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1.
Anticancer Res ; 40(12): 6923-6931, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288586

RESUMO

BACKGROUND/AIM: Examine features of blood and lymphatic vessels in ovarian tumors and their significance to prognosis of ovarian cancer. PATIENTS AND METHODS: A total of 139 women with epithelial ovarian tumors were included: 86 malignant, 17 borderline and 36 benign. Density, percentage, mean size and number of blood microvessels in tumors were measured by immunohistochemistry with antibodies against CD34 and CD105. Lymphatic vessel density was assayed using the D2-40 antibody against podoplanin. RESULTS: Angiogenesis was most profuse in malignant tumors. Small size of lymph vessels predicted 26% shorter 5-year survival of ovarian cancer patients. Further, high percentage of lymphatic vessels in tumors was associated with lymph node metastasis, and high density with cancer recurrence. Lower number of microvessels, as assessed by CD34 staining, predicted shorter progression-free survival. Additionally, the large size of microvessels assessed by CD34 and the high number of vessels assessed by CD105 were related to residual tumor >1 cm at primary surgery and also, large vessel size was associated with stage III, as assessed by CD105 staining. CONCLUSION: CD34 and CD105 define different characteristics of microvessels. Parameters of lymph vessels may predict the prognosis of ovarian cancer.

2.
PLoS One ; 15(11): e0241484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151982

RESUMO

BACKGROUND: Antiangiogenic therapy, although part of standard treatment in ovarian cancer, has variable efficacy. Furthermore, little is known about the prognostic biomarkers and factors influencing angiogenesis in cancer tissue. We evaluated the expression of angiopoietin-2 and two endothelial tyrosine kinase receptors, Tie-1 and Tie-2, and assessed their value in the prediction of survival in patients with malignant epithelial ovarian cancer. We also compared the expression of these factors between primary high grade serous tumors and their distant metastasis. MATERIALS AND METHODS: We evaluated 86 women with primary epithelial ovarian cancer. Matched distal omental metastasis were investigated in 18.6% cases (N = 16). The expression levels of angiogenic factors were evaluated by immunohistochemistry in 306 specimens and by qRT-PCR in 111 samples. RESULTS: A high epithelial expression level of Tie-2 is a significant prognostic factor in primary high grade serous ovarian cancer. It predicted significantly shorter overall survival both in univariate (p<0.001) and multivariate survival analyses (p = 0.022). Low angiopoietin-2 expression levels in primary ovarian tumors were significantly associated with shorter overall survival (p = 0.015) in the univariate survival analysis. A low expression of angiopoietin-2 was also significantly related to high grade tumors, size of residual tumor after primary surgery and the recurrence of cancer (p = 0.008; p = 0.012; p = 0.018) in the whole study population. The expression of angiopoietin-2 and Tie-2 was stronger in distal omental metastasis than in primary high grade serous tumors in matched-pair analysis (p = 0.001; p = 0.002). CONCLUSIONS: The angiogenic factor, angiopoietin-2, and its receptor Tie-2 seem to be significant prognostic factors in primary epithelial ovarian cancer. Their expression levels are also increased in metastatic lesions in comparison with primary tumors.

3.
Sci Rep ; 10(1): 11044, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632202

RESUMO

Breast cancer (BC) is a multifactorial disease and the most common cancer in women worldwide. We describe a machine learning approach to identify a combination of interacting genetic variants (SNPs) and demographic risk factors for BC, especially factors related to both familial history (Group 1) and oestrogen metabolism (Group 2), for predicting BC risk. This approach identifies the best combinations of interacting genetic and demographic risk factors that yield the highest BC risk prediction accuracy. In tests on the Kuopio Breast Cancer Project (KBCP) dataset, our approach achieves a mean average precision (mAP) of 77.78 in predicting BC risk by using interacting genetic and Group 1 features, which is better than the mAPs of 74.19 and 73.65 achieved using only Group 1 features and interacting SNPs, respectively. Similarly, using interacting genetic and Group 2 features yields a mAP of 78.00, which outperforms the system based on only Group 2 features, which has a mAP of 72.57. Furthermore, the gene interaction maps built from genes associated with SNPs that interact with demographic risk factors indicate important BC-related biological entities, such as angiogenesis, apoptosis and oestrogen-related networks. The results also show that demographic risk factors are individually more important than genetic variants in predicting BC risk.

4.
Cancer Med ; 9(16): 5922-5931, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32602248

RESUMO

BACKGROUND: High tumor mutation burden is shown to be associated with a poor clinical outcome. As the tumor-derived fraction of circulating cell-free DNA (cfDNA) is shown to reflect the genetic spectrum of the tumor, we examined whether the mutation burden of cfDNA could be used to predict the clinical outcomes of early-stage breast cancer (BC) patients. METHODS: We selected a set of 79 Finnish early-stage BC cases with a good prognosis based on traditional prognostic parameters but some of which still developed relapsed disease during follow-up. cfDNA was isolated from the serum collected at the time of diagnosis, sequenced, and compared to matched primary tumors, clinical parameters, and survival data. RESULTS: High cfDNA mutation burden was associated with the poor relapse-free survival (RFS) (P = .016, HR = 2.23, 95% Cl 1.16-4.27) when patients were divided into high and low mutation burden according to the median number of somatic variants. A high discordance was observed between the matched tumor and cfDNA samples, thus highlighting the challenges related to the liquid biopsy of early-stage cancer cases. Despite the low number of detected tumor-specific variants, the presence of tumor-specific somatic variants in the cfDNA was associated with the poor RFS (P = .009, HR = 2.31, 95% Cl 1.23-4.31). CONCLUSIONS: Our results confirm previously observed challenges about the accuracy of liquid biopsy-based genotyping of early-stage cancers and support the parallel sequencing of tumor and cfDNA while also demonstrating how the presence of tumor-specific somatic variants and the high mutation burden in the cfDNA are both associated with the poor RFS, thus indicating the prognostic potential of liquid biopsy in the context of early-stage cancers.

5.
Anticancer Res ; 40(7): 3713-3722, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620610

RESUMO

BACKGROUND/AIM: MicroRNAs (miRNAs) regulate the development of colorectal cancer (CRC). We aimed to investigate miRNAs and their relation to cancer-related signaling pathways in site-specific CRC. MATERIALS AND METHODS: We used a total of 24 left- and right-sided Finnish CRC samples (discovery cohort) and The Cancer Genome Atlas public mature miRSeq dataset of 201 CRC samples (validation cohort). MiRNA differential expression and biological pathway analyses were performed using DESeq2 and the DIANA/mirPath tool, respectively. RESULTS: We found 17 significantly differentially up-regulated [false discovery rate (FDR) <0.05] miRNAs in left-sided CRC ("left miRNAs"), and 15 in right-sided CRC ("right miRNAs"). The left miRNAs participate in the mTor, Wnt, PI3K-Akt signaling pathways (FDR<0.05). The right miRNAs participate in the TGF-ß signaling pathway. We also observed that both cohorts share six miRNAs. One of these (hsa-miR-196b-5p) was significantly (FDR<0.05) up-regulated in left-sided CRC. The rest of them (hsa-miR-625-3p, hsa-miR-155-5p, hsa-miR-625-5p, hsa-miR-31-5p and hsa-miR-330-5p) showed significant (FDR<0.05) up-regulation in right-sided CRC. CONCLUSION: Left and right miRNAs are associated with predominant biological pathways of left- and right-sided CRC, respectively. Our results may be beneficial for classifying CRC and for future biomarker studies of site-specific CRC.


Assuntos
Neoplasias Colorretais/genética , Transdução de Sinais/genética , Idoso , Estudos de Coortes , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Crescimento Transformador beta/genética , Regulação para Cima/genética
6.
PLoS One ; 15(6): e0235278, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584887

RESUMO

PURPOSE: The apparent diffusion coefficient (ADC) is increasingly used to characterize breast cancer. The peritumor/tumor ADC ratio is suggested to be a reliable and generally applicable index. However, its overall prognostication value remains unclear. We aimed to evaluate the associations between the peritumor/tumor ADC ratio and histopathological biomarkers and published prognostic tools in patients with invasive breast cancer. MATERIALS AND METHODS: This prospective study included 88 lesions (five bilateral) in 83 patients with primary invasive breast cancer who underwent preoperative 3.0-T magnetic resonance imaging. The lowest intratumoral mean ADC value on the slice with the largest tumor cross-sectional area was designated the tumor ADC, and the highest mean ADC value on the peritumoral breast parenchymal tissue adjacent to the tumor border was designated the peritumor ADC. The peritumor/tumor ADC ratio was then calculated. The tumor and peritumor ADC values and peritumor/tumor ADC ratios were compared with histopathological parameters using an unpaired t test, and their correlations with published prognostic tools were evaluated with Pearson's correlation coefficient. RESULTS: The peritumor/tumor ADC ratio was significantly associated with tumor size (p<0.001), histological grade (p = 0.005), Ki-67 index (p = 0.006), axillary-lymph-node metastasis (p = 0.001), and lymphovascular invasion (p = 0.006), but was not associated with estrogen receptor status (p = 0.931), progesterone receptor status (p = 0.160), or human epidermal growth factor receptor 2 status (p = 0.259). The peritumor/tumor ADC ratio showed moderate positive correlations with the Nottingham Prognostic Index (r = 0.498, p<0.001) and mortality predicted using PREDICT (r = 0.436, p<0.001). CONCLUSION: The peritumor/tumor ADC ratio was correlated with histopathological biomarkers in patients with invasive breast cancer, showed significant correlations with published prognostic indexes, and may provide an easily applicable imaging index for the preoperative prognostic evaluation of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/diagnóstico por imagem , Mama/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/mortalidade , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Antígeno Ki-67/metabolismo , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Prospectivos , Receptores Estrogênicos/metabolismo , Taxa de Sobrevida
7.
BMC Cancer ; 19(1): 584, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200683

RESUMO

BACKGROUND: In many malignancies including ovarian cancer, different angiogenic factors have been related to poor prognosis. However, data on their relations to each other or importance as a prognostic factor in ovarian cancer is missing. Therefore, we investigated the expressions of VEGF-A, VEGF-C, and VEGF-D, and the receptors VEGFR1, VEGFR2, and VEGFR3 in patients with malignant epithelial ovarian neoplasms. We further compared expression levels between primary tumors and related distant omental metastases. METHODS: This study included 86 patients with malignant ovarian epithelial tumors and 16 related distant metastases. Angiogenic factor expression was evaluated using immunohistochemistry (n = 102) and qRT-PCR (n = 29). RESULTS: Compared to primary high grade serous ovarian tumors, the related omental metastases showed higher expressions of VEGF-A (p = 0.022), VEGF-D (p = 0.010), and VEGFR1 (p = 0.046). In univariate survival analysis, low epithelial expression of VEGF-A in primary tumors was associated with poor prognosis (p = 0.024), and short progression-free survival was associated with high VEGF-C (p = 0.034) and low VEGFR3 (p = 0.002). The relative expressions of VEGF-D, VEGFR1, VEGFR2, and VEGFR3 mRNA determined by qRT-PCR analyses were significantly correlated with the immunohistochemically detected levels of these proteins in primary high grade serous ovarian cancer and metastases (p = 0.004, p = 0.009, p = 0.015, and p = 0.018, respectively). CONCLUSIONS: The expressions of VEGF receptors and their ligands significantly differed between malignant ovarian tumors and paired distant metastases. VEGF-A, VEGF-D, and VEGFR1 protein expressions seem to be higher in distant metastases than in the primary high grade serous ovarian cancer lesions.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Neoplasias Ovarianas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/secundário , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/secundário , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neovascularização Patológica/diagnóstico , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Sci Rep ; 8(1): 13149, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177847

RESUMO

We propose an effective machine learning approach to identify group of interacting single nucleotide polymorphisms (SNPs), which contribute most to the breast cancer (BC) risk by assuming dependencies among BCAC iCOGS SNPs. We adopt a gradient tree boosting method followed by an adaptive iterative SNP search to capture complex non-linear SNP-SNP interactions and consequently, obtain group of interacting SNPs with high BC risk-predictive potential. We also propose a support vector machine formed by the identified SNPs to classify BC cases and controls. Our approach achieves mean average precision (mAP) of 72.66, 67.24 and 69.25 in discriminating BC cases and controls in KBCP, OBCS and merged KBCP-OBCS sample sets, respectively. These results are better than the mAP of 70.08, 63.61 and 66.41 obtained by using a polygenic risk score model derived from 51 known BC-associated SNPs, respectively, in KBCP, OBCS and merged KBCP-OBCS sample sets. BC subtype analysis further reveals that the 200 identified KBCP SNPs from the proposed method performs favorably in classifying estrogen receptor positive (ER+) and negative (ER-) BC cases both in KBCP and OBCS data. Further, a biological analysis of the identified SNPs reveals genes related to important BC-related mechanisms, estrogen metabolism and apoptosis.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Máquina de Vetores de Suporte , Ubiquitina-Proteína Ligases/genética , Sequência de Bases , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/metabolismo , Feminino , Finlândia , Redes Reguladoras de Genes , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Prognóstico , Mapeamento de Interação de Proteínas , Risco , Ubiquitina-Proteína Ligases/metabolismo
9.
Hum Pathol ; 81: 211-219, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030117

RESUMO

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population-based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin-stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P < .001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P < .001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16-3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17-7.15; P < .001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46-6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Evasão Tumoral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Feminino , Finlândia , Humanos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
10.
Int J Epidemiol ; 47(2): 526-536, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315403

RESUMO

Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests). Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Interação Gene-Ambiente , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
11.
Breast Cancer Res ; 19(1): 119, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116004

RESUMO

BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP. CONCLUSIONS: Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , História Reprodutiva , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/etiologia , Adulto Jovem
12.
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
13.
Int J Gynecol Cancer ; 27(5): 879-886, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28498260

RESUMO

OBJECTIVES: Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. METHODS: An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses. RESULTS: AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy. CONCLUSIONS: Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Terapia Genética/métodos , Neoplasias Ovarianas/terapia , Receptor TIE-2/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adenoviridae/genética , Animais , Ascite/tratamento farmacológico , Ascite/genética , Ascite/patologia , Ascite/terapia , Carboplatina/administração & dosagem , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Distribuição Aleatória , Receptor TIE-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Eur Radiol ; 27(9): 4002-4012, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28289938

RESUMO

OBJECTIVES: We aimed to investigate whether apparent diffusion coefficients (ADCs) measured by 3.0T diffusion-weighted magnetic resonance imaging (DWI) associate with histological aggressiveness of ovarian cancer (OC) or predict the clinical outcome. This prospective study enrolled 40 patients with primary OC, treated 2011-2014. METHODS: DWI was performed prior to surgery. Two observers used whole lesion single plane region of interest (WLsp-ROI) and five small ROIs (S-ROI) to analyze ADCs. Samples from tumours and metastases were collected during surgery. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure the expression of vascular endothelial growth factor (VEGF) and its receptors. RESULTS: The interobserver reliability of ADC measurements was excellent for primary tumours ICC 0.912 (WLsp-ROI). Low ADCs significantly associated with poorly differentiated OC (WLsp-ROI P = 0.035). In primary tumours, lower ADCs significantly associated with high Ki-67 (P = 0.001) and low VEGF (P = 0.001) expression. In metastases, lower ADCs (WLsp-ROI) significantly correlated with low VEGF receptors mRNA levels. ADCs had predictive value; 3-year overall survival was poorer in patients with lower ADCs (WLsp-ROI P = 0.023, S-ROI P = 0.038). CONCLUSION: Reduced ADCs are associated with histological severity and worse outcome in OC. ADCs measured with WLsp-ROI may serve as a prognostic biomarker of OC. KEY POINTS: • Reduced ADCs correlate with prognostic markers: poor differentiation and high Ki-67 expression • ADCs also significantly correlated with VEGF protein expression in primary tumours • Lower ADC values are associated with poorer survival in ovarian cancer • Whole lesion single plane-ROI ADCs may be used as a prognostic biomarker in OC.


Assuntos
Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Imagem de Difusão por Ressonância Magnética/métodos , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/mortalidade , Variações Dependentes do Observador , Neoplasias Ovarianas/mortalidade , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Reprodutibilidade dos Testes , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Oncotarget ; 8(11): 18381-18398, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28179588

RESUMO

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Ligases SKP Culina F-Box/genética , Análise de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto Jovem
16.
Br J Cancer ; 116(5): 640-648, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28095396

RESUMO

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. METHODS: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. RESULTS: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. CONCLUSIONS: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.


Assuntos
Carcinoma de Células Escamosas/patologia , Fibronectinas/metabolismo , Células Estromais/metabolismo , Tenascina/metabolismo , Neoplasias da Língua/patologia , Carcinoma de Células Escamosas/metabolismo , Gerenciamento Clínico , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Neoplasias da Língua/metabolismo
17.
BMC Cancer ; 16(1): 833, 2016 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-27806715

RESUMO

BACKGROUND: To investigate whether very low mammographic breast density (VLD), HER2, and hormone receptor status holds any prognostic significance within the different prognostic categories of the widely used Nottingham Prognostic Index (NPI). We also aimed to see whether these factors could be incorporated into the NPI in an effort to enhance its performance. METHODS: This study included 270 patients with newly diagnosed invasive breast cancer. Patients with mammographic breast density of <10 % were considered as VLD. In this study, we compared the performance of NPI with and without VLD, HER2, ER and PR. Cox multivariate analysis, time-dependent receiver operating characteristic curve (tdROC), concordance index (c-index) and prediction error (0.632+ bootstrap estimator) were used to derive an updated version of NPI. RESULTS: Both mammographic breast density (VLD) (p < 0.001) and HER2 status (p = 0.049) had a clinically significant effect on the disease free survival of patients in the intermediate and high risk groups of the original NPI classification. The incorporation of both factors (VLD and HER2 status) into the NPI provided improved patient outcome stratification by decreasing the percentage of patients in the intermediate prognostic groups, moving a substantial percentage towards the low and high risk prognostic groups. CONCLUSIONS: Very low density (VLD) and HER2 positivity were prognostically significant factors independent of the NPI. Furthermore, the incorporation of VLD and HER2 to the NPI served to enhance its accuracy, thus offering a readily available and more accurate method for the evaluation of patient prognosis.


Assuntos
Biomarcadores Tumorais , Densidade da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Expressão Gênica , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Carga Tumoral
18.
Breast Cancer Res Treat ; 160(2): 237-247, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27683279

RESUMO

PURPOSE: Obesity and oversupply of glucose, e.g., due to nutritional factors may shape the tumor microenvironment favorable for tumor progression. O-GlcNAcylation, a reversible modification of intracellular proteins, influences on several cellular functions and is connected to many diseases including cancer. Glycosaminoglycan hyaluronan (HA) enhances tumor progression and in breast cancer HA accumulation associates strongly with poor outcome. In vitro studies have suggested that O-GlcNAcylation may enhance HA synthesis. The aim of this study was to investigate the correlations between O-GlcNAcylation, HA-related parameters, and disease outcome in a clinical breast cancer material consisting of 278 breast cancer cases. METHODS: In microscopic analyses, O-GlcNAc staining of the breast carcinoma cells was evaluated in several randomly picked high-power fields of each section. The extent of cytoplasmic O-GlcNAc staining was graded as either low or high according to the intensity of the staining and the percentage of stained cells. The extent of nuclear O-GlcNAc staining was categorized as either low or high according to the percentage of stained nuclei. RESULTS: A high extent of both cytoplasmic and nuclear O-GlcNAcylation correlated with an increased relapse rate, development of distant metastases, and poor outcome. A high extent of cytoplasmic O-GlcNAcylation correlated also with the accumulation of all hyaluronan synthase (HAS1-3) proteins and with a large amount of HA in the tumor stroma. In addition, a high extent of nuclear O-GlcNAcylation associated with obesity. CONCLUSIONS: The results suggest a mechanistic association between increased O-GlcNAcylation and HA synthesis, leading to a HA-rich microenvironment favorable for breast cancer progression.


Assuntos
Acetilglucosamina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Hialuronan Sintases/metabolismo , Ácido Hialurônico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias da Mama/diagnóstico , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Glicosilação , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Obesidade/metabolismo , Prognóstico , Células Estromais
19.
PLoS One ; 11(8): e0160316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27556229

RESUMO

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.


Assuntos
Neoplasias da Mama/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Locos de Características Quantitativas , Alelos , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Gradação de Tumores , Polimorfismo de Nucleotídeo Único , Vigilância da População , Medição de Risco
20.
Int J Cancer ; 139(12): 2760-2770, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27542569

RESUMO

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09-2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5-5.76, p = 1.80 × 10-3 ). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR = 1.8, 95% CI 1.09-2.98, p = 0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR = 3.43, 95% CI 1.6-7.34, p = 1.50 × 10-3 ) but not among radiotherapy treated patients (HR = 1.35, 95% CI 0.82-2.23, p = 0.237). Significant interaction was found between the mutation and radiotherapy (p = 0.040). Immunohistochemical analyses show that c.5101C > T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C > T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , DNA Helicases/genética , Mutação Puntual , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Terapia Combinada , DNA Helicases/metabolismo , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Fenótipo , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
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