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1.
Br J Cancer ; 123(5): 793-802, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32555365

RESUMO

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.


Assuntos
PTEN Fosfo-Hidrolase/biossíntese , Adenocarcinoma de Células Claras/enzimologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Fatores Etários , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Regulação para Baixo , Feminino , Técnicas de Inativação de Genes , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Estudos Prospectivos , Receptores Androgênicos/biossíntese , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/deficiência
2.
Cancers (Basel) ; 12(12)2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33291454

RESUMO

Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel-Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59-2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71-0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3-4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.

3.
J Clin Endocrinol Metab ; 105(11)2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791518

RESUMO

CONTEXT: The identification of markers able to determine medullary thyroid cancer (MTC) patients at high-risk of disease progression is critical to improve their clinical management and outcome. Previous studies have suggested that expression of the stem cell marker CD133 is associated with MTC aggressiveness. OBJECTIVE: To evaluate CD133 impact on disease progression in MTC and explore the regulatory mechanisms leading to the upregulation of this protein in aggressive tumors. PATIENTS: We compiled a series of 74 MTCs with associated clinical data and characterized them for mutations in RET and RAS proto-oncogenes, presumed to be related with disease clinical behavior. RESULTS: We found that CD133 immunohistochemical expression was associated with adverse clinicopathological features and predicted a reduction in time to disease progression even when only RET-mutated cases were considered in the analysis (log-rank test P < 0.003). Univariate analysis for progression-free survival revealed CD133 expression and presence of tumor emboli in peritumoral blood vessels as the most significant prognostic covariates among others such as age, gender, and prognostic stage. Multivariate analysis identified both variables as independent factors of poor prognosis (hazard ratio = 16.6 and 2; P = 0.001 and 0.010, respectively). Finally, we defined hsa-miR-30a-5p, a miRNA downregulated in aggressive MTCs, as a CD133 expression regulator. Ectopic expression of hsa-miR-30a-5p in MZ-CRC-1 (RETM918T) cells significantly reduced CD133 mRNA expression. CONCLUSIONS: Our results suggest that CD133 expression may be a useful tool to identify MTC patients with poor prognosis, who may benefit from a more extensive primary surgical management and follow-up.


Assuntos
Antígeno AC133/metabolismo , Carcinoma Medular/metabolismo , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Antígeno AC133/genética , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Medular/genética , Carcinoma Medular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-ret/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Proteínas ras/genética
4.
Breast Cancer Res Treat ; 113(3): 545-51, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18302019

RESUMO

Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.


Assuntos
Neoplasias da Mama/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Idoso , Neoplasias da Mama Masculina/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Linhagem , Espanha
5.
JAMA Oncol ; 3(12): e173290, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29049607

RESUMO

Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures: Overall survival time. Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.


Assuntos
Antígenos CD8/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/imunologia , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento
6.
J Gynecol Oncol ; 27(1): e7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26463438

RESUMO

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.


Assuntos
Cistadenocarcinoma Seroso/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/biossíntese , Células Tumorais Cultivadas
7.
Mol Oncol ; 9(2): 422-36, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25454820

RESUMO

Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Ovarianas/terapia , Taxa de Sobrevida
8.
Fam Cancer ; 3(3-4): 259-64, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15516850

RESUMO

Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA 1 and BRCA 2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2 mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.


Assuntos
Predisposição Genética para Doença/etnologia , Judeus/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Adulto , Distribuição por Idade , Idoso , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Ovarianas/etnologia , Linhagem , Medição de Risco , Análise de Sobrevida , Estados Unidos/epidemiologia
9.
Clin Transl Oncol ; 15(1): 20-5, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22911548

RESUMO

INTRODUCTION: Approximately 5 % of all cancer cases are hereditary. Cancer genetic counseling assesses individual and family risks of cancer, conducts genetic studies, interprets results, and advises patients regarding strategies for prevention and risk reduction. Currently, many networks of hereditary cancer genetic counseling units (HCGCUs) are integrated in the medical oncology services of most Spanish hospitals, which are comprised of multidisciplinary teams and offer high-quality care for the treatment of hereditary cancer. MATERIALS AND METHODS: The Spanish Society of Medical Oncology (SEOM) analyzed key issues involving the integration of HCGCUs into the National Health Service. These included basic compliance issues by these units regarding their operation and organization, as well as prerequisites in quality control thereof. RESULTS: This document describes the specific roles and clinical processes performed in HCGCUs in addition to basic services provided by molecular diagnostic laboratories. It also provides a summary on the coordination of care across different levels for patients and families with hereditary cancers. Finally, this document describes the human and material resources needed for the organization of HCGCUs. CONCLUSIONS: SEOM has been a pioneer in the creation and development of HCGCUs. This paper seeks to ensure high-quality care to individuals and families with inherited susceptibility to cancer in Spain.


Assuntos
Aconselhamento Genético/organização & administração , Neoplasias/diagnóstico , Neoplasias/genética , Detecção Precoce de Câncer , Aconselhamento Genético/métodos , Predisposição Genética para Doença , Humanos , Medição de Risco , Sociedades Médicas , Espanha
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