Browsing by Subject "Colorectal cancer"

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  • Kondelin, Johanna; Tuupanen, Sari; Gylfe, Alexandra E.; Aavikko, Mervi; Renkonen-Sinisalo, Laura; Järvinen, Heikki; Bohm, Jan; Mecklin, Jukka-Pekka; Andersen, Claus L.; Vahteristo, Pia; Pitkanen, Esa; Aaltonen, Lauri A. (2015)
    Approximately 15 % of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5 %) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.
  • Kaprio, Tuomas; Hagstrom, Jaana; Fermer, Christian; Mustonen, Harri; Bockelman, Camilla; Nilsson, Olle; Haglund, Caj (2014)
  • Nykänen, Sonja (Helsingin yliopisto, 2019)
    Colorectal cancer (CRC) kills more than half a million people a year worldwide. Usually the disease develops over several years via multiple steps which involve both genetic and epigenetic alterations. CRC is often diagnosed at late stage, when the cancer has already metastasized, and the prognosis is relatively poor. Several studies suggest that the first changes towards colorectal cancer occur and can be detected in histologically normal tissue before the appearance of any detectable lesion. The precancerous cells harbouring those changes may form a field of tissue, which is predisposed to malignant transformation. The study of pre-cancerous tissue might reveal the earliest changes in CRC development, which can be used as biomarkers for early detection and prevention of CRC. The aim of this thesis was to revise and investigate whether the aberrant expression of the six chromosomal segregation genes, Bub1, Mis18a, Pms2, Rad9a, Tpx2, and Mlh1, would signal carcinogenesis in mouse colon mucosa. Altogether fourteen mice, of which six had a proximal colon carcinoma, were selected for the study. The expression analysis was performed to histologically normal colon mucosa collected from the proximal and distal colon of each mice in order to investigate whether the possible pre-cancerous changes are found exclusively in the close proximity to the carcinoma. The expression was quantified with reverse transcription quantitative polymerase chain reaction (RTqPCR). No statistically significant gene expression differences were found between the carcinoma and control mice, indicating that the studied mice did not display cancer-preceding expression changes of the six studied genes in the carcinoma adjacent histologically normal colon mucosa. The results differed from the previously reported results, where the expressions of the six genes were found to be downregulated in the carcinoma adjacent mucosa. Here, the sample size was presumably not large enough to reveal statistically significant clustering of the expression patterns. However, Bub1 seemed to have a downregulated trend in the carcinoma adjacent mucosa, which supports the previously suggested role of Bub1 alterations in CRC initiation.
  • Gunnarsson, Ulf; Strigård, Karin; Edin, Sofia; Gkekas, Ioannis; Mustonen, Harri; Kaprio, Tuomas; Böckelman, Camilla; Hagström, Jaana; Palmqvist, Richard; Haglund, Caj (2020)
    Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.
  • Gunnarsson, Ulf; Strigård, Karin; Edin, Sofia; Gkekas, Ioannis; Mustonen, Harri; Kaprio, Tuomas; Böckelman, Camilla; Hagström, Jaana; Palmqvist, Richard; Haglund, Caj (BioMed Central, 2020)
    Abstract Background Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities. Methods Complete clinical and long-term survival data were retrieved for 316 CRC patients operated at Helsinki University Hospital between the years 1998 and 2003. Tissue microarrays were prepared from surgical specimens and further processed and analyzed for local immune cell infiltration using multispectral imaging with a Vectra quantitative pathology imaging system and Inform software. Multiplex immunohistochemistry was applied using antibodies against CD66b, CD8, CD20, FoxP3, CD68 and pan-Cytokeratin. After exclusions, data on immune infiltration were available for 275 patients. Mismatch repair status was determined by immunohistochemistry. Results CRP was seen to be an independent predictor of cancer-specific survival but not overall survival in uni- and multivariable (HR 1.01 (1.00–1.02); p = 0.028) analyses of non-irradiated patients. There was no significant difference in CRP according to mismatch repair status, but all cases (n = 10) with CRP ≥ 75 mg/l had proficient mismatch repair (pMMR). There was a significant negative correlation between intratumor stromal infiltration by T-regulatory FOXP3+ cells and CRP (p = 0.006). There was significantly lower intratumor stromal infiltration by FOXP3+ cells (p = 0.043) in the right colon compared to the rectum, but no significant difference in CRP (p = 0.44). CRP was not a predictor of overall survival (HR 0.99, 95% CI 0.98–1.01) nor cancer-specific survival in irradiated patients (HR 0.94, 95% CI 0.94–1.02). Conclusions There was a significant negative relationship between SIR, defined as an elevated CRP, and intratumor stromal infiltration by T-regulatory FOXP3+ cells. This and the fact that all cases with a CRP > 75 mg/l had pMMR suggests that SIR and dMMR are independent entities in CRC. Indeed, the general lack of difference in CRP between cases with dMMR and pMMR may be evidence of overlap in cases with a less pronounced SIR.
  • Talibov, Madar; Sormunen, Jorma; Hansen, Johnni; Kjaerheim, Kristina; Martinsen, Jan-Ivar; Sparen, Per; Tryggvadottir, Laufey; Weiderpass, Elisabete; Pukkala, Eero (2018)
    Objective: The aim of this case-control study was to assess the effect of occupational benzene exposure on the risk of colorectal cancer, including its subtypes. Methods: The study included 181,709 colon cancer and 109,227 rectal cancer cases diagnosed between 1961 and 2005 in Finland, Iceland, Norway and Sweden. Cases were identified from the Nordic Occupational Cancer Study (NOCCA) cohort. Five controls per case were selected from the same cohort, matched for country, birth year, and sex. Occupational benzene exposure for each study participant was estimated by linking their job titles to country specific job-exposure matrices. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by using conditional logistic regression models. The results were adjusted for physical strain at work, formaldehyde, ionizing radiation and wood dust. Results: Increased risk was observed for all colorectal cancer (OR = 1.12, 95% CI 1.05-1.18) for the high decile of cumulative benzene exposure, indicating a statistically significant dose-response relationship. This excess risk was mainly seen in ascending colon (OR = 1.27, 95% CI 1.13-1.43), and transversal colon (OR = 1.21, 95% CI 1.01-1.41). The ORs in the highest exposure category were markedly higher in women than in men in all subsites of colon and rectum. Conclusion: This study showed an association between workplace benzene exposure and colorectal cancer. The risk was restricted to ascending and transversal colon, and was the strongest among women.
  • Seppala, Toni; Pylvanainen, Kirsi; Evans, Dafydd Gareth; Jarvinen, Heikki; Renkonen-Sinisalo, Laura; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind; Rodland, Einar Andreas; Tharmaratnam, Kukatharmini; Cappel, Wouter H. de Vos tot Nederveen; Hill, James; Wijnen, Juul; Jenkins, Mark; Genuardi, Maurizio; Green, Kate; Lalloo, Fiona; Sunde, Lone; Mints, Miriam; Bertario, Lucio; Pineda, Marta; Navarro, Matilde; Morak, Monika; Frayling, Ian M.; Plazzer, John-Paul; Sampson, Julian R.; Capella, Gabriel; Moslein, Gabriela; Mecklin, Jukka-Pekka; Moller, Pal; Collaboration Mallorca Grp (2017)
    Background: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.
  • Zamora-Ros, Raul; Cayssials, Valerie; Jenab, Mazda; Rothwell, Joseph A.; Fedirko, Veronika; Aleksandrova, Krasimira; Tjonneland, Anne; Kyro, Cecilie; Overvad, Kim; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Mahamat-Saleh, Yahya; Kaaks, Rudolf; Kuehn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; Valanou, Elissavet; Vasilopoulou, Effie; Masala, Giovanna; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Ricceri, Fulvio; Weiderpass, Elisabete; Lukic, Marko; Sandanger, Torkjel M.; Lasheras, Cristina; Agudo, Antonio; Sanchez, Maria-Jose; Amiano, Pilar; Navarro, Carmen; Ardanaz, Eva; Sonestedt, Emily; Ohlsson, Bodil; Nilsson, Lena Maria; Rutegard, Martin; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Khaw, Kay-Thee; Wareham, Nicholas J.; Bradbury, Kathryn; Freisling, Heinz; Romieu, Isabelle; Cross, Amanda J.; Vineis, Paolo; Scalbert, Augustin (2018)
    Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2=1.06, 95% CI 0.99-1.14) or in men (HRlog2=0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2=0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2=1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.
  • Holm, Matilda; Joenväärä, Sakari; Saraswat, Mayank; Tohmola, Tiialotta; Ristimäki, Ari; Renkonen, Risto; Haglund, Caj (BioMed Central, 2019)
    Abstract Background Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence is expected to increase to over 2.2 million new cases in 2030. Stage II CRC is classified as localized disease, while stage III CRC has spread to regional lymph nodes. The 5-year survival rate is over 80% for patients with stage II CRC, but less than 60% for patients with stage III CRC. Proteins, especially plasma proteins that are detectable in easily obtained blood samples, that differ between stage II and III CRC could be useful for predicting and monitoring disease progression. CRC displays differences depending on primary tumor location (right colon, left colon, or rectum), and how plasma protein expression changes during CRC progression from stage II to III depending on primary tumor location is not well-characterized. Methods In this study, we have used Ultra Performance Liquid Chromatography-Ultra Definition Mass Spectrometry (UPLC-UDMSE)-based proteomics to analyze plasma samples from 83 patients with stage II or III CRC, followed by statistical and pathway analysis (data are available via ProteomeXchange). The patients were divided into groups according to tumor stage (II or III) and changes in plasma protein expression between stage II and III (localized and regional disease) samples were studied both regardless of primary tumor location and also within each primary tumor location (right colon, left colon, rectum). Results We discovered differences in plasma protein expression within all groups analyzed and identified proteins whose levels changed in one, two, or all three primary tumor locations between stage II and III CRC. Proteins were identified that could separate the groups compared and pathway analysis by IPA discovered altered pathways involved in lipid metabolism and inflammation, among others. Conclusions Plasma protein expression changes significantly as CRC progresses from stage II to III. While the levels of certain plasma proteins changed during cancer progression in only one or two primary tumor locations, the levels of 13 proteins changed in all primary tumor locations and are therefore common to CRC progression.
  • Al-Samadi, Ahmed; Moossavi, Shirin; Salem, Abdelhakim; Sotoudeh, Masoud; Tuovinen, Sarianna M.; Konttinen, Yrjo T.; Salo, Tuula; Bishehsari, Faraz (2016)
    Colorectal cancer (CRC) is one of the most common cancers in both genders. Even though interleukin (IL)-17A was shown to play an important role in intestinal tumourigenesis and CRC, other IL-17 family members were not studied well. We therefore studied the expression of IL-17 cytokine family members in CRC. Ten healthy colons and ten CRC mucosa were immunostained for IL-17B, IL-17C, IL-17E, and IL-17F, and their receptors IL-17RA, IL-17RB, and IL-17RC. Double immunofluorescence staining of the CRC mucosa was done for IL-17B with markers of neutrophils, endothelial cells, macrophages, T cells, mast cells, or fibroblasts. While IL-17B was increased in CRC with a strong presence both in the epithelial and stromal compartments, IL-17C showed different expression depending on the grade of differentiation and IL-17E remained unchanged. In contrast, IL-17F was decreased in CRC compared to healthy control. Colon epithelial cells stained positive for IL-17RA, IL-17RB, and IL-17RC in both healthy control and CRC. Neutrophils were the main source of IL-17B in the stroma. IL-17 family members demonstrated distinct expression patterns in CRC, suggesting a differential role exerted by each member in colon carcinogenesis.
  • Ukwattage, Sanjeevi (Helsingin yliopisto, 2019)
    Background- Colorectal cancer (CRC) is the third most common epithelial carcinoma. There is an increased risk of colorectal cancer in people with longstanding inflammation in the large intestine, including individuals with ulcerative colitis (UC). Epigenetic changes in CRC such as aberrant DNA methylation alterations are common changes in human cancer. The aim of this study is to identify the DNA methylation alterations of selected inflammation related genes in UC-CRC vs. Lynch syndrome (LS). Method- DNA was extracted from archival tissue specimens from normal and tumor samples from UC-CRC (n= 31), and LS-CRC (n=29). Methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) assays were used to detect CIMP status and CpG promoter methylation status of seven inflammation related genes. Microsatellite instability analysis was carried out using two mononucleotide repeat markers BAT25 and BAT26. Results- Increased hypermethylation frequencies in carcinoma vs. normal colonic mucosa were detected for all the inflammatory marker genes in specimens of UC-CRC patients. Statistically significant differences for methylation frequencies were observed in the NTSR1 gene (p value =0.008) and SOCS2 gene (p value =0.04) in specimens of UC-CRC patients. NTSR1 gene showed significantly increased methylation of normal colonic mucosae from UC-CRC vs. LS patients (p value=0.01). Conclusion- UC-CRC and LS tumor specimens revealed varying frequencies of hypermethylation in all the inflammatory genes. Methylation of the NTSR1 in the normal colonic mucosa suggests a possible field defect in UC-CRC, and could thus be used as an early biomarker to detect increased UC-CRC risk in non-neoplastic epithelium.
  • Birkman, Eva-Maria; Avoranta, Tuulia; Algars, Annika; Korkeila, Eija; Lintunen, Minnamaija; Lahtinen, Laura; Kuopio, Teijo; Ristamäki, Raija; Carpen, Olli; Sundström, Jari (2018)
    Epidermal growth factor receptor (EGFR) gene copy number (GCN) increase is associated with a favorable anti-EGFR antibody treatment response in RAS wild-type metastatic colorectal cancer. However, there are limited and comparative data regarding the EGFR GCN in primary colorectal cancer tumors and corresponding metastases or the effect of anti-EGFR antibody treatment on EGFR GCN in recurrent disease. In addition, little is known about the potential EGFR GCN changes during anti-EGFR therapy in comparison with other treatment regimens. EGFR GCN was analyzed by EGFR immunohistochemistry-guided silver in situ hybridization in primary and corresponding recurrent local or metastatic tumors from 80 colorectal cancer patients. GCN levels were compared between KRAS wild-type patients having received antiEGFR therapy and patients having received other forms of treatment after primary surgery. The EGFR GCN decrease between primary and recurrent tumors was more pronounced among the anti EGFR-treated patients than among patients not treated with anti-EGFR therapy (P=.047). None of the patients experiencing an EGFR GCN increase of at least 1.0 between the primary and recurrent tumors were treated with antiEGFR antibodies. When including only patients with distant metastases, an EGFR GCN decrease of at least 1.0 was more common among the anti EGFR-treated patients than among patients not treated with anti-EGFR therapy (P=.028). Our results suggest that anti-EGFR antibody treatment is associated with EGFR GCN decrease between the primary and recurrent colorectal adenocarcinomas, whereas no GCN change is observed among patients receiving other forms of treatment after primary surgery. (C) 2018 The Authors. Published by Elsevier Inc.
  • Lähde, Marianne; Heino, Sarika; Högström, Jenny; Kaijalainen, Seppo; Anisimov, Andrey; Flanagan, Dustin; Kallio, Pauliina; Leppänen, Veli-Matti; Ristimäki, Ari; Ritvos, Olli; Wu, Katherine; Tammela, Tuomas; Hodder, Michael; Sansom, Owen; Alitalo, Kari (Helsingin yliopisto, 2020)
    Suolistosyövät ovat läntisen maailman kolmanneksi yleisimpiä syöpiä. Alati kehittyvistä hoitomuodoista huolimatta edelleenkin joka kolmas suolistosyövistä leviää muihin elimiin, ja merkittävä osa potilaista menehtyy. Yleisesti tiedetään, että syöpäsolut vaativat jakautuakseen useita erilaisia mutaatioita, joiden ansiosta ne pääsevät karkaamaan elimistön kontrollista. Suolistosyövissä tyypillinen mutaatio on solunsisäistä Wnt-signalointireittiä säätelevässä APC-geenissä. APC:n periytyvä mutaatio aiheuttaa Familial Adenomatous Polyposis (FAP)-nimisen sairauden, jossa potilaan suolistoon kehittyy jopa satoja adenoomia. Nämä etenevät hoitamattomana syöväksi lähes 100% todennäköisyydellä. Tämän tutkielman tarkoituksena oli selvittää tarkemmin suolistosyövän kantasolujen ja niitä säätelevien, Wnt-signalointia vahvistavien kasvutekijöiden, R-spondiinien (RSPO), toimintaa, erityisesti kasvainten kehityksen alkuvaiheissa. Tätä tarkoitusta varten tuotettiin AAV-vektori, jonka avulla voitiin käynnistää systeeminen R-spondiinituotanto suolistosyövän Apc-mutantissa hiirimallissa. R-spondiinien tiedetään edistävän suoliston terveiden kantasolujen toimintaa, ja niiden on ajateltu olevan merkittävässä roolissa myös suolistosyöpien kehityksessä. AAV-RSPO1-vektori aikaansaikin villityypin hiirissä odotetusti suolen kantasolujen toiminnan kiihtymisen. Kuitenkin hiiren suolistokasvaimissa vaikutus oli päinvastainen; RSPO1-käsittely hidasti ApcMin-hiirten adenoomien kasvua, kiihdytti apoptoosia spesifisti adenoomasoluissa sekä pidensi kasvaimista kärsivien hiirten elinikää verrokkeihin nähden merkittävästi. Mekanistisissa tutkimuksissa kävi ilmi, että AAV-RSPO1-käsittely aktivoi TGFB-signalointireitin, jonka tiedetään aktivoivan solunsisäistä apoptoosikoneistoa yksinomaan kasvainsoluissa, ja siten rajoittavan niiden kasvua. Tämän seurauksena suolen terveet solut saavuttivat kilpailuedun kasvainsoluihin nähden, ja syrjäyttivät kasvainsoluja, jolloin adenoomista päästiin eroon lähes kokonaan. Näiden löydösten perusteella voisikin olla mahdollista kehittää uusia hoitomuotoja suolistosyöpiin, erityisesti FAP:tä sairastaville potilaille.
  • Yu, Hongyao; Hemminki, Akseli; Sundquist, Kristina; Hemminki, Kari (2019)
    BACKGROUND: Many studies have indicated that colon and rectal cancers differ in etiology and histology. OBJECTIVE: The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific. DESIGN: A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer. SETTINGS: The study was conducted using the Swedish Family-Cancer Database. MAIN OUTCOME MEASURES: The outcome measure was relative risk. RESULTS: Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% Cl, 1.74-1.90) vs 1.61 (95% Cl, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% Cl, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant. LIMITATIONS: Genetic data are unavailable in the database. CONCLUSIONS: Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition.
  • Shen, Zhanlong; Wang, Bo; Luo, Jianyuan; Jiang, Kewei; Zhang, Hui; Mustonen, Harri; Puolakkainen, Pauli; Zhu, Jun; Ye, Yingjiang; Wang, Shan (2016)
    Lysine acetylated modification was indicated to impact colorectal cancer (CRC)'s distant metastasis. However, the global acetylated proteins in CRC and the differential expressed acetylated proteins and acetylated sites between CRC primary and distant metastatic tumor remains unclear. Our aim was to construct a complete atlas of acetylome in CRC and paired liver metastases. Combining high affinity enrichment of acetylated peptides with high sensitive mass spectrometry, we identified 603 acetylation sites from 316 proteins, among which 462 acetylation sites corresponding to 243 proteins were quantified. We further classified them into groups according to cell component, molecular function and biological process and analyzed the metabolic pathways, domain structures and protein interaction networks. Finally, we evaluated the differentially expressed lysine acetylation sites and revealed that 31 acetylated sites of 22 proteins were downregulated in CRC liver metastases compared to that in primary CRC while 40 acetylated sites of 32 proteins were upregulated, of which HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. These results provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC. Biological significance: This study described provides, for the first time, that full-scale profiling of lysine acetylated proteins were identified and quantified in colorectal cancer (CRC) and paired liver metastases. The novelty of the study is that we constructed a complete atlas of acetylome in CRC and paired liver metastases. Moreover, we analyzed these differentially expressed acetylated proteins in cell component, molecular function and biological process. In addition, metabolic pathways, domain structures and protein interaction networks of acetylated proteins were also investigated. Our approaches shows that of the differentially expressed proteins, HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. Our findings provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC. (C) 2016 Elsevier B.V. All rights reserved.
  • Peltonen, Reetta; Hagström, Jaana; Tervahartiala, Taina; Sorsa, Timo; Haglund, Caj; Isoniemi, Helena (2021)
    Introduction: The liver metastases of colorectal cancer (CRC) can be surgically treated in selected cases, with continuously improving results. Matrix metalloproteinases (MMPs) contribute to cancer invasion by degrading the extracellular matrix, and elevated levels of MMP-2, MMP-8, and MMP-9 have been detected in several malignancies. Myeloperoxidase (MPO) is a mediator of tissue damage that can oxidatively activate latent MMPs. We evaluated the prognostic value of MMP-2, MMP-8, and MMP-9 in tissue samples of primary tumors and liver metastases and the pre- and postoperative serum levels of MMP-8, MMP-9, and MPO in CRC patients undergoing liver resection. Methods: Tissue and serum samples were obtained from 111 patients who had primary colorectal tumors and their liver metastases surgically treated at the Helsinki University Hospital between 1988 and 2007. Tissue expression of MMP-2, MMP-8, and MMP-9 in primary tumors and liver metastases was evaluated by immunohistochemistry. Pre- and postoperative serum concentrations of MMP-8, MMP-9, and MPO were determined using a time-resolved immunofluorometric assay or commercially available enzyme-linked immunosorbent assay kits. Clinical data were retrieved from patient records and the Central Statistical Office of Finland. Associations with disease-free survival (DFS) and overall survival (OS) were estimated using Cox regression analysis and the Kaplan-Meier method. Results: High expression of MMP-9 in colorectal tumor tissue was associated with better DFS (p = 0.010), and high preoperative MPO in serum with improved DFS and OS (p < 0.001 and p = 0.014, respectively). The prognostic significance varied according to gender, age, and the synchronicity of liver metastases. Conclusion: Low preoperative MPO in serum might identify patients at high risk of recurrence and death after resection of colorectal liver metastases. Elevated preoperative MPO and high expression of MMP-9 in colorectal tumor tissue indicate an improved prognosis. The use of these biomarkers should be adjusted according to clinical characteristics.
  • Bazzocco, Sarah; Dopeso, Higinio; Martínez-Barriocanal, Águeda; Anguita, Estefanía; Nieto, Rocío; Li, Jing; García-Vidal, Elia; Maggio, Valentina; Rodrigues, Paulo; de Marcondes, Priscila G; Schwartz, Simo; Aaltonen, Lauri A; Sánchez, Alex; Mariadason, John M; Arango, Diego (BioMed Central, 2021)
    Abstract Background Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
  • Bazzocco, Sarah; Dopeso, Higinio; Martinez-Barriocanal, Agueda; Anguita, Estefania; Nieto, Rocio; Li, Jing; Garcia-Vidal, Elia; Maggio, Valentina; Rodrigues, Paulo; de Marcondes, Priscila Guimaraes; Schwartz, Simo; Aaltonen, Lauri A.; Sanchez, Alex; Mariadason, John M.; Arango, Diego (2021)
    Background Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
  • Seppälä, Toni T; Ahadova, Aysel; Dominguez-Valentin, Mev; Macrae, Finlay; Evans, D. G; Therkildsen, Christina; Sampson, Julian; Scott, Rodney; Burn, John; Möslein, Gabriela; Bernstein, Inge; Holinski-Feder, Elke; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Lautrup, Charlotte K; Lindblom, Annika; Plazzer, John-Paul; Winship, Ingrid; Tjandra, Douglas; Katz, Lior H; Aretz, Stefan; Hüneburg, Robert; Holzapfel, Stefanie; Heinimann, Karl; Valle, Adriana D; Neffa, Florencia; Gluck, Nathan; de Vos tot Nederveen Cappel, Wouter H; Vasen, Hans; Morak, Monika; Steinke-Lange, Verena; Engel, Christoph; Rahner, Nils; Schmiegel, Wolff; Vangala, Deepak; Thomas, Huw; Green, Kate; Lalloo, Fiona; Crosbie, Emma J; Hill, James; Capella, Gabriel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; ten Broeke, Sanne; Nielsen, Maartje; Ljungmann, Ken; Nakken, Sigve; Lindor, Noralane; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka-Pekka; Kalager, Mette; Møller, Pål (BioMed Central, 2019)
    Abstract Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.
  • Seppala, Toni T.; Ahadova, Aysel; Dominguez-Valentin, Mev; Macrae, Finlay; Evans, D. Gareth; Therkildsen, Christina; Sampson, Julian; Scott, Rodney; Burn, John; Möslein, Gabriela; Bernstein, Inge; Holinski-Feder, Elke; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Lautrup, Charlotte Kvist; Lindblom, Annika; Plazzer, John-Paul; Winship, Ingrid; Tjandra, Douglas; Katz, Lior H.; Aretz, Stefan; Hueneburg, Robert; Holzapfel, Stefanie; Heinimann, Karl; Della Valle, Adriana; Neffa, Florencia; Gluck, Nathan; Cappel, Wouter H. de Vos Tot Nederveen; Vasen, Hans; Morak, Monika; Steinke-Lange, Verena; Engel, Christoph; Rahner, Nils; Schmiegel, Wolff; Vangala, Deepak; Thomas, Huw; Green, Kate; Lalloo, Fiona; Crosbie, Emma J.; Hill, James; Capella, Gabriel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; ten Broeke, Sanne; Nielsen, Maartje; Ljungmann, Ken; Nakken, Sigve; Lindor, Noralane; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka-Pekka; Kalager, Mette; Moller, Pal (2019)
    BackgroundRecent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.MethodsTo inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.ResultsStage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within 3.5years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p=0.34). The cancers detected more than 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.