Publications by authors named "Ari Ristimäki"

149 Publications

Altered linkage pattern of N-glycan sialic acids in pseudomyxoma peritonei.

Glycobiology 2020 Aug 17. Epub 2020 Aug 17.

Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, FI-00290, Helsinki, Finland.

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 < 0.025). More specifically, increased α2,6-sialylation (P < 0.05) and decreased α2,3-sialylation (P < 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 < 0.01). Importantly, the increase in α2,6-sialylation was also detected between PMP and the appendiceal precursor lesion LAMN (P < 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.
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http://dx.doi.org/10.1093/glycob/cwaa079DOI Listing
August 2020

Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer.

Int J Cancer 2021 Jan 31. Epub 2021 Jan 31.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n = 27) were investigated for microsatellite instability, CpG island methylator phenotype and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n = 28). Mutational loads and signatures stratified CA-CRCs into three subgroups: hypermutated microsatellite-unstable (Group 1, n = 1), hypermutated microsatellite-stable (Group 2, n = 9) and nonhypermutated microsatellite-stable (Group 3, n = 17). The Group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency-associated Signatures 21 and 15. Signatures 30 and 32 characterized Group 2, whereas no prominent single signature existed in Group 3. TP53, the most common mutational target in CA-CRC (16/27, 59%), was similarly affected in Groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in Group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA-CRC Groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, Groups 1 (4%) and 3 (63%) comply with published studies, whereas Group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA-CRC may guide clinical management, such as therapy options.
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http://dx.doi.org/10.1002/ijc.33492DOI Listing
January 2021

Fecal Microbiota Transplantation in Chronic Pouchitis: A Randomized, Parallel, Double-Blinded Clinical Trial.

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastrointestinal Surgery, Helsinki University Hospital, Helsinki, Finland.

Background: In ulcerative colitis, a pouchitis is the most common long-term adverse effect after proctocolectomy and ileal pouch-anal anastomosis. Approximately 5% of patients develop chronic antibiotic-dependent or antibiotic-refractory pouchitis without any effective treatment. The aim of this trial was to investigate the efficacy and safety of fecal microbiota transplantation in the treatment of chronic pouchitis.

Methods: This was a single-center, double-blinded, parallel group trial comparing donor fecal microbiota transplantation with placebo (autologous transplant) in chronic pouchitis. Twenty-six patients were recruited at the Helsinki University Hospital between December 2017 and August 2018 and were randomly allocated a 1:1 ratio to either donor fecal microbiota transplantation or placebo. The protocol included 2 transplantations into the pouch on weeks 0 and 4, and patients were followed up for 52 weeks.

Results: Nine patients in the intervention group and 8 patients in the placebo group relapsed during the 52-week follow-up, and the relapse-free survival did not differ between the groups (P = 0.183, log-rank; hazard ratio, 1.90 [95% confidence interval, 0.73-4.98; P = 0.190]). In the subgroup analysis of patients using continuous antibiotics before the study, the relapse-free survival was shorter in the intervention group (P = 0.004, log-rank; hazard ratio, 13.08 [95% confidence interval, 1.47-116.60; P = 0.021]). No major adverse effects were reported.

Conclusions: The fecal microbiota transplantation treatment regime used in our study was not effective in the treatment of chronic pouchitis. The safety profile of fecal microbiota transplantation was good.

Clinicaltrials.gov Identifier: NCT03378921.
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http://dx.doi.org/10.1093/ibd/izab001DOI Listing
January 2021

Author's Reply: Fecal Microbiota Transplantation for Chronic Pouchitis: Promising Novel Therapeutic or Lost Cause?

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastrointestinal Surgery, Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1093/ibd/izab003DOI Listing
January 2021

Detection of KRAS mutations in liquid biopsies from metastatic colorectal cancer patients using droplet digital PCR, Idylla, and next generation sequencing.

PLoS One 2020 25;15(11):e0239819. Epub 2020 Nov 25.

Department of Pathology, Medicum, Faculty of Medicine, University of Helsinki and HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.

Circulating tumor DNA (ctDNA) is released from cancer cells and oncogenic mutations in ctDNA can be measured from plasma samples. Droplet digital PCR (ddPCR) is a sensitive and specific method for the detection of mutations in ctDNA. We analyzed serial plasma samples (n = 80) from ten metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor. The patients were undergoing oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan. Baseline ddPCR KRAS mutation allele frequency (MAF) values ranged from 0% to 63%. The first radiologic response evaluation criteria in solid tumors (RECIST) evaluation was performed 45-63 days after the initiation of treatment, and by this time three patients had an undetectable level of KRAS mutation, one had a MAF value of 0.5%, and one had a MAF value of 3% that had been reduced by 95% from the baseline value. In three of these patients the RECIST assessment was stable disease and in two partial response. In seven patients, ddPCR MAF values increased before radiological disease progression or death, while one patient remained disease-free with an undetectable KRAS mutation level. Next, we analyzed all available plasma samples with the Idylla ctKRAS system (n = 60), and found that the overall degree of agreement between ddPCR and Idylla was almost perfect (kappa value = 0.860). We used next-generation sequencing (NGS) to detect treatment-induced mutations in the last serial plasma sample of each patient, but were unable to find any new mutations when compared to the primary tumor. This study shows that ddPCR and Idylla are equally efficient for the detection of KRAS mutations in the liquid biopsies from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones and serve as an early sign of disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688175PMC
January 2021

Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.

Virchows Arch 2020 Nov 10. Epub 2020 Nov 10.

Departments of Pathology and Molecular Genetics, Hospital U Arnau de Vilanova and Hospital U de Bellvitge, University of Lleida, IRBLLEIDA, IDIBELL, CIBERONC, Av. Alcalde Rovira Roure, 80 25198, Lleida, Spain.

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
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http://dx.doi.org/10.1007/s00428-020-02962-xDOI Listing
November 2020

Cohort profile: gastric cancer in the population-based, Finnish National Esophago-Gastric Cancer Cohort (FINEGO) Study.

BMJ Open 2020 10 16;10(10):e039574. Epub 2020 Oct 16.

Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Purpose: The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established with the aim of identifying factors that could contribute to improved outcomes in oesophago-gastric cancer. The aim of this study is to describe the patients with gastric cancer included in FINEGO.

Participants: A total of 10 457 patients with gastric cancer or tumour diagnosis in the Finnish Cancer Registry or the Finnish Patient Registry during 1987-2016 were included in the cohort, with follow-up from Causes of Death Registry until 31 December 2016. All of the participants were at least 18 years of age, and had undergone either resectional or endoscopic mucosal surgery with curative or palliative intent.

Findings To Date: Of the 10 457 patients, 90.1% were identified to have cancer in both cancer and patient registries. In all, the median age was 70 at the time of surgery, 54.5% of the patients were men and 64.4% had no comorbidities. Education data were available for 31.1% of the patients, of whom the majority had had <12 years of formal education. Of the 7798 with cancer staging data available, 41.1% had a local cancer. Adenocarcinoma was the most common (94.2%) histological type. Almost all patients underwent open gastrectomy and 214% in hospitals with annual volume of more than 30 gastrectomies per year. A total of 8561 deaths occurred during the study period, of which 6474 were due to oesophago-gastric cancers. The 5-year survival was 34.6% and 5-year cancer-specific survival was 39.7%.

Future Plans: The data in FINEGO can be currently used for registry-based research but is being expanded by data extraction from patient records and scanning of histological samples from the Finnish biobanks. Initially, we are planning on studies on the national trends in treatment and mortality, and studies on the demographic factors and their influence on survival.
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http://dx.doi.org/10.1136/bmjopen-2020-039574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569918PMC
October 2020

Cohort profile: a nationwide population-based retrospective assessment of oesophageal cancer in the Finnish National Esophago-Gastric Cancer Cohort (FINEGO).

BMJ Open 2020 10 14;10(10):e039575. Epub 2020 Oct 14.

Surgery Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland

Purpose: The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established to combine the available registry data with detailed patient information to form a comprehensive, retrospective, population-based research platform of surgically treated oesophageal and gastric cancer in Finland. This cohort profile describes the 2045 surgically treated patients with oesophageal cancer included in the FINEGO cohort.

Participants: Registry data were collected from the National Cancer, Patient, Education and Death Registries from 1 January 1987 to 31 December 2016. All patients over 18 years of age, who had either curative surgery, palliative surgery or salvage surgery for primary cancer in the oesophagus are included in this study.

Findings To Date: 2045 patients had surgery for oesophageal cancer in the selected time period. 67.2% were man, and the majority had only minor comorbidities. The proportions of adenocarcinomas and squamous cell carcinomas were 43.1% and 44.4%, respectively, and 12.5% had other or missing histology. Only about 23% of patients received neoadjuvant therapy. Oesophagectomy was the treatment of choice and most patients were treated at low-volume centres, but median annual hospital volume increased over time. Median overall survival was 23 months, 5-year survival for all patients in the cohort was 32.9% and cancer-specific survival was 36.5%.

Future Plans: Even though Finland only has a population of 5.5 million, surgery for oesophageal carcinoma has not been centralised and therefore previously reported results have mostly been small, single-centre cohorts. Because of FINEGO, we now have a population-based, unselected cohort of surgically treated patients, enabling research on national trends over time regarding oesophageal cancer, including patient characteristics, tumour histology, stage and neoadjuvant treatment, surgical techniques, hospital volumes and patient mortality. Data collection is ongoing, and the cohort will be expanded to include more detailed data from patient records and national biobanks.
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http://dx.doi.org/10.1136/bmjopen-2020-039575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559040PMC
October 2020

Expression of R-Spondin 1 in Apc Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling.

Gastroenterology 2021 Jan 14;160(1):245-259. Epub 2020 Sep 14.

Translational Cancer Medicine Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland. Electronic address:

Background & Aims: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in Apc mutant mice.

Methods: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into Apcmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry.

Results: Intestines from Apc mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced Apc mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of Apc mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from Apc mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from Apc mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector.

Conclusions: Expression of RSPO1 in Apc mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.
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http://dx.doi.org/10.1053/j.gastro.2020.09.011DOI Listing
January 2021

N-glycomic profiling of colorectal cancer according to tumor stage and location.

PLoS One 2020 29;15(6):e0234989. Epub 2020 Jun 29.

Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Alterations in glycosylation are seen in many types of cancer, including colorectal cancer (CRC). Glycans, the sugar moieties of glycoconjugates, are involved in many important functions relevant to cancer and can be of value as biomarkers. In this study, we have used mass spectrometry to analyze the N-glycan profiles of 35 CRC tissue samples and 10 healthy tissue samples from non-CRC patients who underwent operations for other reasons. The tumor samples were divided into groups depending on tumor location (right or left colon) and stage (II or III), while the healthy samples were divided into right or left colon. The levels of neutral and acidic N-glycan compositions and glycan classes were analyzed in a total of ten different groups. Surprisingly, there were no significant differences in glycan levels when all right- and left-sided CRC samples were compared, and few differences (such as in the abundance of the neutral N-glycan H3N5) were seen when the samples were divided according to both location and stage. Multiple significant differences were found in the levels of glycans and glycan classes when stage II and III samples were compared, and these glycans could be of value as candidates for new markers of cancer progression. In order to validate our findings, we analyzed healthy tissue samples from the right and left colon and found no significant differences in the levels of any of the glycans analyzed, confirming that our findings when comparing CRC samples from the right and left colon are not due to normal variations in the levels of glycans between the healthy right and left colon. Additionally, the levels of the acidic glycans H4N3F1P1, H5N4F1P1, and S1H5N4F1 were found to change in a cancer-specific but colon location-nonspecific manner, indicating that CRC affects glycan levels in similar ways regardless of tumor location.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234989PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323945PMC
September 2020

Plasma protein expression differs between colorectal cancer patients depending on primary tumor location.

Cancer Med 2020 07 26;9(14):5221-5234. Epub 2020 May 26.

Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Colorectal cancer (CRC) includes tumors in the right colon, left colon, and rectum, although they differ significantly from each other in aspects such as prognosis and treatment. Few previous mass spectrometry-based studies have analyzed differences in protein expression depending on the tumor location. In this study, we have used mass spectrometry-based proteomics to analyze plasma samples from 83 CRC patients to study if differences in plasma protein expression can be seen depending on primary tumor location (right colon, left colon, or rectum). Differences were studied between the groups both regardless of and according to tumor stage (II or III). Large differences in plasma protein expression were seen, and we found that plasma samples from patients with rectal cancer separated from samples from patients with colon cancer when analyzed by principal component analysis and hierarchical clustering. Samples from patients with cancer in the right and left colon also tended to separate from each other. Pathway analysis discovered canonical pathways involved in lipid metabolism and inflammation to be enriched. This study will help to further define CRC as distinct entities depending on tumor location, as shown by the widespread differences in plasma protein profile and dysregulated pathways.
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http://dx.doi.org/10.1002/cam4.3178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367633PMC
July 2020

Preoperative Radiotherapy Leads to Significant Differences in the Plasma Protein Profile of Rectal Cancer Patients.

Oncology 2020 15;98(7):493-500. Epub 2020 Apr 15.

Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for 10% of the global cancer burden. Rectal cancer accounts for around 30% of CRC cases, and patients with resectable rectal cancer are often given preoperative radiotherapy (PRT) to reduce the rate of local recurrence. The human plasma proteome is an exceptionally complex proteome and ideal to study due to its ability to reflect the presence of diseases such as cancer and the ease of obtaining blood samples. Previous proteomic studies involving rectal cancer patients have mostly focused on the identification of proteins involved in resistance to radiotherapy.

Objective: The aim of this study was to investigate the overall effects of PRT on plasma protein expression in rectal cancer patients, as there is a lack of such studies.

Methods: Here, we have used mass spectrometry and subsequent statistical analyses to analyze the plasma samples of 30 rectal cancer patients according to PRT status (positive or negative) and tumor stage (II or III).

Results And Conclusions: We discovered 42 proteins whose levels differed significantly between stage II and III rectal cancer patients who did or did not receive PRT. This study shows that PRT, although localized to the pelvis, leads to measurable, tumor stage-specific changes in plasma protein expression. Future studies of plasma proteins should, when relevant, take this into account and be aware of the widespread effects that PRT has on the plasma proteome.
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http://dx.doi.org/10.1159/000505697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384342PMC
July 2020

Association between chronic pancreatitis and pancreatic cancer: A 10-year retrospective study of endoscopically treated and surgical patients.

Int J Cancer 2020 Sep 3;147(5):1450-1460. Epub 2020 Apr 3.

Gastroenterological Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Pancreatic cancer (PC) has a poor prognosis. Chronic pancreatitis (CP) associates with high morbidity and mortality, and serves as a risk factor for PC. Our study aimed to assess the association between endoscopically treated CP patients and PC, and to establish the rate of CP among patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC). We retrospectively analyzed 458 CP patients undergoing endoscopic treatment (ET) between 2000 and 2010 and 349 PDAC patients undergoing pancreatic resection between 2000 and 2014 at the Helsinki University Hospital. The likelihood of diagnosing PC was highest within 2 years of a CP diagnosis: 21 of 30 PC diagnoses occurred during this time. After 2 years follow-up: 9 of 30 PC diagnoses occurred 2-12 years from CP diagnosis. Two patients were diagnosed with CP before PDAC. Multivariate analysis showed two prognostic factors indicative of PC development: biliary stricture (HR 9.21; 95% CI 3.76-22.08) and a higher age (per 5-year increases) at CP onset (HR 1.55; 95% CI 1.30-1.85). Among 458 CP patients, the median overall survival without PC was 14.7 years (95% CI 12.0-17.3), falling to 1.6 years (95% CI 1.2-2.0) with PC. The high incidence of PC among CP patients at the beginning of follow-up likely reflected an initially missed PC diagnoses. In long-term follow-up, an increasing PC incidence might reflect the PC-predisposing impact of CP. Thus, we recommend careful follow-up for patients presenting with a recently diagnosed CP and risk factors for PC.
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http://dx.doi.org/10.1002/ijc.32971DOI Listing
September 2020

Identification of several plasma proteins whose levels in colorectal cancer patients differ depending on outcome.

FASEB Bioadv 2019 Dec 23;1(12):723-730. Epub 2019 Nov 23.

Department of Surgery Faculty of Medicine University of Helsinki and Helsinki University Hospital Helsinki Finland.

Colorectal cancer (CRC) stands for 10% of the worldwide cancer burden and has recently become the second most common cause of cancer death. The 5-year survival rate depends mainly on stage at diagnosis. Mass spectrometric proteomic analysis is widely used to study the plasma proteome, which is complex and contains multitudes of proteins. In this study, we have used Ultra Performance Liquid Chromatography-Ultra Definition Mass Spectrometry (UPLC-UDMS)-based proteomics to analyze plasma samples from 76 CRC patients. We identified several plasma proteins, such as CP, TVP23C, FETUB, and IGFBP3, of which altered levels led to significant differences in survival, as seen by Cox regression and Kaplan-Meier analysis. Additionally, during Cox regression analysis, samples were adjusted for age and/or tumor stage, enabling stringent analysis. These proteins, although in need of further validation, could be of use during patient follow-up, as their levels can non-invasively be measured from blood samples, and could be of use in predicting patient outcome. Several of these proteins additionally have roles in metabolism and inflammation, two processes central to the development and progression of cancer, further indicating their importance in cancer.
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http://dx.doi.org/10.1096/fba.2019-00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996405PMC
December 2019

Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature.

Am J Surg Pathol 2020 02;44(2):162-173

Laboratory of Pathology, National Cancer Institute, Bethesda, MD.

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.
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http://dx.doi.org/10.1097/PAS.0000000000001377DOI Listing
February 2020

Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival.

Nat Commun 2019 09 6;10(1):4022. Epub 2019 Sep 6.

Applied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki, Biomedicum Helsinki, PO Box 63,  (Haartmaninkatu 8), FI-00014, Helsinki, Finland.

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
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http://dx.doi.org/10.1038/s41467-019-11770-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731219PMC
September 2019

L1TD1 - a prognostic marker for colon cancer.

BMC Cancer 2019 Jul 23;19(1):727. Epub 2019 Jul 23.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.

Background: Prognostic markers specific to a particular cancer type can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities.

Methods: Gene expression data was analyzed from three independent colon cancer microarray gene expression data sets (N = 1052). Survival analysis was performed for the three data sets, stratified by the expression level of the LINE-1 type transposase domain containing 1 (L1TD1). Correlation analysis was performed to investigate the role of the interactome of L1TD1 in colon cancer patients.

Results: We found L1TD1 as a novel positive prognostic marker for colon cancer. Increased expression of L1TD1 associated with longer disease-free survival in all the three data sets. Our results were in contrast to a previous study on medulloblastoma, where high expression of L1TD1 was linked with poor prognosis. Notably, in medulloblastoma L1TD1 was co-expressed with its interaction partners, whereas our analysis revealed lack of co-expression of L1TD1 with its interaction partners in colon cancer.

Conclusions: Our results identify increased expression of L1TD1 as a prognostic marker predicting longer disease-free survival in colon cancer patients.
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http://dx.doi.org/10.1186/s12885-019-5952-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651905PMC
July 2019

Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium.

Nature 2019 07 10;571(7765):398-402. Epub 2019 Jul 10.

Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α), and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.
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http://dx.doi.org/10.1038/s41586-019-1383-0DOI Listing
July 2019

Neoplastic cell percentage estimation in tissue samples for molecular oncology: recommendations from a modified Delphi study.

Histopathology 2019 Sep 18;75(3):312-319. Epub 2019 Jul 18.

Biomedical Quality Assurance Research Unit, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Aims: Results from external quality assessment revealed considerable variation in neoplastic cell percentages (NCP) estimation in samples for biomarker testing. As molecular biology tests require a minimal NCP, overestimations may lead to false negative test results. We aimed to develop recommendations to improve the NCP determination in a prototypical entity - colorectal carcinoma - that can be adapted for other cancer types.

Methods And Results: A modified Delphi study was conducted to reach consensus by 10 pathologists from 10 countries with experience in determining the NCP for colorectal adenocarcinoma. This study included two online surveys and a decision-making meeting. Consensus was defined a priori as an agreement of > 80%. All pathologists completed both surveys. Consensus was reached for 8 out of 19 and 2 out of 13 questions in the first and second surveys, respectively. Remaining issues were resolved during the meeting. Twenty-four recommendations were formulated. Major recommendations resulted as follows: only pathologists should conduct the morphological evaluation; nevertheless molecular biologists/technicians may estimate the NCP, if specific training has been performed and a pathologist is available for feedback. The estimation should be determined in the area with the highest density of viable neoplastic cells and lowest density of inflammatory cells. Other recommendations concerned: the determination protocol itself, needs for micro- and macro-dissection, reporting and interpreting, referral practices and applicability to other cancer types.

Conclusion: We believe these recommendations may lead to more accurate NCP estimates, ensuring the correct interpretation of test results, and might help in validating digital algorithms in the future.
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http://dx.doi.org/10.1111/his.13891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851675PMC
September 2019

BRAF V600E expression in ameloblastomas-A 36-patient cohort from Helsinki University Hospital.

Oral Dis 2019 May 19;25(4):1169-1174. Epub 2019 Mar 19.

Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: We aimed to investigate BRAF V600E percentage immunohistochemically in ameloblastomas of a single institute cohort. We were interested if age, location, histological properties, or tumor recurrence depend on the BRAF status.

Subjects, Materials And Methods: We had 36 formalin-fixed, paraffin-embedded ameloblastoma tissue samples of patients treated at the Helsinki University Hospital between the years 1983-2016. Tissue sections underwent immunohistochemistry by Ventana BenchMark XT immunostainer using Ms Anti-Braf V600E (VE1) MAB. We used R 3.4.2 and RStudio 1.1.383 to conduct statistical analysis for BRAF positivity and earlier onset as well as tumor location. We used chi-squared tests and 2-by-2 table functions to determine connections between BRAF positivity and recurrence, growth pattern, and type.

Results: BRAF-positive tumors occurred in younger patients compared to BRAF-negative tumors (p = 0.015) and they located mostly to the mandible (p < 0.001). Growth patterns were limited to two in BRAF-negative tumors when BRAF-positive tumors presented with one to four growth patterns (p = 0.02). None of the maxillary tumors showed BRAF positivity and of these, 72.2% recurred.

Conclusions: An immunohistochemical BRAF marker could be a beneficial tool to predict the outcome of patients with this aggressive, easily recurring tumor.
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http://dx.doi.org/10.1111/odi.13072DOI Listing
May 2019

Finnish National Esophago-Gastric Cancer Cohort (FINEGO) for studying outcomes after oesophageal and gastric cancer surgery: a protocol for a retrospective, population-based, nationwide cohort study in Finland.

BMJ Open 2019 01 15;9(1):e024094. Epub 2019 Jan 15.

Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.

Introduction: Surgery for oesophageal and gastric cancers is associated with high morbidity, mortality and poor quality of life postoperatively. The Finnish National Esophago-Gastric Cancer Cohort has been established with the aim of identifying factors that could contribute to improved outcomes in oesophago-gastric cancer.

Methods And Analysis: All patients with oesophageal and gastric cancer diagnosed in Finland between 1987 and 2015 will be identified from the Finnish national registries. The Finnish Cancer Registry and Finnish Patient Registry will be used to identify patients that fulfil the inclusion criteria for the study: (1) diagnosis of oesophageal, gastro-oesophageal junction, or gastric cancer, (2) any surgical treatment for the diagnosed cancer and (3) age of 18 or over at the time of diagnosis. Clinical variables and complication information will be retrieved in extensive data collection from the medical records of the relevant Finnish hospitals and complete follow-up for vital status from Statistics Finland. Primary endpoint is overall all-cause mortality and secondary endpoints include complications, reoperations, medication use and sick leaves. Sub-studies will be implemented within the cohort to investigate specific populations undergoing oesophageal and gastric cancer surgery. The initial estimated sample size is 1800 patients with surgically treated oesophageal cancer and 7500 patients with surgically treated gastric cancer.

Ethics And Dissemination: The study has been approved by the Ethical Committee in Northern Ostrobothnia, Finland and The National Institute for Health and Welfare, Finland. Study findings will be disseminated via presentations at conferences and publications in peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2018-024094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340442PMC
January 2019

A High Prevalence of Gastrointestinal Manifestations in Common Variable Immunodeficiency.

Am J Gastroenterol 2019 04;114(4):648-655

Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID.

Methods: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files.

Results: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 T lymphocytes but lower counts of CD19CD27 memory B cells and/or CD19 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels.

Discussion: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.
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http://dx.doi.org/10.14309/ajg.0000000000000140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455088PMC
April 2019

DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression.

EBioMedicine 2019 Jan 18;39:280-291. Epub 2018 Dec 18.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR.

Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing.

Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas.

Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. FUND: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Juselius Foundation, and HiLIFE.
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http://dx.doi.org/10.1016/j.ebiom.2018.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355728PMC
January 2019

Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.

Genet Med 2019 08 21;21(8):1868-1873. Epub 2018 Dec 21.

Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes.

Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility.

Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability.

Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
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http://dx.doi.org/10.1038/s41436-018-0405-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752675PMC
August 2019

Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei.

Mol Cell Proteomics 2018 Nov 28;17(11):2107-2118. Epub 2020 Aug 28.

Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland; Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, P.O. Box 400, FI-00029 HUS, Finland. Electronic address:

Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma that most often originates from the appendix, and grows in the peritoneal cavity filling it with mucinous ascites. KRAS and GNAS mutations are frequently found in PMP, but other common driver mutations are infrequent. As altered glycosylation can promote carcinogenesis, we compared N-linked glycan profiles of PMP tissues to those of normal appendix. Glycan profiles of eight normal appendix samples and eight low-grade and eight high-grade PMP specimens were analyzed by mass spectrometry. Our results show differences in glycan profiles between PMP and the controls, especially in those of neutral glycans, and the most prominent alteration was increased fucosylation. We further demonstrate up-regulated mRNA expression of four fucosylation-related enzymes, the core fucosylation performing fucosyltransferase 8 and three GDP-fucose biosynthetic enzymes in PMP tissues when compared with the controls. Up-regulated protein expression of the latter three enzymes was further observed in PMP cells by immunohistochemistry. We also demonstrate that restoration of fucosylation either by salvage pathway or by introduction of an expression of intact GDP-mannose 4,6-dehydratase enhance expression of MUC2, which is the predominant mucin molecule secreted by the PMP cells, in an intestinal-derived adenocarcinoma cell line with defective fucosylation because of deletion in the GDP-mannose 4,6-dehydratase gene. Thus, altered glycosylation especially in the form of fucosylation is linked to the characteristic mucin production of PMP. Glycomic data are available via ProteomeXchange with identifier PXD010086.
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http://dx.doi.org/10.1074/mcp.RA118.000615DOI Listing
November 2018

Contribution of allelic imbalance to colorectal cancer.

Nat Commun 2018 09 10;9(1):3664. Epub 2018 Sep 10.

Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.

Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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http://dx.doi.org/10.1038/s41467-018-06132-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131244PMC
September 2018

Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei.

Mol Cell Proteomics 2018 11 2;17(11):2107-2118. Epub 2018 Aug 2.

From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland;

Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma that most often originates from the appendix, and grows in the peritoneal cavity filling it with mucinous ascites. and mutations are frequently found in PMP, but other common driver mutations are infrequent. As altered glycosylation can promote carcinogenesis, we compared -linked glycan profiles of PMP tissues to those of normal appendix. Glycan profiles of eight normal appendix samples and eight low-grade and eight high-grade PMP specimens were analyzed by mass spectrometry. Our results show differences in glycan profiles between PMP and the controls, especially in those of neutral glycans, and the most prominent alteration was increased fucosylation. We further demonstrate up-regulated mRNA expression of four fucosylation-related enzymes, the core fucosylation performing fucosyltransferase 8 and three GDP-fucose biosynthetic enzymes in PMP tissues when compared with the controls. Up-regulated protein expression of the latter three enzymes was further observed in PMP cells by immunohistochemistry. We also demonstrate that restoration of fucosylation either by salvage pathway or by introduction of an expression of intact GDP-mannose 4,6-dehydratase enhance expression of , which is the predominant mucin molecule secreted by the PMP cells, in an intestinal-derived adenocarcinoma cell line with defective fucosylation because of deletion in the GDP-mannose 4,6-dehydratase gene. Thus, altered glycosylation especially in the form of fucosylation is linked to the characteristic mucin production of PMP. Glycomic data are available via ProteomeXchange with identifier PXD010086.
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http://dx.doi.org/10.1074/mcp.RA118.000615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210226PMC
November 2018

Colorectal cancer patients with different C-reactive protein levels and 5-year survival times can be differentiated with quantitative serum proteomics.

PLoS One 2018 9;13(4):e0195354. Epub 2018 Apr 9.

Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

Over 1.4 million people are diagnosed with colorectal cancer (CRC) each year, making it the third most common cancer in the world. Increased screening and therapeutic modalities including improved combination treatments have reduced CRC mortality, although incidence and mortality rates are still increasing in some areas. Serum-based biomarkers are mainly used for follow-up of cancer, and are ideal due to the ease and minimally invasive nature of sample collection. Unfortunately, CEA and other serum markers have too low sensitivity for screening and preoperative diagnostic purposes. Increasing interest is focused on the possible use of biomarkers for predicting treatment response and prognosis in cancer. In this study, we have performed mass spectrometry analysis (UPLC-UDMSE) of serum samples from 19 CRC patients. Increased levels of C-reactive protein (CRP), which occur during local inflammation and the presence of a systemic inflammatory response, have been linked to poor prognosis in CRC patients. We chose to analyze samples according to CRP values by dividing them into the categories CRP <30 and >30, and, separately, according to short and long 5-year survival. The aim was to discover differentially expressed proteins associated with poor prognosis and shorter survival. We quantified 256 proteins and performed detailed statistical analyses and pathway analysis. We discovered multiple proteins that are up- or downregulated in patients with CRP >30 as compared to CRP <30 and in patients with short as compared to long 5-year survival. Pathways that were enriched include LXR/RXR activation, FXR/RXR activation, complement and coagulation cascades and acute phase signaling response, with some of the proteins we identified having roles in these pathways. In this study, we have identified multiple proteins, of which a few have been previously identified as potential biomarkers, and others that have been identified as potential biomarkers for CRC for the first time, to the best of our knowledge. While these proteins still need to be validated in larger patient series, this pilot study will pave the way for future studies aiming to provide better biomarkers for patients with CRC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195354PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891022PMC
July 2018

Exome-wide somatic mutation characterization of small bowel adenocarcinoma.

PLoS Genet 2018 03 9;14(3):e1007200. Epub 2018 Mar 9.

Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.
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http://dx.doi.org/10.1371/journal.pgen.1007200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871010PMC
March 2018

Does a histologically inflamed resection margin increase postoperative complications in patients with Crohn's disease?

Scand J Gastroenterol 2018 Mar 12;53(3):279-283. Epub 2018 Feb 12.

a Department of Colorectal Surgery , Helsinki University Hospital , Helsinki , Finland.

Objectives: Our study assessed whether the presence of histologically inflamed resection margins increased postoperative anastomotic complications in Crohn's disease (CD) patients. We also examined the influence of other risk factors for postoperative complications.

Materials And Methods: Presence of chronic inflammation and activity of inflammation was scored from the resection margin specimens of 70 patients undergoing surgery due to CD. Anastomotic complications were recorded with a one-month follow-up. We also analysed other risk factors for postoperative complications, such as patient age, previous surgeries, preoperative C-reactive protein, faecal calprotectin, albumin and haemoglobin levels, American Society of Anesthesiologists (ASA) classification, preoperative immunosuppressive medication, surgical approach and the presence of intraoperative fistula or abscess.

Results: In total, 46 patients (65.7%) had active inflammation in the bowel resection margin - 12 patients (17.1%) with mild, five patients (7.1%) with moderate and 29 patients (41.4%) with strong activity. We found 14 (20.0%) postoperative complications, of which three (4.6%) were anastomotic. The presence of active inflammation at the resection margin did not significantly influence the occurrence of postoperative anastomotic complications. None of the other risk factors examined significantly increased postoperative complications among our sample.

Conclusions: After bowel-sparing surgery for CD, the frequency of histologically inflamed resection margins is high. However, postoperative complication rate remains low. The current practice with resection of only the most affected bowel segments for CD seems to be a safe choice. We still need further research concerning risk factors for postoperative complications in Crohn's patients.
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http://dx.doi.org/10.1080/00365521.2018.1435717DOI Listing
March 2018