Browsing by Subject "CARCINOMAS"

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  • Scheinin, Ilari; Ferreira, Jose A.; Knuutila, Sakari; Meijer, Gerrit A.; van de Wiel, Mark A.; Ylstra, Bauke (2010)
  • Slik, Khadija; Blom, Sami; Turkki, Riku; Välimäki, Katja; Kurki, Samu; Mustonen, Harri; Haglund, Caj; Carpén, Olli; Kallioniemi, Olli; Korkeila, Eija; Sundström, Jari; Pellinen, Teijo (2019)
    Tumour budding predicts survival of stage II colorectal cancer (CRC) and has been suggested to be associated with epithelial-to-mesenchymal transition (EMT). However, the underlying molecular changes of tumour budding remain poorly understood. Here, we performed multiplex immunohistochemistry (mIHC) to phenotypically profile tumours using known EMT-associated markers: E-cadherin (adherence junctions), integrin beta 4 (ITGB4; basement membrane), ZO-1 (tight junctions), and pan-cytokeratin. A subpopulation of patients showed high ITGB4 expression in tumour buds, and this coincided with a switch of ITGB4 localisation from the basal membrane of intact epithelium to the cytoplasm of budding cells. Digital image analysis demonstrated that tumour budding with high ITGB4 expression in tissue microarray (TMA) cores correlated with tumour budding assessed from haematoxylin and eosin (H&E) whole sections and independently predicted poor disease-specific survival in two independent stage II CRC cohorts (hazard ratio [HR] = 4.50 (95% confidence interval [CI] = 1.50-13.5), n = 232; HR = 3.52 (95% CI = 1.30-9.53), n = 72). Furthermore, digitally obtained ITGB4-high bud count in random TMA cores was better associated with survival outcome than visual tumour bud count in corresponding H&E-stained samples. In summary, the mIHC-based phenotypic profiling of human tumour tissue shows strong potential for the molecular characterisation of tumour biology and for the discovery of novel prognostic biomarkers.
  • Ahadova, Aysel; Pfuderer, Pauline Luise; Ahtiainen, Maarit; Ballhausen, Alexej; Bohaumilitzky, Lena; Kösegi, Svenja; Müller, Nico; Tang, Yee Lin; Kosmalla, Kosima; Witt, Johannes; Endris, Volker; Stenzinger, Albrecht; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Kloor, Matthias (2021)
    Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.
  • Scala, Giovanni; Federico, Antonio; Palumbo, Domenico; Cocozza, Sergio; Greco, Dario (2020)
    DNA methylation alterations are related to multiple molecular mechanisms. The DNA context of CpG sites plays a crucial role in the maintenance and stability of methylation patterns. The quantitative relationship between DNA composition and DNA methylation has been studied in normal as well as pathological conditions, showing that DNA methylation status is highly dependent on the local sequence context. In this work, we describe this relationship by analyzing the DNA sequence context associated to methylation profiles in both physiological and pathological conditions. In particular, we used DNA motifs to describe methylation stability patterns in normal tissues and aberrant methylation events in cancer lesions. In this manuscript, we show how different groups of DNA sequences can be related to specific epigenetic events, across normal and cancer tissues, and provide a thorough structural and functional characterization of these sequences.
  • Ali, Abir Salwa; Grönberg, Malin; Langer, Seppo W.; Ladekarl, Morten; Hjortland, Geir Olav; Vestermark, Lene Weber; Österlund, Pia; Welin, Staffan; Gronbaek, Henning; Knigge, Ulrich; Sorbye, Halfdan; Janson, Eva Tiensuu (2018)
    High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.
  • Janson, Eva Tiensuu; Knigge, Ulrich; Dam, Gitte; Federspiel, Birgitte; Gronbaek, Henning; Stålberg, Peter; Langer, Seppo W.; Kjaer, Andreas; Arola, Johanna; Schalin-Jäntti, Camilla; Sundin, Anders; Welin, Staffan; Thiis-Evensen, Espen; Sorbye, Halfdan (2021)
    Background The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. Aim These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.
  • Sokolenko, Anna P.; Savonevich, Elena L.; Ivantsov, Alexandr O.; Raskin, Grigory A.; Kuligina, Ekatherina S.; Gorodnova, Tatiana V.; Preobrazhenskaya, Elena V.; Kleshchov, Maxim A.; Tiurin, Vladislav I.; Mukhina, Marina S.; Kotiv, Khristina B.; Shulga, Andrey V.; Kuznetsov, Sergey G.; Berlev, Igor V.; Imyanitov, Evgeny N. (2017)
    Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.
  • Sonnenblick, Amir; Salmon-Divon, Mali; Salgado, Roberto; Dvash, Efrat; Pondé, Noam; Zahavi, Tamar; Salmon, Asher; Loibl, Sibylle; Denkert, Carsten; Joensuu, Heikki; Ameye, Lieveke; Van den Eynden, Gert; Kellokumpu-Lehtinen, Pirkko-Liisa; Azaria, Amos; Loi, Sherene; Michiels, Stefan; Richard, Francois; Sotiriou, Christos (2020)
    We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; >= 50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC
  • Blows, Fiona M.; Driver, Kristy E.; Schmidt, Marjanka K.; Broeks, Annegien; van Leeuwen, Flora E.; Wesseling, Jelle; Cheang, Maggie C.; Gelmon, Karen; Nielsen, Torsten O.; Blomqvist, Carl; Heikkilä, Päivi; Heikkinen, Tuomas; Nevanlinna, Heli; Akslen, Lars A.; Begin, Louis R.; Foulkes, William D.; Couch, Fergus J.; Wang, Xianshu; Cafourek, Vicky; Olson, Janet E.; Baglietto, Laura; Giles, Graham G.; Severi, Gianluca; McLean, Catriona A.; Southey, Melissa C.; Rakha, Emad; Green, Andrew R.; Ellis, Ian O.; Sherman, Mark E.; Lissowska, Jolanta; Anderson, William F.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Provenzano, Elena; Dawson, Sarah-Jane; Dunning, Alison M.; Humphreys, Manjeet; Easton, Douglas F.; Garcia-Closas, Montserrat; Caldas, Carlos; Pharoah, Paul D.; Huntsman, David (2010)
  • Andersson, Saana; Ilonen, Ilkka; Järvinen, Tommi; Rauma, Ville; Räsänen, Jari; Salo, Jarmo (2018)
    The role of positive lymph node location in non-small-cell lung cancer (NSCLC) patients and effects on survival was assessed. A total of 88 operated patients with unsuspected N2 disease or station 10 lymph nodes were included. No difference was found in survival between inferior positive mediastinal N2 node patients compared to multilevel N2 disease patients. The survival of patients with positive hilar disease was similar to the inferior mediastinal positive N2 group. Background: The role of surgery in the treatment of non-small-cell lung cancer that has spread to ipsilateral mediastinal or hilar lymph nodes (LNs) is controversial. We examined whether the location of LNs positive for non-small-cell lung cancer in mediastinum or hilum influences the survival of these patients. Patients and Methods: We reviewed data from 881 patients and analyzed those with unsuspected N2 disease or hilar (station 10) LNs. The patients were stratified into the following groups: group A, positive hilar Naruke 10; group B, superior mediastinal and aortic nodes (Naruke 1, 2, 3, 4, 5, and 6); group C, inferior mediastinal nodes (Naruke 7, 8, and 9), and multilevel group D (2 or more positive N2 levels). Results: A total of 69 pN2 and 19 pN1 patients were included. Progression-free survival (PFS) was statistically significant better in group B versus group C (P = .044) and group B versus group D (P = .0086). The overall survival (OS) of group A did not differ from that of group C. A statistically significant better OS was found between groups B and D (P= .051). Conclusion: Inferior positive mediastinal N2 node patients seem to have an OS and PFS as poor as multilevel N2 disease patients. The OS and PFS of patients with positive hilar disease are similar to those in the inferior mediastinal positive N2 group. Superior positive mediastinal N2 node patients have better OS and PFS than the inferior mediastinal positive N2 group. (C) 2018 Elsevier Inc. All rights reserved.
  • Lagström, Sonja; Umu, Sinan Ugur; Lepistö, Maija; Ellonen, Pekka; Meisal, Roger; Christiansen, Irene Kraus; Ambur, Ole Herman; Rounge, Trine B. (2019)
    HPV genomic variability and chromosomal integration are important in the HPV-induced carcinogenic process. To uncover these genomic events in an HPV infection, we have developed an innovative and cost-effective sequencing approach named TaME-seq (tagmentation-assisted multiplex PCR enrichment sequencing). TaME-seq combines tagmentation and multiplex PCR enrichment for simultaneous analysis of HPV variation and chromosomal integration, and it can also be adapted to other viruses. For method validation, cell lines (n = 4), plasmids (n = 3), and HPV16, 18, 31, 33 and 45 positive clinical samples (n = 21) were analysed. Our results showed deep HPV genome-wide sequencing coverage. Chromosomal integration breakpoints and large deletions were identified in HPV positive cell lines and in one clinical sample. HPV genomic variability was observed in all samples allowing identification of low frequency variants. In contrast to other approaches, TaME-seq proved to be highly efficient in HPV target enrichment, leading to reduced sequencing costs. Comprehensive studies on HPV intra-host variability generated during a persistent infection will improve our understanding of viral carcinogenesis. Efficient identification of both HPV variability and integration sites will be important for the study of HPV evolution and adaptability and may be an important tool for use in cervical cancer diagnostics.
  • Abdel-Rahman, Wael M.; Lotsari-Salomaa, Johanna E.; Kaur, Sippy; Niskakoski (o.s. Tieva), Anni; Knuutila, Sakari; Järvinen, Heikki; Mecklin, Jukka-Pekka; Peltomaki, Paivi (2016)
    All colorectal cancer cell lines except RKO displayed active beta-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various beta-catenin localizations as a surrogate marker for beta-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors withmembranous beta-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.