Browsing by Subject "COLORECTAL-CANCER"

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  • MISiCOL Task Force (2018)
    Aim: To investigate the rate of laparoscopic colectomies for colon cancer using registries and population based studies. To provide a position paper on mini-invasive (MIS) colon cancer surgery based on the opinion of experts leader in this field. Methods: A systematic review of the literature was conducted using PRISMA guidelines for the rate of laparoscopy in colon cancer. Moreover, Delphi methodology was used to reach consensus among 35 international experts in four study rounds. Consensus was defined as an agreement >= 75.0%. Domains of interest included nosology, essential technical/oncological requirements, outcomes and MIS training. Results: Forty-four studies from 42 articles were reviewed. Although it is still sub-optimal, the rate of MIS for colon cancer increased over the years and it is currently >50% in Korea, Netherlands, UK and Australia. The remaining European countries are un-investigated and presented lower rates with highest variations, ranging 7-35%. Using Delphi methodology, a laparoscopic colectomy was defined as a "colon resection performed using key-hole surgery independently from the type of anastomosis". The panel defined also the oncological requirements recognized essential for the procedure and agreed that when performed by experienced surgeons, it should be marked as best practice in guidelines, given the principles of oncologic surgery be respected (RO procedure, vessel ligation and mesocolon integrity). Conclusion: The rate of MIS colectomies for cancer in Europe should be further investigated. A panel of leaders in this field defined laparoscopic colectomy as a best practice procedure when performed by an experienced surgeon respecting the standards of surgical oncology. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Sundqvist, Benjamin; Kilpinen, Sami; Böhling, Tom; Koljonen, Virve; Sihto, Harri (2022)
    Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin with a poor prognosis. Improving the prognosis of MCC by means of targeted therapies requires further understanding of the mechanisms that drive tumor progression. In this study, we aimed to identify the genes, processes, and pathways that play the most crucial roles in determining MCC outcomes. Methods: We investigated transcriptomes generated by RNA sequencing of formalin-fixed paraffin-embedded tissue samples of 102 MCC patients and identified the genes that were upregulated among survivors and in patients who died from MCC. We subsequently cross-referenced these genes with online databases to investigate the functions and pathways they represent. We further investigated differential gene expression based on viral status in patients who died from MCC. Results: We found several novel genes associated with MCC-specific survival. Genes upregulated in patients who died from MCC were most notably associated with angiogenesis and the PI3K-Akt and MAPK pathways; their expression predominantly had no association with viral status in patients who died from MCC. Genes upregulated among survivors were largely associated with antigen presentation and immune response. Conclusion: This outcome-based discrepancy in gene expression suggests that these pathways and processes likely play crucial roles in determining MCC outcomes.
  • Nummela, Pirjo; Heiskanen, Annamari; Kytölä, Soili; Haglund, Caj; Lepistö, Anna; Satomaa, Tero; Ristimäki, Ari (2021)
    Pseudomyxoma peritonei (PMP) is a highly mucinous adenocarcinoma growing in the peritoneal cavity and most commonly originating from the appendix. Glycans play an important role in carcinogenesis, and glycosylation is altered in malignant diseases, including PMP. We have previously demonstrated that fucosylation of N-glycans is increased in PMP, but we did not observe modulation of overall sialylation. As sialic acids can be attached to the rest of the glycan via α2,3- or α2,6-linkage, we have now analyzed the linkage patterns of sialic acids in tissue specimens of normal appendices, low-grade appendiceal mucinous neoplasms (LAMN), low-grade (LG) PMP and high-grade (HG) PMP. For the linkage analysis, the enzymatically released acidic N-glycans were first treated with ethyl esterification or α2,3-sialidase digestion followed by MALDI-TOF mass spectrometry. Significant increase in the relative abundance of α2,6-sialylated and decrease in α2,3-sialylated N-glycans was observed in PMP tumors as compared to the normal appendices (P \lt; 0.025). More specifically, increased α2,6-sialylation (P \lt; 0.05) and decreased α2,3-sialylation (P \lt; 0.01) were detected in afucosylated and monofucosylated N-glycans of PMPs, whereas the less abundant multifucosylated glycans, containing terminal fucose, demonstrated increased α2,3-sialylation (P \lt; 0.01). Importantly, the increase in α2,6-sialylation was also detected between PMP and the appendiceal precursor lesion LAMN (P \lt; 0.01). The identified glycosylation alterations produce ligands for sialic acid-binding immunoglobulin-like lectins (Siglecs) and sialofucosylated glycans binding selectins, which play a role in the peritoneal dissemination and progression of the disease.
  • Heervä, Eetu; Väliaho, Vesa; Salminen, Tapio; Nieminen, Lasse; Carpelan, Anu; Kurki, Samu; Sundström, Jari; Huhtinen, Heikki; Rantala, Arto; Carpen, Olli; Minn, Heikki; Österlund, Pia; Ålgars, Annika; Ristamäki, Raija (2020)
  • Leroy, Frédéric; Abraini, Fabien; Beal, Ty; Domínguez-Salas, Paula; Gregorini, Pablo; Manzano, Pablo; Rowntree, Jason; van Vliet, Stephan (2022)
    Animal source foods are evolutionarily appropriate foods for humans. It is therefore remarkable that they are now presented by some as unhealthy, unsustainable, and unethical, particularly in the urban West. The benefits of consuming them are nonetheless substantial, as they offer a wide spectrum of nutrients that are needed for cell and tissue development, function, and survival. They play a role in proper physical and cognitive development of infants, children, and adolescents, and help promote maintenance of physical function with ageing. While high-red meat consumption in the West is associated with several forms of chronic disease, these associations remain uncertain in other cultural contexts or when consumption is part of wholesome diets. Besides health concerns, there is also widespread anxiety about the environmental impacts of animal source foods. Although several production methods are detrimental (intensive cropping for feed, overgrazing, deforestation, water pollution, etc.) and require substantial mitigation, damaging impacts are not intrinsic to animal husbandry. When well-managed, livestock farming contributes to ecosystem management and soil health, while delivering high-quality foodstuffs through the upcycling of resources that are otherwise non-suitable for food production, making use of marginal land and inedible materials (forage, by-products, etc.), integrating livestock and crop farming where possible has the potential to benefit plant food production through enhanced nutrient recycling, while minimising external input needs such as fertilisers and pesticides. Moreover, the impacts on land use, water wastage, and greenhouse gas emissions are highly contextual, and their estimation is often erroneous due to a reductionist use of metrics. Similarly, whether animal husbandry is ethical or not depends on practical specificities, not on the fact that animals are involved. Such discussions also need to factor in that animal husbandry plays an important role in culture, societal well-being, food security, and the provision of livelihoods. We seize this opportunity to argue for less preconceived assumptions about alleged effects of animal source foods on the health of the planet and the humans and animals involved, for less top-down planning based on isolated metrics or (Western) technocratic perspectives, and for more holistic and circumstantial approaches to the food system.
  • Siltanen, Sanna; Fischer, Daniel; Rantapero, Tommi; Laitinen, Virpi; Mpindi, John Patrick; Kallioniemi, Olli; Wahlfors, Tiina; Schleutker, Johanna (2013)
  • Amatya, Sajeen Bahadur; Salmi, Sonja; Kainulainen, Veera; Karihtala, Peeter; Reunanen, Justus (2021)
    Simple Summary:& nbsp;Microbial dysbiosis has been credited as one of the contributing factors to the development and progression of gastrointestinal tract cancer. The altered microbiota influences carcinogenesis through the induction of instability and damage to genetic material, modulation of host metabolic and inflammatory pathways, production of carcinogenic metabolites, and suppression of host antitumor response. These microbes secrete extracellular vesicles that are possibly carrying carcinogenic bioactive metabolites within their cargo. Studies have illustrated the ability of bacterial extracellular vesicles to cross the intestinal epithelial barrier and selectively accumulate near intestinal tumor cells. The purpose of this systemic review was to highlight the possible role of gut bacterial vesicles in the development, progression, and pathogenesis of gastrointestinal tract cancer and their possible involvement in the modulation of the tumor microenvironment. An infinitesimal amount of research has been carried out on the impact of bacterial extracellular vesicles on oncogenesis and tumor progression. This review aimed to encourage more investigations on this subject.Bacterial extracellular vesicles are membrane-enclosed, lipid bi-layer nanostructures that carry different classes of biomolecules, such as nucleic acids, lipids, proteins, and diverse types of small molecular metabolites, as their cargo. Almost all of the bacteria in the gut secrete extracellular vesicles to assist them in competition, survival, material exchange, host immune modulation, infection, and invasion. The role of gut microbiota in the development, progression, and pathogenesis of gastrointestinal tract (GIT) cancer has been well documented. However, the possible involvement of bacterial extracellular vesicles (bEVs) in GIT cancer pathophysiology has not been given due attention. Studies have illustrated the ability of bEVs to cross physiological barriers, selectively accumulate near tumor cells, and possibly alter the tumor microenvironment (TME). A systematic search of original published works related to bacterial extracellular vesicles on gastrointestinal cancer was performed for this review. The current systemic review outlines the possible impact of gut microbiota derived bEVs in GIT cancer in light of present-day understanding. The necessity of using advanced sequencing technologies, such as genetic, proteomic, and metabolomic investigation methodologies, to facilitate an understanding of the interrelationship between cancer-associated bacterial vesicles and gastrointestinal cancer is also emphasized. We further discuss the clinical and pharmaceutical potential of bEVs, along with future efforts needed to understand the mechanism of interaction of bEVs in GIT cancer pathogenesis.
  • Sievanen, Tero; Tormakangas, Timo; Laakkonen, Eija K.; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Seppälä, Toni T.; Peltomäki, Paivi; Sipila, Sarianna; Sillanpää, Elina (2021)
    Simple Summary Lifestyle modifies cancer risk in the general public. How lifestyle modifies cancer risk in individuals carrying the inherited pathogenic gene variants in DNA mismatch repair genes (Lynch syndrome) remains understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, physical activity, and cancer risk among Finnish Lynch syndrome carriers (n = 465, 54% women). The results of our study indicated that longitudinal weight gain increases cancer risk, whereas being highly physically active during adulthood could decrease cancer risk in men. Further, women were observed to be less prone to lifestyle-related risk factors than men. The results emphasize the role of weight maintenance and high-intensity physical activity throughout the lifespan, especially in men with Lynch syndrome. Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00-1.04) and CRC (HR 1.03, 1.01-1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92-0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15-0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.
  • Kaapu, Kalle J.; Rantaniemi, Lauri; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L. J.; Auvinen, Anssi; Murtola, Teemu J. (2018)
    In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34-1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.
  • CAPP2 Investigators; Mathers, John C.; Elliott, Faye; Macrae, Finlay; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Burn, John (2022)
    The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P= 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. Prevention Relevance: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.
  • But, Anna; De Bruin, Marie L.; Bazelier, Marloes T.; Hjellvik, Vidar; Andersen, Morten; Auvinen, Anssi; Starup-Linde, Jakob; Schmidt, Marjanka K.; Furu, Kari; de Vries, Frank; Karlstad, Oystein; Ekstrom, Nils; Haukka, Jari (2017)
    Aims/hypothesis The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. Methods National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. Results A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for 6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. Conclusions/interpretation The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.
  • Pussila, Marjaana; Sarantaus, Laura; Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi Mari-Anna; Peltomäki, Päivi T; Mutanen, Marja; Nyström, Minna (2013)
  • Scheinin, Ilari; Ferreira, Jose A.; Knuutila, Sakari; Meijer, Gerrit A.; van de Wiel, Mark A.; Ylstra, Bauke (2010)
  • Forsgard, Richard A.; Marrachelli, Vannina G.; Korpela, Katri; Frias, Rafael; Carmen Collado, Maria; Korpela, Riitta; Monleon, Daniel; Spillmann, Thomas; Osterlund, Pia (2017)
    Purpose Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT. Methods A total of 48 male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR). Results Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)(3) moieties and decreased the levels of Krebs cycle metabolites and free amino acids. Conclusions Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes.
  • Landais, Edwige; Moskal, Aurelie; Mullee, Amy; Nicolas, Genevieve; Gunter, Marc J.; Huybrechts, Inge; Overvad, Kim; Roswall, Nina; Affret, Aurelie; Fagherazzi, Guy; Mahamat-Saleh, Yahya; Katzke, Verena; Kuehn, Tilman; La Vecchia, Carlo; Trichopoulou, Antonia; Valanou, Elissavet; Saieva, Calogero; de Magistris, Maria Santucci; Sieri, Sabina; Braaten, Tonje; Skeie, Guri; Weiderpass, Elisabete; Ardanaz, Eva; Chirlaque, Maria-Dolores; Garcia, Jose Ramon; Jakszyn, Paula; Rodriguez-Barranco, Miguel; Brunkwall, Louise; Huseinovic, Ena; Nilsson, Lena; Wallstroem, Peter; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Aune, Dagfinn; Key, Tim; Lentjes, Marleen; Riboli, Elio; Slimani, Nadia; Freisling, Heinz (2018)
    Background: Coffee and tea are among the most commonly consumed nonalcoholic beverages worldwide, but methodological differences in assessing intake often hamper comparisons across populations. We aimed to (i) describe coffee and tea intakes and (ii) assess their contribution to intakes of selected nutrients in adults across 10 European countries. Method: Between 1995 and 2000, a standardized 24-h dietary recall was conducted among 36,018 men and women from 27 European Prospective Investigation into Cancer and Nutrition (EPIC) study centres. Adjusted arithmetic means of intakes were estimated in grams (=volume) per day by sex and centre. Means of intake across centres were compared by sociodemographic characteristics and lifestyle factors. Results: In women, the mean daily intake of coffee ranged from 94 g/day (similar to 0.6 cups) in Greece to 781 g/day (similar to 4.4 cups) in Aarhus (Denmark), and tea from 14 g/day (similar to 0.1 cups) in Navarra (Spain) to 788 g/day (similar to 4.3 cups) in the UK general population. Similar geographical patterns for mean daily intakes of both coffee and tea were observed in men. Current smokers as compared with those who reported never smoking tended to drink on average up to 500 g/day more coffee and tea combined, but with substantial variation across centres. Other individuals' characteristics such as educational attainment or age were less predictive. In all centres, coffee and tea contributed to less than 10% of the energy intake. The greatest contribution to total sugar intakes was observed in Southern European centres (up to similar to 20%). Conclusion: Coffee and tea intake and their contribution to energy and sugar intake differed greatly among European adults. Variation in consumption was mostly driven by geographical region.
  • Frank, Christoph; Sundquist, Jan; Yu, Hongyao; Hemminki, Akseli; Hemminki, Kari (2017)
    Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.
  • Siltanen, Sanna; Wahlfors, Tiina; Schindler, Martin; Saramaki, Outi R.; Mpindi, John Patrick; Latonen, Leena; Vessella, Robert L.; Tammela, Teuvo L. J.; Kallioniemi, Olli; Visakorpi, Tapio; Schleutker, Johanna (2011)
  • Roine, Eija; Farkkila, Niilo; Sintonen, Harri; Taari, Kimmo; Roine, Risto P.; Saarto, Tiina (2019)
    Background/Aim: This cross-sectional study estimated direct cancer-related health care, productivity and informal care costs for a six-month period for different states of breast cancer (BC). Patients and Methods: A total of 827 BC patients answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Direct health care resource use and productivity costs were obtained from registries. Mutually exclusive groups were formed based on disease state and time from diagnosis: primary treatment (first six months after diagnosis), rehabilitation (>six months after diagnosis), remission (>1.5 years after diagnosis), and metastatic. Results: Mean total costs were: primary treatment (sic)22,876, rehabilitation (sic)3,456, remission (sic)1,728, and metastatic (sic)24,320. Mean direct health care costs were: primary treatment (sic)11,798, rehabilitation (sic)2,398, remission (sic)1,147, and metastatic (sic)13,923. Mean productivity costs varied between 18-39% and indirect costs (productivity and informal care costs) between 31-48% of the total costs. Conclusion: Direct medical costs were highest, but indirect costs constituted up to half of the total costs and are essential when estimating the total cost burden, as many patients are of working age.
  • Christensen, Jon; El-Gebali, Sara; Natoli, Manuela; Sengstag, Thierry; Delorenzi, Mauro; Bentz, Susanne; Bouzourene, Hanifa; Rumbo, Martin; Felsani, Armando; Siissalo, Sanna; Hirvonen, Jouni; Vila, Maya R.; Saletti, Piercarlo; Aguet, Michel; Anderle, Pascale (2012)
  • Kuuluvainen, Emilia; Domenech-Moreno, Eva; Niemela, Elina H.; Makela, Tomi P. (2018)
    In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta-catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.