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Background: The diffuse sclerosing variant (DSV) is among the aggressive variants of papillary thyroid carcinoma (PTC) and is more prevalent in pediatric patients than in adult patients. Few studies have assessed its characteristics owing to its low incidence. We aimed to evaluate the relationship between recurrence and age in the DSV of PTC. Methods: We retrospectively reviewed patients diagnosed with the DSV or conventional PTC (cPTC) after surgery at a medical center between May 1988 and January 2019. We compared the clinico-pathological characteristics and surgical outcomes of the DSV and cPTC groups and between adult and pediatric patients with DSV. Results: Among the 24,626 patients, 202 had the DSV, and 24,424 were diagnosed with cPTC. The recurrence rate was significantly higher in the DSV group than in the cPTC group. In the DSV group, the recurrence rate was significantly higher in the pediatric patient group than in the adult patient group. Moreover, the association between recurrence and age group showed different patterns between the DSV and cPTC groups with restricted cubic splines (RCS). While both RCS curves showed a U-shaped distribution, the RCS curve tended to be located within the younger age group. Conclusions: This study demonstrated that pediatric patients with DSV are at a greater risk for recurrence compared with adult patients; moreover, the pattern of recurrence risk according to age is different from that of cPTC.
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Recidiva Local de Neoplasia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Feminino , Masculino , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/epidemiologia , Criança , Adulto , Adolescente , Fatores Etários , Pessoa de Meia-Idade , Adulto Jovem , Pré-Escolar , Prognóstico , Tireoidectomia , Idoso , Seguimentos , Relevância ClínicaRESUMO
We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.
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Antígeno B7-H1 , Biomarcadores Tumorais , Neoplasias Primárias Desconhecidas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Primárias Desconhecidas/metabolismo , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Adulto , Imuno-Histoquímica , Análise Serial de Tecidos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologiaRESUMO
BACGROUND: Breast phyllodes tumors (BPTs) are difficult to differentiate from other tumor types. In-depth research is needed due to the insufficient description of the amine oxidase protein family, particularly in BPTs. OBJECTIVE: This study investigated the expression and clinical implications of amine oxidase-related proteins in BPTs. METHODS: Tissue microarrays were constructed (n=181), and amine oxidase-related proteins of monoamine oxidase (MAO) A, MAOB, lysyl oxidase (LOX), and primary-amine oxidase 3 (AOC3) were assessed using immunohistochemical staining. Staining patterns of these proteins were compared and analyzed with clinicopathologic parameters. RESULTS: In all, 149, 27, and 5 cases were classified as benign, borderline, and malignant, respectively. A higher grade of BPT was associated with increased MAOB (p<0.001), LOX (p=0.035), and AOC3 (p<0.001) expression. BPT cases with tumor recurrence and distant metastasis had higher proportions of MAOB positivity in stromal components (P=0.002 and 0.018, respectively). During follow-up, there was a significant association between MAOB positivity in the stromal component and shorter disease-free survival (DFS) (P=0.001) as well as overall survival (P=0.003). Moreover, MAOB positivity emerged as an independent factor for shorter DFS (hazard ratio: 4.253, 95% confidence interval: 1.034-17.49, P=0.045). CONCLUSIONS: Higher MAOB, LOX, and AOC3 expression were observed in higher-grade BPTs, and MAOB expression was identified as a significant prognostic factor.
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The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader implications of this. Tissue microarrays were constructed for 132 cases of adrenal cortical neoplasms (ACN) (adrenal cortical adenoma (115 cases), and carcinoma (17 cases)) and 189 cases of pheochromocytoma. Immunohistochemical staining was performed to identify EMP 1, 2, and 3, and was compared with clinicopathological parameters. The H-score of EMP 3 (p < 0.001) was higher in pheochromocytoma when compared to that of ACN, and the H-score of EMP 1 (p < 0.001) and EMP 3 (p < 0.001) was higher in adrenal cortical carcinomas when compared to that of adrenal cortical adenomas. A higher EMP 1 H-score was observed in pheochromocytomas with a GAPP score ≥3 (p = 0.018). In univariate analysis, high levels of EMP 1 and EMP 3 expression in ACN were associated with shorter overall survival (p = 0.001). Differences were observed in the expression of EMPs between ACN and pheochromocytoma. EMPs are associated with malignant tumor biology in adrenal cortical neoplasm and pheochromocytoma, suggesting the role of a prognostic and/or predictive factor for EMPs in adrenal tumor.
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Neoplasias do Córtex Suprarrenal , Neoplasias das Glândulas Suprarrenais , Adenoma Adrenocortical , Carcinoma Adrenocortical , Feocromocitoma , HumanosRESUMO
We delved into the expression of amine oxidase family proteins and their potential significance in adrenal gland neoplasm. Tissue microarrays were prepared for 132 cases of adrenal cortical neoplasm (ACN) consisting of 115 cases of adrenal cortical adenoma (ACA), 17 cases of adrenal cortical carcinoma (ACC), and 163 cases of pheochromocytoma (PCC). Immunohistochemical stainings for MAOA, MAOB, LOX, and AOC3 were performed to evaluate the H-scores and compare them with clinicopathological parameters. The H-scores of MAOA (T; p = 0.005) and MAOB (T; p = 0.006) in tumor cells (T) were high in ACN, whereas LOX (T, S; p < 0.001) in tumor and stromal cells (S) and AOC3 (T; p < 0.001) were higher in PCC. In stromal cells, MAOA (S; p < 0.001) and AOC3 (S; p = 0.010) were more expressed in ACA than in ACC. MAOB (S) in PCC showed higher H-scores when the grading of adrenal pheochromocytoma and paraganglioma (GAPP) score was 3 or higher (p = 0.027). In the univariate analysis, low MAOA expression in stromal cells of ACN was associated with shorter overall survival (p = 0.008). In conclusion, monoamine oxidase proteins revealed differences in expression between ACN and PCC and also between benign and malignant cells.
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BACKGROUND: Phyllodes tumor (PT) is a relatively rare breast tumor, accounting for <1% of all breast tumors. MAIN BODY: Adjuvant therapy with chemotherapy or radiation therapy, other than surgical excision, has not been established yet. PT, similar to other breast tumors, is classified as benign, borderline, and malignant according to the World Health Organization classification system, depending on stromal cellularity, stromal atypia, mitotic activity, stromal overgrowth, and tumor border. However, this histological grading system cannot effectively or fully reflect the clinical prognosis of PT. Several studies have investigated prognostic factors for PT as some PTs recur or metastasize to distant sites, and thus, prediction of prognosis is clinically imperative. CONCLUSION: This review discusses clinicopathological factors, immunohistochemical markers, and molecular factors that have been investigated in previous studies to have an impact on the clinical prognosis of PT.
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Neoplasias da Mama , Tumor Filoide , Humanos , Feminino , Tumor Filoide/diagnóstico , Prognóstico , Recidiva Local de Neoplasia/patologia , Células Estromais/patologia , Estudos RetrospectivosRESUMO
Patient morbidity and mortality is significantly increased in metastatic breast cancer. The metastasis process of breast cancer is very complicated and is delicately controlled by various factors. Autophagy is one of the important regulatory factors affecting metastasis in breast cancer by engaging in cell mobility, metabolic adaptation, tumor dormancy, and cancer stem cells. Here, we discuss the effects of autophagy on metastasis in breast cancer and assess the potential use of autophagy modulators for metastasis treatment.
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Thyroid cancer is the most common cancer in the endocrine system. Most thyroid cancers have good prognosis, but some of them are resistant to treatment or show aggressive behavior. Like other tumors, thyroid cancers harbor tumor microenvironment (TME) composed of cancer associated fibroblasts (CAF) and immune cells. Autoimmune lymphocytic thyroiditis can occur in the thyroid, and it may be associated with cancer development. TME is involved in tumor progression through various mechanisms: (1) CAF is involved in tumor progression through cell proliferation and extracellular matrix (ECM) remodeling; and (2) immune cells are involved in tumor progression through cell proliferation, angiogenesis, epithelial mesenchymal transformation (EMT), and immune suppression. These events are activated by various cytokines, chemokines, and metabolites secreted from cells that comprise TME. This review is focused on how CAF and immune cells, two important cell components of thyroid cancer TME, are involved in tumor progression, and will explore their potential as therapeutic targets.
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Fibroblastos Associados a Câncer , Neoplasias da Glândula Tireoide , Humanos , Microambiente Tumoral , Neoplasias da Glândula Tireoide/patologia , Fibroblastos Associados a Câncer/metabolismo , Citocinas/metabolismo , Quimiocinas/metabolismoRESUMO
Objective: This study aimed to evaluate the association between vitamin D receptor (an essential component in the vitamin D signaling pathway) and serum vitamin D as well as its clinical significance in papillary thyroid cancer. Methods: This prospective cohort study comprised patients with thyroid tumors who visited our hospital, from 2017 to 2018. The level of vitamin D receptor expression from thyroid tissue was measured in patients with thyroid tumor and evaluated for correlation with serum vitamin D levels and clinicopathologic characteristics of papillary thyroid cancer. Data from 501 patients with papillary thyroid cancer from The Cancer Genome Atlas database were analyzed. Results: Increased vitamin D receptor protein and mRNA expression were observed in papillary thyroid cancer compared to those in normal and benign tissues. Lower vitamin D receptor protein expression was associated with high TNM stage papillary thyroid cancer and low p21 protein expression. Lower relative vitamin D receptor mRNA expression in papillary thyroid cancer was associated with low serum 25-hydroxyvitamin D level. The Cancer Genome Atlas database showed a positive correlation among mRNA expression of vitamin D receptor, CYP24A1, and p21. Conclusions: An association between decreased vitamin D receptor protein expression and advanced stage papillary thyroid cancer, and a correlation between low vitamin D receptor mRNA expression with low serum 25-hydroxyvitamin D level was observed. Low vitamin D receptor expression in papillary thyroid cancer was shown to positively correlate with low serum vitamin D level and disease aggressiveness.
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Receptores de Calcitriol , Neoplasias da Glândula Tireoide , Humanos , Estudos Prospectivos , Receptores de Calcitriol/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
Glucose and glutamine metabolism is involved in important tumor mechanisms. Metabolism-related protein expression has been previously reported to predict tumor prognosis. We aimed to investigate glucose and glutamine metabolism-related protein expression and its implication in breast ductal carcinoma in situ (DCIS). A tissue microarray was prepared for 205 DCIS cases. Glucose and glutamine metabolism-related proteins were immunostained. Based on the results of estrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER)-2, and Ki-67, DCIS was classified into the luminal type, HER-2 type, and triple-negative breast cancer (TNBC). DCIS stroma was classified into non-inflammatory and inflammatory types per stromal histology. DCIS (N=205) was classified into luminal type (n=112), HER-2 type (n=81), and TNBC (n=12). Hexokinase II (p=0.044), GLS (p=0.003), and SLC7A5 (p<0.001) expression rates were the highest in TNBC. Inflammatory type stroma showed higher SLC7A5 (p<0.001) and SLC7A11 (p=0.008) expression rates than non-inflammatory type stroma. In summary, DCIS demonstrated differential expression of metabolism-related proteins according to the molecular subtype and stromal features. TNBC showed the highest glucose and glutamine metabolism-related protein expression, and inflammatory type stroma showed higher glutamine metabolism-related protein expression than non-inflammatory type stroma.
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Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Glucose , Glutamina , Humanos , Transportador 1 de Aminoácidos Neutros Grandes , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
High-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) is a useful metabolic profiling technique for human tissue. However, the impact of intratumoral heterogeneity on the metabolite levels of breast cancers is not yet established. The purpose of this prospective study was to investigate whether the tumor cell fraction of core needle biopsy (CNB) specimens of breast cancers affect metabolic profiles assessed with HR-MAS MRS. From June 2015 to December 2016, 46 patients with 47 breast cancers were enrolled. HR-MAS MRS was used for the metabolic profiling of 285 CNB specimens from the 47 cancers. Multiple CNB samples (range 2-8) for the HR-MAS MRS experiment were obtained from surgical specimens under ultrasound guidance following surgical removal of the tumor. Tumor cell fraction was expressed as a percentage of the tumor cell volume relative to the total tumor volume contained in each CNB sample. Metabolite quantification levels were compared according to primary tumor characteristics using the t-test. Multivariate analyses were performed including primary tumor characteristics and tumor cell percentages as variables. Correlations between tumor cell percentage and metabolite levels in the CNB specimens were assessed according to the immunohistochemical status of the primary tumor. In univariate analysis, levels of choline-containing compounds, glutamate, glutamine, glycine, serine, and taurine were correlated with primary tumor characteristics. In multivariate analysis, most metabolite levels were not affected by tumor cell percentage. Tumor cell percentage showed poor correlation with metabolite levels in hormone receptor-positive cancer and triple-negative cancer, and poor to fair correlation with metabolite levels in HER2-positive cancer. This study showed that differences in the tumor cell fraction of CNB samples do not affect predictions on the primary cancer from which the samples are obtained.
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Neoplasias da Mama , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/patologia , Feminino , Humanos , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Estudos ProspectivosRESUMO
Purpose Epithelial membrane protein (EMP) 1, EMP2, and EMP3 are expressed in various types of tumors and have been reported to be involved in carcinogenesis. In this study, we aimed to investigate the expression of these proteins in primary and metastatic thyroid cancer and its clinical implication. Methods EMP1, EMP2, and EMP3 immunohistochemistry was performed using tissue microarrays of 545 primary thyroid carcinomas [338 papillary thyroid carcinoma (PTC), 111 follicular carcinoma (FC), 69 medullary carcinoma (MC), 23 poorly differentiated carcinoma (PDC), and 4 anaplastic carcinoma (AC)] and 59 recurrent or metastatic PTCs. Results EMP1 showed high expression in AC, PTC, FC (P<0.001), and EMP2 was highly expressed in AC (P<0.001). EMP1 and EMP2 were not expressed in stromal cells. Expression of EMP3 in tumor cells [EMP3 (T)] was higher in PDC, PTC, and AC (P<0.001), and expression in stromal cells [EMP3 (S)] was observed only in AC and PTC (P=0.001). The expression of EMP1 (P=0.002) and EMP3 (T) (P<0.001) was higher in conventional PTC than in follicular variant PTC. PTC with BRAF V600E mutation showed higher expression of EMP1 (P<0.001), EMP3 (T) (P<0.001), and EMP3 (S) (P=0.012) than PTC without BRAF V600E mutation. In the PTC without BRAF V600E mutation group, expression of EMP3 (S) was associated with shorter disease free survival (P=0.004). Metastatic PTC showed higher EMP2 (3.4% vs. 0%, P=0.022) and lower EMP3 (T) (44.1% vs. 66%, P=0.001) than primary PTC. Conclusions Expression of EMP1, EMP2, and EMP3 is different according to the subtypes of thyroid cancer. Further studies are needed to determine their role as prognostic markers and treatment target in thyroid cancer.
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Adenocarcinoma Folicular , Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Receptores de Superfície Celular , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologiaRESUMO
The aim of this research was to evaluate the expression and concomitant implications of LC3A, LC3B, beclin-1, and p62, which are key components of autophagy in human adrenal gland tumors. Tissue microarray was made for 321 cases of adrenal gland tumor (adrenal cortical adenoma (ACA): 115, adrenal cortical carcinoma (ACC): 17, and pheochromocytoma (PCC): 189). Immunohistochemical staining was performed for beclin-1, p62, LC3A, and LC3B, and the results were compared with the patients' clinicopathologic parameters. LC3A, LC3B, beclin-1, and LC3B isolated single positive cells (ISPC) positivity rates were higher in PCC than in adrenal cortical tumor (ACT), whereas p62 positivity was lower in PCC than in ACT. The proportion of positive LC3B (ISPC) was higher in ACC than in ACA. In addition, the proportion of cells positive for p62 and LC3B (ISPC) was significantly higher in PCCs with a GAPP score of ≥3. In univariate Cox analysis, p62 positivity (p = 0.014) and the presence of p62 (ISPC) (p = 0.001) were associated with shorter disease-free survival in PCC. Moreover, p62 positivity was predictive of shorter overall survival (OS) in patients with PCC by multivariate analysis (relative risk, 6.240; 95% CI, 1.434-27.15; p = 0.015). Differences were found in the expression of autophagy-related proteins according to adrenal gland tumor types. Compared to ACT, the proportion of LC3A, LC3B, beclin-1, and LC3B (ISPC) positivity was higher in PCC, whereas p62 positivity was lower. Similarly, p62 positivity in PCC was associated with patient prognosis of OS.
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Neoplasias do Córtex Suprarrenal , Proteínas Relacionadas à Autofagia/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Feocromocitoma , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/metabolismo , Feocromocitoma/mortalidade , Feocromocitoma/patologia , Taxa de SobrevidaRESUMO
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.
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PURPOSE: The aim of this study was to investigate the expression patterns of glucose metabolism-related proteins and their clinicopathologic implications in adrenal cortical neoplasms (ACN) and pheochromocytoma (PCC). METHODS: Immunohistochemical staining was performed to evaluate glucose metabolism-related proteins (GLUT1, CAIX, hexokinase II, G6PDH, PHGDH, and SHMT1) in 132 ACN cases (115 adrenal cortical adenoma [ACA] and 17 adrenal cortical carcinoma [ACC]) and 189 PCC cases. RESULTS: Expression levels of GLUT1 in tumor cells ([T]; p < 0.001), GLUT1 in stromal cells ([S]; p < 0.001), G6PDH (p < 0.001), and SHMT1 (p = 0.002) were higher in ACN than in PCC. GLUT1 (T; p = 0.045) and PHGDH (p = 0.043) levels were higher in ACC than in ACA. In a univariate analysis of ACN, GLUT1 (T; p = 0.017), CAIX (S; p = 0.003), and PHGDH (p = 0.009) levels were correlated with a shorter overall survival (OS). GLUT1 (T; p = 0.001) and PHGDH (p < 0.001) were related to a shorter OS in PCC. GLUT1 (T) positivity (p = 0.043) in ACN predicted a poor OS in a multivariate Cox analysis. In PCC, high GAPP score (p = 0.026), GLUT1 (T; p = 0.002), and PHGDH (p < 0.001) were independent prognostic factors for poor OS. CONCLUSIONS: The adrenal gland tumors ACN and PCC had different expression patterns of glucose metabolism-related proteins (GLUT1, G6PDH, and SHMT1), with higher expression levels in ACN than in PCC. GLUT1 and PHGDH were significant prognostic factors in these adrenal neoplasms.
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Neoplasias das Glândulas Suprarrenais , Glucose , Transportador de Glucose Tipo 1 , HumanosRESUMO
The most common genetic backgrounds of hereditary paraganglioma and pheochromocytoma (PPGL) are SDHx germline mutations. Given the fact that the immunohistochemistry (IHC) result for SDHB is always negative regardless of the type of SDHx mutation, we aimed to evaluate the efficacy of using SDHB IHC for screening SDHx mutations in PPGL cases. In total, 52 patients who underwent surgery for PPGL treatment between 2006 and 2020 and underwent genetic analysis at diagnosis were included. Tissue microarrays (TMAs) were constructed with PPGL tissues and IHC for SDHB was performed on TMA sections. All 10 patients with SDHB-negative IHC contained SDHB or SDHD mutations. The genetic test results of patients with SDHB-weakly positive IHC varied (one SDHB, two RET, one VHL, and three unknown gene mutations). There were no SDHx mutations in the SDHB-positive IHC group. Six patients with weakly positive SDHB IHC with primarily unknown genetic status were re-called and underwent next-generation sequencing. None of them had SDHx mutations. In conclusion, SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations. However, in the case of weakly positive SDHB staining, an additional gene study should be considered.
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Extreme responders to anticancer therapy are rare among advanced breast cancer patients. Researchers, however, have yet to investigate treatment responses therein on the whole exome level. We performed whole exome analysis to characterize the genomic landscape of extreme responders among metastatic breast cancer patients. Clinical samples were obtained from breast cancer patients who showed exceptional responses to anti-HER2 therapy or hormonal therapy and from those who did not. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 30 responders and 15 non-responders. Whole exome sequencing using Illumina HiSeq2500 was performed for all 45 patients (90 samples). Somatic single nucleotide variants (SNVs), indels, and copy number variants (CNVs) were identified for the genomes of each patient. Group-specific somatic variants and mutational burden were statistically analyzed. Sequencing of cancer exomes for all patients revealed 1839 somatic SNVs (1661 missense, 120 nonsense, 43 splice-site, 15 start/stop-lost) and 368 insertions/deletions (273 frameshift, 95 in-frame), with a median of 0.7 mutations per megabase (range, 0.08 to 4.2 mutations per megabase). Responders harbored a significantly lower nonsynonymous mutational burden (median, 26 vs. 59, P = 0.02) and fewer CNVs (median 13.6 vs. 97.7, P = 0.05) than non-responders. Multivariate analyses of factors influencing progression-free survival showed that a high mutational burden and visceral metastases were significantly related with disease progression. Extreme responders to treatment for metastatic breast cancer are characterized by fewer nonsynonymous mutations and CNVs.
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Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Genoma Humano , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Adulto , Animais , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Sequenciamento do ExomaRESUMO
BACKGROUND: Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. However, the role of YAP1 in breast cancer remains controversial. Here, we investigated the impact of different levels of nuclear YAP1 expression on the clinical characteristics and survival outcome in patients with breast cancer. PATIENTS AND METHODS: Retrospectively obtained 455 breast tumor samples at Gangnam Severance Hospital were examined for YAP1 expression by immunohistochemistry, and the clinical data were analyzed. External validation was performed using a retrospective cohort and tissues in 482 patients from Severance Hospital. RESULTS: High nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS, hazard ratio [HR] 2.271, 95% confidence intervals [CIs] 1.109-4.650, P = 0.0249), and also confirmed inferior disease free survival (HR 3.208, 95% CIs 1.313-7.833, P = 0.0105) in external validation cohort. In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor DMFS (HR 2.384, 95% CIs 1.055-5.386, P = 0.0367). CONCLUSION: Our findings suggest that nuclear YAP1 expression is a biomarker of adverse prognosis and a potential therapeutic target in patients with breast cancer, especially in TNBC.
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BACKGROUND: Glutamine metabolism is considered an important metabolic phenotype of proliferating tumor cells. OBJECTIVE: The objective of this study was to investigate the expression of glutamine metabolism-related and amino acid transporter proteins in adrenal cortical neoplasms (ACNs) and pheochromocytomas (PCCs) in the adrenal gland. METHODS: A tissue microarray was constructed for 132 cases of ACN (115 cases of adrenal cortical adenoma and 17 cases of adrenal cortical carcinoma) and 189 cases of PCC. Immunohistochemical staining for glutamine metabolism-related proteins GLS1 and GDH and amino acid transporter proteins SLC1A5, SLC7A5, and SLC7A11 as well as SDHB was performed and compared with clinicopathologic parameters. RESULTS: The expression levels of GLS (p < 0.001), SLC7A5 (p = 0.049), and SDHB (p = 0.007) were higher in ACN than in PCC, whereas the expression levels of SLC1A5 (p < 0.001) and SLC7A11 (p < 0.001) were higher in PCC than in ACN. In ACN, GLS positivity was associated with a higher Fuhrman grade (p = 0.009), and SLC1A5 positivity was associated with SDHB positivity (p = 0.004) and a clear cell proportion < 25% (p = 0.010). SDHB negativity was also associated with tumor cell necrosis (p = 0.007). In PCC, SLC7A11 positivity was associated with nonnorepinephrine type (p = 0.008). In Kaplan-Meier analysis, patients with GLS positivity (p = 0.039) and SDHB negativity (p = 0.005) had significantly shorter overall survival in ACN. In PCC patients with a GAPP score ≥ 3, GLS positivity (p = 0.001) and SDHB positivity (p = 0.001) were associated with shorter disease-free survival, whereas GLS positivity (p = 0.004) was also associated with shorter overall survival. CONCLUSIONS: The expression of glutamine metabolism-related and amino acid transporter proteins in ACN and PCC is distinct and associated with prognosis.