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2.
Clin Infect Dis ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31344234

RESUMO

BACKGROUND: There is no baseline prognostic test to ascertain whether cervical intraepithelial neoplasia (CIN) will regress or progress. The majority of CIN regress in young women and since local treatments are known to increase the risk of adverse pregnancy outcomes interventions need to be sparing. We investigated the ability of a DNA methylation panel (the S5-classifier) to discriminate between progression and regression among women of childbearing age with untreated CIN grade 2 (CIN2). METHODS: Pyrosequencing methylation and HPV genotyping assays were performed on exfoliated cervical cells from 149 young women with CIN2 in a 2-year cohort study of active surveillance. RESULTS: Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 lesions persisted as CIN1/2. When cytology, HPV16/18- and HPV16/18/31/33-genotyping, and S5 at baseline were compared to outcomes, S5 was the strongest biomarker associated with regression versus progression. S5 alone or in combination with HPV16/18/31/33-genotyping also showed significantly increased sensitivity versus cytology, comparing regression vs. persistence/progression. With both S5 and cytology tests set at a specificity of 38.6% (95% CI 28.4-49.6) the sensitivity of S5 was significantly higher (83.6%, 95% CI 71.9-91.8) than for cytology (62.3%, 95% CI 49.0-74.4) (p=0.005). The highest area under the curve (AUC) was 0.735 (95% CI 0.621-0.849) in the regression vs. progression outcome with a combination of S5 and cytology, whereas HPV16/18 or HPV16/18/31/33-genotyping did not provide additional prognostic information. CONCLUSIONS: The S5-classifier shows high potential as a prognostic biomarker to identify women with progressive CIN2.

3.
Int J Cancer ; 145(10): 2692-2700, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30927251

RESUMO

Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58-18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate-risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2-negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate-risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15-5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.

4.
Int J Gynecol Cancer ; 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898936

RESUMO

OBJECTIVE: To study the association of the American Society of Anesthesiologists (ASA) physical status score with long-term outcome in endometrial cancer. METHODS: Overall, disease-specific and non-cancer-related survival were estimated using simple and multivariable Cox regression analyses and the Kaplan-Meier method. RESULTS: A total of 1166 patients were included in the study. Median follow-up time was 76 (range 1-136) months. All-cause and non-cancer-related mortality were increased in patients whose ASA physical status score was III (HRs 2.5 and 8.0, respectively) or IV (HRs 5.7 and 25, respectively), and cancer-related mortality was increased in patients whose score was IV (HR 2.7). Kaplan-Meier analyses demonstrated a worse overall, disease-specific and non-cancer-related survival for patients whose score was ≥III (p<0.0001 for all). Disease-specific survival was also separately analyzed for patients with stage I and stage II-IV cancer. Compared with patients whose score was ≤II, the survival was worse for patients whose score was ≥III in both subgroups of stages (p=0.003 and p=0.017 for stage I and stages II-IV, respectively). ASA physical status score remained an independent predictor of all-cause mortality (HR 2.2 for scores ≥III), cancer-related mortality (HRs 1.7 and 2.2 for scores ≥III and IV, respectively) and non-cancer related mortality (HR 3.1 for scores ≥III) after adjustment for prognostically relevant clinicopathologic and blood-based covariates. ASA physical status score also remained an independent predictor of cancer-related mortality after exclusion of patients who were at risk for nodal involvement based on features of the primary tumor but who did not undergo lymphadenectomy, and patients with advanced disease who received suboptimal chemotherapy (HRs 1.6 and 2.5 for scores ≥III and IV, respectively). CONCLUSIONS: ASA physical status score independently predicts overall survival, disease-specific survival, and non-cancer-related survival in endometrial cancer.

5.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
6.
Cancer Res ; 79(3): 505-517, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30559148

RESUMO

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

7.
Cancer ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423196

RESUMO

BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.

8.
Elife ; 72018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30226466

RESUMO

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

9.
Int J Mol Sci ; 19(9)2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134598

RESUMO

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

10.
Cancer Res ; 78(18): 5419-5430, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054336

RESUMO

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

11.
PLoS One ; 13(7): e0197561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29979793

RESUMO

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

12.
Gynecol Oncol ; 150(1): 92-98, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29716739

RESUMO

OBJECTIVE: The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). METHODS: MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. RESULTS: Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. CONCLUSIONS: Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias do Endométrio/etiologia , Neoplasias Ovarianas/etiologia , Carcinogênese/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia
13.
Br J Cancer ; 118(8): 1123-1129, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29555990

RESUMO

BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

14.
Mod Pathol ; 31(8): 1291-1301, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29588532

RESUMO

Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are clinically relevant for the classification of endometrial hyperplasias and have potential implications in cancer prevention in Lynch syndrome and beyond.

15.
Br J Cancer ; 117(12): 1855-1864, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29073636

RESUMO

BACKGROUND: Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH. The aim of this study was to identify metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas. METHODS: We performed global metabolomic profiling of 25 uterine leiomyomas and 17 corresponding myometrium specimens using liquid chromatography-tandem mass spectroscopy. RESULTS: A total of 641 metabolites were detected. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels. We identified a clearly distinct metabolomic profile for leiomyomas of the FH subtype, characterised by metabolic alterations in the tricarboxylic acid cycle and pentose phosphate pathways, and increased levels of multiple lipids and amino acids. Several metabolites were uniquely elevated in leiomyomas of the FH subtype, including N6-succinyladenosine and argininosuccinate, serving as potential biomarkers for FH deficiency. In contrast, leiomyomas of the MED12 subtype displayed reduced levels of vitamin A, multiple membrane lipids and amino acids, and dysregulation of vitamin C metabolism, a finding which was also compatible with gene expression data. CONCLUSIONS: The study reveals the metabolomic heterogeneity of leiomyomas and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumours.


Assuntos
Leiomioma/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Aminoácidos/metabolismo , Ácido Argininossuccínico/metabolismo , Ácido Ascórbico/metabolismo , Ciclo do Ácido Cítrico , Feminino , Fumarato Hidratase/genética , Proteína HMGA2/genética , Humanos , Leiomioma/genética , Metabolismo dos Lipídeos , Complexo Mediador/genética , Redes e Vias Metabólicas , Metaboloma , Via de Pentose Fosfato , Vitamina A/metabolismo
16.
Int J Gynecol Cancer ; 27(7): 1318-1324, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-29059097

RESUMO

OBJECTIVE: Preoperative or intraoperative risk assessment models are used to stratify patients with endometrial carcinoma to lymphadenectomy. Our aim was to determine whether preoperative analysis of L1 cell adhesion molecule (L1CAM) can improve risk assessment. METHODS: Immunohistochemical L1CAM staining was performed on endometrial biopsies of 241 patients and paired hysterectomy samples of 75 patients. Risk assessment models based on preoperative histologic type and grade, myometrial invasion, and/or tumor diameter and alternative models incorporating preoperative L1CAM were compared with regard to their capability of predicting lymph nodal or distant metastasis. Soluble L1 levels were measured by enzyme-linked immunosorbent assay in serum samples of 40 patients with endometrial carcinoma. RESULTS: The concordance rate between L1CAM staining results of preoperative and hysterectomy samples was moderate (κ = 0.586, P < 0.0001). Preoperative L1CAM expression was associated with nonendometrioid histology, lymph node involvement, advanced stage, and positive peritoneal cytology. Receiver operating characteristic curve analyses showed that L1CAM did not significantly improve risk stratification algorithms based on traditional risk factors. Intraoperative tumor diameter was an effective surrogate for myometrial invasion. There was no statistical difference between L1 serum levels of patients with an L1CAM-positive or L1CAM-negative endometrial carcinoma (P = 0.786). CONCLUSIONS: L1 cell adhesion molecule expression in endometrial biopsy correlates with high-risk features of endometrial carcinoma but does not significantly improve risk stratification algorithms based on traditional factors. Soluble L1 detected in the serum of patients with endometrial carcinoma does not correlate with tumoral L1CAM expression.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Molécula L1 de Adesão de Célula Nervosa/sangue , Idoso , Algoritmos , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Molécula L1 de Adesão de Célula Nervosa/análise , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Medição de Risco
17.
Breast Cancer Res Treat ; 166(1): 217-226, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28702895

RESUMO

PURPOSE: The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. METHODS: We genotyped the FANCM c.5791C>T mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. RESULTS: The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87-4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65-16.0, P = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32-2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77-5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. CONCLUSIONS: These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.


Assuntos
Alelos , DNA Helicases/genética , Predisposição Genética para Doença , Mutação , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Estudos de Casos e Controles , Reparo do DNA , Feminino , Finlândia/epidemiologia , Duplicação Gênica , Frequência do Gene , Genótipo , Humanos , Razão de Chances , Vigilância da População , Medição de Risco , Fatores de Risco , Deleção de Sequência
18.
Mol Cancer ; 16(1): 101, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28592321

RESUMO

Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.


Assuntos
Biomarcadores Tumorais , Fumarato Hidratase/genética , Proteína HMGA2/genética , Complexo Mediador/genética , Tumor de Músculo Liso/genética , Tumor de Músculo Liso/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Análise Mutacional de DNA , Feminino , Fumarato Hidratase/metabolismo , Expressão Gênica , Proteína HMGA2/metabolismo , Humanos , Complexo Mediador/metabolismo , Mutação , Gradação de Tumores , Estudos Retrospectivos , Tumor de Músculo Liso/metabolismo , Neoplasias Uterinas/metabolismo
19.
Gynecol Oncol ; 146(3): 615-622, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28625395

RESUMO

OBJECTIVE: Our aim was to study the expression of L1CAM in endometrioid and clear cell ovarian carcinomas and to evaluate its correlation with clinical parameters and patient prognosis. METHODS: Tissue microarray -based immunohistochemical analysis of L1CAM expression was performed in 249 endometrioid and 140 clear cell ovarian carcinomas. Concurrent endometrial carcinoma was found in 57 of these patients. RESULTS: L1CAM expression was found in 15% of endometrioid and 23% of clear cell ovarian carcinomas. L1CAM expression was strongly associated with poor disease-specific overall survival and poor disease-free survival in endometrioid (p<0.0001, p=0.0005), but not in clear cell ovarian carcinomas. Significant association of L1CAM expression with poor overall survival was observed in grade 1-2 carcinomas (p<0.0001), but not in grade 3 tumors. In endometrioid ovarian carcinomas, L1CAM expression was associated with aggressive tumor characteristics, such as higher grade and stage, and incomplete response to primary therapy. However, L1CAM expression was not an independent prognostic factor for overall or disease-free survival. Of the 57 patients with concurrent endometrial carcinoma L1CAM positivity was found in 4 cases both in the ovarian and endometrial tumors, and in 3 cases only in the endometrial tumor. All these seven patients with L1CAM positive tumors had poor outcome. CONCLUSIONS: L1CAM expression could serve as a biomarker for predicting clinical outcome and response to therapy in patients with endometrioid ovarian carcinoma, but not in clear cell carcinomas. L1CAM positivity also predicts poor outcome in patients with concurrent endometrioid ovarian and endometrial carcinomas.


Assuntos
Adenocarcinoma de Células Claras/química , Carcinoma Endometrioide/química , Neoplasias do Endométrio/química , Neoplasias Primárias Múltiplas/química , Molécula L1 de Adesão de Célula Nervosa/análise , Neoplasias Ovarianas/química , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Intervalo Livre de Doença , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Taxa de Sobrevida , Resultado do Tratamento
20.
Int J Gynecol Cancer ; 27(5): 923-930, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28498250

RESUMO

OBJECTIVE: The aim of this study was to investigate the association of predictors of an advanced disease and/or poor outcome with the occurrence of tumor relapses in different anatomical sites in patients with stage I-II endometrioid endometrial cancer. METHODS: A total of 929 patients were included in the study. The median follow-up time was 57 months (range, 1-108 months). The studied variables were: poor tumor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, lymphovascular space invasion, cervical stromal invasion, positive peritoneal cytology, old age (>77 years), obesity (body mass index ≥30 kg/m), and diabetes. RESULTS: A relapse was diagnosed in 98 patients (10.5%) (vaginal in 15, pelvic in 27, intra-abdominal beyond the pelvis in 27, extra-abdominal in 29). None of the variables were associated with an altered risk of vaginal or pelvic relapses in univariate analyses. Poor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, and positive peritoneal cytology were associated with an increased risk of intra-abdominal relapses beyond the pelvis (odds ratios [ORs] between 2.2 and 9.6). With the exception of obesity and diabetes, all variables were associated with an increased risk of extra-abdominal relapses (ORs between 2.3 and 13). Tumor size 3 cm or greater (OR, 3.1) and positive peritoneal cytology (OR, 16) predicted intra-abdominal relapses beyond the pelvis in multivariate analysis, whereas poor differentiation (OR, 2.9), myometrial invasion 50% or greater (OR, 4.0), and positive peritoneal cytology (OR, 27) predicted extra-abdominal relapses. Compared with vaginal relapses, intra-abdominal relapses beyond the pelvis and extra-abdominal relapses were associated with a worse disease-specific survival. Survival of patients with a pelvic relapse did not differ from that of patients with a vaginal relapse. CONCLUSIONS: Risk variables of endometrial cancer are differently associated with relapses in different locations. Our findings may promote studies that explore the most efficient adjuvant therapy in high-risk early-stage endometrioid endometrial cancer.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Idoso , Carcinoma Endometrioide/diagnóstico , Diferenciação Celular/fisiologia , Neoplasias do Endométrio/diagnóstico , Feminino , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Recidiva
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