incidence of second cancers following early onset (age less than 50 y) colorectal cancer. METHODS: The initial study population was assembled using records from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER*Stat MP-SIR (multiple primary-standardized incidence ratio) tool was used to calculate SIRs and excess risk for second primary malignancies. The SIR is expressed as the ratio of observed-to-expected (O/E) cases. We used The Cancer Genome Atlas (TCGA) and AACR Project Genie for genetic analysis. The data were accessed with the online Xena Browser and cBioportal. RESULTS: Acute myelogenous leukemia (AML) O/E ratios were significantly >1 in patients aged less than 50 years, at 12 to 59 months after colorectal cancer. In patients aged 50 years and older, O/E ratios were equal to 1 or quite close at 12 to 59 months after colorectal cancer. Alterations in 3 AML genes, CEBPA-AS1, MLLT1, and MLLT6, affected the prognosis of colorectal cancer patients less than 50 years but not older than 50 years. One AML gene, FLT3, had the highest copy number alteration frequency of any gene in 1438 colorectal patients 18 to 48 years of age. Genetic alterations of FLT3/TP53 were mutually exclusive. Genetic alterations of FLT3/JAK2 and JAK2/CTNNB1 were co-occurrent. CONCLUSION: These observations suggest that early onset colorectal cancer and AML may be related diseases.


Assuntos
Neoplasias Colorretais/genética , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Mutação , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Adulto Jovem
19.
Mutat Res ; 847: 403032, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31699349

RESUMO

Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.


Assuntos
Aneuploidia , Carcinogênese/genética , Carcinógenos/toxicidade , Instabilidade Cromossômica , Testes de Mutagenicidade/métodos , Neoplasias/induzido quimicamente , Animais , Centrossomo , Transtornos Cromossômicos/genética , Cromossomos/efeitos dos fármacos , Síndrome de Down/complicações , Síndrome de Down/genética , Predisposição Genética para Doença , Humanos , Camundongos , Modelos Animais , Testes de Mutagenicidade/normas , Mutagênicos/toxicidade , Neoplasias/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Fuso Acromático/efeitos dos fármacos , Moduladores de Tubulina/toxicidade
20.
Genes (Basel) ; 10(11)2019 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-31717496

RESUMO

National cancer databases document that melanoma is the most aggressive and deadly cutaneous malignancy with worldwide increasing incidence in the Caucasian population. Around 10% of melanomas occur in families. Several germline mutations were identified that might help to indicate individuals at risk for preventive interventions and early disease detection. More than 50% of sporadic melanomas carry mutations in Ras/Raf/mitogen-activated protein kinase (MAPK/MEK) pathway, which may represent aims of novel targeted therapies. Despite advances in targeted therapies and immunotherapies, the outcomes in metastatic tumor are still unsatisfactory. Here, we review animal models that help our understanding of melanoma development and treatment, including non-vertebrate, mouse, swine, and other mammal models, with an emphasis on those with spontaneously developing melanoma. Special attention is paid to the melanoma-bearing Libechov minipig (MeLiM). This original swine model of hereditary metastatic melanoma enables studying biological processes underlying melanoma progression, as well as spontaneous regression. Current histological, immunohistochemical, biochemical, genetic, hematological, immunological, and skin microbiome findings in the MeLiM model are summarized, together with development of new therapeutic approaches based on tumor devitalization. The ongoing study of molecular and immunological base of spontaneous regression in MeLiM model has potential to bring new knowledge of clinical importance.


Assuntos
Melanoma/genética , Neoplasias Cutâneas/genética , Porco Miniatura/genética , Animais , Modelos Animais de Doenças , Progressão da Doença , Segunda Neoplasia Primária/genética , Suínos/genética
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