Browsing by Subject "CYCLIN D1"

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  • Markkanen, Anttoni; Aro, Katri; Laury, Anna Ray; Mäkitie, Antti A.; Haglund, Caj; Atula, Timo; Hagström, Jaana (2022)
    The objective of this retrospective study was to explore possible changes in histopathological features and expression of cyclin D1 and MIB-1 in salivary gland pleomorphic adenoma (PA) that recur or undergo malignant transformation. Knowledge of these characteristics might help to guide the management of these rare tumors. The histopathology and immunohistochemical staining characteristics of such tumors were analyzed in a cohort of 65 patients constituting three different groups of tumors: PA, recurrent pleomorphic adenoma (RPA) and carcinoma ex PA (CxPA). The RPAs were divided into two subgroups: primary PA that were known to recur later (PA-prim) and recurrent tumors appearing after a primary tumor (PA-rec). RPAs and CxPAs were compared with PAs without recurrence, which served as a control group. In our study, CxPA and PA-rec, but not PA-prim, showed increased MIB-1 expression compared with the control group. Neither cyclin D1 expression nor any histopathological features showed any association in statistical analyses. CxPA showed increased mitotic activity, squamous metaplasia, and nuclear atypia. Tumor multifocality was more frequent in PA-rec and CxPA. The different MIB-1 expression in CxPA and PA-rec in comparison to PA-prim suggests that the changes in expression could develop after the primary tumor.
  • Khan, Sofia; Fagerholm, Rainer; Kadalayil, Latha; Tapper, William; Aittomäki, Kristiina; Liu, Jianjun; Blomqvist, Carl; Eccles, Diana; Nevanlinna, Heli (2018)
    The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 x 10(-8)). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 x 10(-8)). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79-27.08, P-interaction = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.
  • Iherman-Hella, Anneliis; Lume, Maria; Miinalainen, Ilkka; Pirttiniemi, Anniina; Gui, Yujuan; Peränen, Johan; Charron, Jean; Saarma, Mart; Costantini, Frank; Kuure, Satu Helena (2014)
  • Rodrigues, Joana M.; Hassan, May; Freiburghaus, Catja; Eskelund, Christian W.; Geisler, Christian; Räty, Riikka; Kolstad, Arne; Sundstrom, Christer; Glimelius, Ingrid; Gronbaek, Kirsten; Kwiecinska, Anna; Porwit, Anna; Jerkeman, Mats; Ek, Sara (2020)
    Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients withTP53missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 andTP53status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression andTP53mutations on survival (hazard ratio of 3 center dot 1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.
  • Cuppens, Tine; Annibali, Daniela; Coosemans, An; Trovik, Jone; ter Haar, Natalja; Colas, Eva; Garcia-Jimenez, Angel; Van de Vijver, Koen; Kruitwagen, Roy P. M.; Brinkhuis, Mariel; Zikan, Michal; Dundr, Pavel; Huvila, Jutta; Carpen, Olli; Haybaeck, Johannes; Moinfar, Farid; Salvesen, Helga B.; Stukan, Maciej; Mestdagh, Carole; Zweemer, Ronald P.; Massuger, Leonardus F.; Mallmann, Michael R.; Wardelmann, Eva; Mints, Miriam; Verbist, Godelieve; Thomas, Debby; Gomme, Ellen; Hermans, Els; Moerman, Philippe; Bosse, Tjalling; Amant, Frederic (2017)
    Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment. Experimental Design: We investigated the expression of several druggable targets (phospho-S6(S240) ribosomal protein, PTEN, PDGFR-alpha, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6(S240), was tested in patient-derived xenograft (PDX) leiomyosarcoma models. Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6(S240) correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6(S240) expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6(S240) in response prediction to PI3K/mTOR inhibition. Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6(S240) expression is a potential predictive biomarker for response to treatment. (C)2017 AACR.
  • Rahmani, Farzad; Hashemzehi, Milad; Avan, Amir; Barneh, Farnaz; Asgharzadeh, Fereshteh; Marjaneh, Reyhaneh Moradi; Soleimani, Atena; Parizadeh, Mohammadreza; Ferns, Gordon A.; Mobarhan, Majid Ghayour; Ryzhikov, Mikhail; Afshari, Amir Reza; Ahmadian, Mohammad Reza; Giovannetti, Elisa; Jafari, Mohieddin; Khazaei, Majid; Hassanian, Seyed Mahdi (2021)
    Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.
  • Patel, Saroor A.; Hirosue, Shoko; Rodrigues, Paulo; Vojtasova, Erika; Richardson, Emma K.; Ge, Jianfeng; Syafruddin, Saiful E.; Speed, Alyson; Papachristou, Evangelia K.; Baker, David; Clarke, David; Purvis, Stephenie; Wesolowski, Ludovic; Dyas, Anna; Castillon, Leticia; Caraffini, Veronica; Bihary, Dora; Yong, Cissy; Harrison, David J.; Stewart, Grant D.; Machiela, Mitchell J.; Purdue, Mark P.; Chanock, Stephen J.; Warren, Anne Y.; Samarajiwa, Shamith A.; Carroll, Jason S.; Vanharanta, Sakari (2022)
    Large-scale human genetic data(1-3) have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)(4-6). VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization(6,7). We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele Cat rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. (8)). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.
  • Sjoblom, A; Stenman, UH; Hagstrom, J; Jouhi, L; Haglund, C; Syrjanen, S; Mattila, P; Makitie, A; Carpen, T (2021)
    Simple Summary Oropharyngeal squamous cell carcinoma (OPSCC) is a form of head and neck cancer in which human papillomavirus (HPV) infection has been shown to play a major role in disease development. The survival rates of HPV-positive patients are favorable compared to HPV-negative patients, but the reason for this phenomenon remains unclear. The management of OPSCC is complex, and development of novel treatment options is urgently required. Various possible factors affecting survival have been explored, including the tumor environment and cancer-related proteases. Our aim was to study a protease inhibitor known as tumor-associated trypsin inhibitor and its correlation with survival and clinical data in OPSCC patients. Background: We studied the role of tumor-associated trypsin inhibitor (TATI) in serum and in tumor tissues among human papillomavirus (HPV)-positive and HPV-negative OPSCC patients. Materials and methods: The study cohort included 90 OPSCC patients treated at the Helsinki University Hospital (HUS), Helsinki, Finland, in 2012-2016. TATI serum concentrations (S-TATIs) were determined by an immunofluorometric assay. Immunostaining was used to assess tissue expression. HPV status was determined with a combination of p16 immunohistochemistry and HPV DNA PCR genotyping. The survival endpoints were overall survival (OS) and disease-specific survival (DSS). Results: A significant correlation was found between S-TATI positivity and poor OS (p < 0.001) and DSS (p = 0.04) in all patients. In HPV-negative cases, S-TATI positivity was linked to poor OS (p = 0.01) and DSS (p = 0.05). In HPV-positive disease, S-TATI positivity correlated with poor DSS (p = 0.01). S-TATI positivity was strongly associated with HPV negativity. TATI serum was negatively linked to a lower cancer stage. TATI expression in peritumoral lymphocytes was associated with favorable OS (p < 0.025) and HPV positivity. TATI expression in tumor and in peritumoral lymphocytes correlated with lower cancer stages. Conclusion: Our results suggest that S-TATI positivity may be a biomarker of poor prognosis in both HPV-positive and HPV-negative OPSCC.