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PURPOSE: To retrospectively evaluate the diagnostic potential of magnetic resonance imaging (MRI)-based features and radiomics analysis (RA)-based features for discriminating ovarian clear cell carcinoma (CCC) from endometrioid carcinoma (EC). MATERIALS AND METHODS: Thirty-five patients with 40 ECs and 42 patients with 43 CCCs who underwent pretherapeutic MRI examinations between 2011 and 2022 were enrolled. MRI-based features of the two groups were compared. RA-based features were extracted from the whole tumor volume on T2-weighted images (T2WI), contrast-enhanced T1-weighted images (cT1WI), and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation method was performed to select features. Logistic regression analysis was conducted to construct the discriminating models. Receiver operating characteristic curve (ROC) analyses were performed to predict CCC. RESULTS: Four features with the highest absolute value of the LASSO algorithm were selected for the MRI-based, RA-based, and combined models: the ADC value, absence of thickening of the uterine endometrium, absence of peritoneal dissemination, and growth pattern of the solid component for the MRI-based model; Gray-Level Run Length Matrix (GLRLM) Long Run Low Gray-Level Emphasis (LRLGLE) on T2WI, spherical disproportion and Gray-Level Size Zone Matrix (GLSZM), Large Zone High Gray-Level Emphasis (LZHGE) on cT1WI, and GLSZM Normalized Gray-Level Nonuniformity (NGLN) on ADC map for the RA-based model; and the ADC value, spherical disproportion and GLSZM_LZHGE on cT1WI, and GLSZM_NGLN on ADC map for the combined model. Area under the ROC curves of those models were 0.895, 0.910, and 0.956. The diagnostic performance of the combined model was significantly superior (p = 0.02) to that of the MRI-based model. No significant differences were observed between the combined and RA-based models. CONCLUSION: Conventional MRI-based analysis can effectively distinguish CCC from EC. The combination of RA-based features with MRI-based features may assist in differentiating between the two diseases.
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Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Imageamento por Ressonância Magnética , Neoplasias Ovarianas , Humanos , Feminino , Estudos Retrospectivos , Diagnóstico Diferencial , Neoplasias Ovarianas/diagnóstico por imagem , Pessoa de Meia-Idade , Carcinoma Endometrioide/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adenocarcinoma de Células Claras/diagnóstico por imagem , Idoso , Adulto , Meios de Contraste , Neoplasias do Endométrio/diagnóstico por imagem , RadiômicaRESUMO
BACKGROUND: Superoxide dismutase (SOD) is an antioxidant enzyme that degrades superoxide, a major causative factor in carcinogenesis. We assessed associations between serum SOD activities and incidence of colorectal carcinoma (CRC) in a case-control study nested in the Japan Collaborative Cohort (JACC) study. METHODS: At baseline, 39,242 subjects donated serum samples. Participants diagnosed with CRC during follow-up were regarded as cases. Odds ratios (ORs) for CRC incidence associated with SOD were evaluated with conditional logistic regression models. In the current study, 176 cases and 524 controls were analyzed. RESULTS: For the overall cohort, a decreasing trend in risk of CRC with increasing SOD was observed (P for trend=0.054) and the fourth quartile of SOD level showed the lowest risk compared to the first (OR=0.52, 95% confidence interval [CI]=0.29-0.93). This was significant in men (P for trend=0.001), with the fourth quartile of SOD level showing the lowest risk compared to the first (OR, 0.23; 95%CI, 0.09-0.60). It was also exclusively observed for rectal cancer and left-sided CRC (P for trend, 0.037 and 0.020, respectively), with the fourth quartile again showing the lowest risk compared to the first (OR, 0.28 and 0.38; 95%CI, 0.09-0.84 and 0.16-0.91, respectively). Limiting subjects to those followed-up over 2 years, all trends remained unchanged. CONCLUSIONS: Our findings suggest that serum SOD activity correlates inversely with risk of CRC, particularly in men and individuals with rectal cancer/left-sided CRC.
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Neoplasias Colorretais , Neoplasias Retais , Masculino , Humanos , Incidência , Estudos de Casos e Controles , Fatores de Risco , Superóxido Dismutase , Neoplasias Colorretais/epidemiologiaRESUMO
BACKGROUND: Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case-control study nested in the Japan Collaborative Cohort Study. METHODS: A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographic area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with sFas. RESULTS: This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (Ptrend = 0.003) and the third tertile of sFas showed a higher risk compared with the first tertile [OR, 3.53; 95% confidence interval (CI), 1.28-9.69]. In hepatocellular carcinoma, high sFas was associated with elevated risk (Ptrend < 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (Ptrend = 0.033) and the third tertile showed a higher risk compared with the first (OR, 2.94; 95% CI, 0.94-9.14). CONCLUSIONS: High serum sFas may be related to future risk of liver cancer. IMPACT: Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.
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Neoplasias Hepáticas , Masculino , Humanos , Idoso , Estudos de Coortes , Estudos de Casos e Controles , Incidência , Neoplasias Hepáticas/epidemiologia , BiomarcadoresRESUMO
Intrahepatic mucinous cholangiocarcinoma (IHMC) is rare and behaves notoriously; however, the details of the clinicopathological characteristics of IHMC remain unknown. A 70-year-old man was admitted for examination of the hepatic mass in the S1 segment. He underwent extended left hepatic lobectomy. Histopathological evaluation demonstrated mixed papillary carcinoma that comprised well to moderately differentiated tubular adenocarcinoma and signet-ring cell carcinoma with large amounts of mucus lakes. Tumor was relapsed 9 months after surgery. Although he received chemotherapy with the combination of gemcitabine and cisplatin, he had renal failure and discontinued the chemotherapy. He received palliative radiotherapy for metastasis in the cervical spine. Then, the patient treated with S-1, however, he died 16 months after the initial diagnosis. The autopsy findings showed multiple nodules in the lungs, pleura, kidneys, adrenal glands, stomach, pancreas, and lymph nodes. Histological examination revealed that all nodules were IHMC. Next-generation sequencing revealed that somatic mutations in ADGRB3, TAF1L and EPHA3 may affect carcinogenesis, and those in TAF1, EPHA3, PIK3C2B, FN1, ERBB3, BRIP1, SYNE1 and TGFBR2 may affect metastasis. Molecular carcinogenesis of IHMC may be distinct from that of ordinary cholangiocarcinoma. Further studies are needed to elucidate the genetic mutations and their functions in IHMC.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Idoso , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Carcinogênese/patologia , Colangiocarcinoma/cirurgia , Genômica , Humanos , MasculinoRESUMO
Purpose: It is unknown whether surgery for endometriosis or recurrence of endometriosis affects obstetric outcomes. Methods: A total of 208 pregnant women with a history of endometriosis were analyzed. Patients who had endometriomas >3 cm and no history of laparoscopic surgery for endometriosis were defined as non-surgery group (n = 60), while those who had a history of surgery for endometriosis (n = 148) were defined as surgery group. We investigated the obstetric outcomes in 208 patients according to with or without postoperative recurrence of endometriosis and the time from surgery to pregnancy. Results: Among 177 cases of on-going pregnancy, in surgery group, there were lower prevalence of placenta previa compared with non-surgery group (8.5% vs. 23.4%; p = 0.020). Subgroup analysis revealed a decreased prevalence of placenta previa in postoperative non-recurrence group (6.0%: p = 0.007) compared with non-surgery (23.4%) and postoperative recurrence group (28.6%). Placenta previa was more prevalent in the patients who got pregnant more than 2 years after surgery (20.0%) than the patients who got pregnant within 2 years (2.4%: p = 0.002). Multivariate analysis revealed that the surgery was associated with a reduction in placenta previa (OR: 0.32, 95% CI [0.11-0.90]; p = 0.032). Conclusions: Pregnancy within two years after laparoscopic surgery for endometriosis may reduce placenta previa.
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There is no useful biomarker to evaluate treatment response and early relapse in head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual diseases and monitoring treatment effect. We investigated whether individualized ctDNA analysis could help monitor treatment response and relapse in HNSCC. Mutation analysis of tumor and peripheral blood mononuclear cell (PBMC) DNAs of 26 patients with HNSCC was performed using a custom squamous cell carcinoma (SCC) panel. The identified individualized mutated genes were defined as ctDNA candidates. We investigated whether frequent ctDNA monitoring via digital PCR (dPCR) is clinically valid for HNSCC patients. TP53 was the most frequently mutated gene and was detected in 14 of 24 cases (58.2%), wherein two cases were excluded owing to the absence of tumor-specific mutations in the SCC panel. Six cases were excluded because of undesignable and unusable primer-probes for dPCR. Longitudinal ctDNA was monitored in a total of 18 cases. In seven cases, ctDNA tested positive again or did not test negative, and all seven cases relapsed after initial curative treatment. In 11 cases, after initial curative treatment, ctDNA remained negative and patients were alive without recurrence. Patients who remained negative for ctDNA during follow-up after initial curative treatment (n = 11) had a significantly better prognosis than those who reverted to ctDNA positivity (n = 7; p < 0.0001; log-rank test). Individualized ctDNA monitoring using SCC panel and dPCR might be a novel and promising biomarker for HNSCC.
Assuntos
Carcinoma de Células Escamosas , DNA Tumoral Circulante , Neoplasias de Cabeça e Pescoço , Humanos , DNA Tumoral Circulante/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Leucócitos Mononucleares , DNA de Neoplasias/genética , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Mutação , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genéticaRESUMO
Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.
Assuntos
Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/patologia , RNA Longo não Codificante/metabolismo , Antígenos de Diferenciação/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Genes Neoplásicos , Código das Histonas , Humanos , Interferons/metabolismo , Neoplasias Bucais/metabolismo , Fosforilação , RNA Longo não Codificante/fisiologia , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/metabolismo , Regulação para CimaRESUMO
We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.
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Antineoplásicos/uso terapêutico , DNA Tumoral Circulante/sangue , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase/métodos , Resultado do TratamentoRESUMO
Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.
Assuntos
Mutação/genética , Tolerância a Radiação/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA/métodos , Feminino , Humanos , Inflamação/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Smad4/genéticaAssuntos
DNA Tumoral Circulante/sangue , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Biomarcadores Tumorais/sangue , Humanos , Reação em Cadeia da Polimerase , Carga TumoralRESUMO
OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.
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Adenocarcinoma/genética , Carcinoma Adenoescamoso/genética , Carcinoma de Células Escamosas/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapiaRESUMO
Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.
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Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Variação Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Resultado do Tratamento , Sequenciamento do ExomaRESUMO
RATIONALE: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test. PATIENT CONCERNS: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes. DIAGNOSIS: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease. INTERVENTIONS: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy. OUTCOMES: The patient continues to exhibit a complete response. LESSONS: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.
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Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Rituximab/uso terapêutico , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/tratamento farmacológico , Idoso , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/cirurgia , Mutação , Indução de Remissão , Esplenectomia , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/cirurgiaRESUMO
The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal- and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear ß-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Neoplasias Duodenais/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Mutação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Variações do Número de Cópias de DNA , Metilação de DNA , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/patologia , Duodeno/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Formalin-fixed paraffin-embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We analyzed 50 cancer-related gene mutations including driver genes in PDAC, using next-generation sequencing (NGS) to clarify the association between gene mutations and prognosis. DNA was extracted from FFPE tissues obtained from 74 patients with untreated resectable PDAC who underwent surgery at our institution between 2013 and 2018. Fifty of the 74 patients with DNA extracts from FFPE samples suitable for NGS were analyzed. The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A. There were no cases of single SMAD4 mutations; its rate of coincidence with KRAS or TP53 mutations was 30% and 2%, respectively. The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse-free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P = .014) and overall survival (OS; MST, 22.3 months vs. not reached, P = .048). On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77-10.08; P = .001) and OS (HR 6.730; 95% CI, 1.93-23.43; P = .003). The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.
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Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Smad4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Análise Mutacional de DNA/métodos , Feminino , Formaldeído , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/mortalidade , Inclusão em Parafina , Prognóstico , Fixação de TecidosRESUMO
Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25-30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.
Assuntos
Manchas Café com Leite/genética , Mosaicismo , Neoplasias Primárias Múltiplas/genética , Neurofibroma Plexiforme/genética , Neurofibromatose 1/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/patologia , Criança , Análise Mutacional de DNA , Feminino , GTP Fosfo-Hidrolases/genética , Testes Genéticos , Humanos , Proteínas de Membrana/genética , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/patologia , Neurofibroma Plexiforme/diagnóstico , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear ß-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Mutação , Via de Sinalização Wnt/genética , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Osteonectina/genética , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.