Publications by authors named "Per Arne Andresen"

16 Publications

  • Page 1 of 1

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients.

Epigenomics 2020 10 30;12(19):1689-1706. Epub 2020 Oct 30.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.

To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. : HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.
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http://dx.doi.org/10.2217/epi-2020-0127DOI Listing
October 2020

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor.

Cells 2020 01 16;9(1). Epub 2020 Jan 16.

Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Blindern, 0318 Oslo, Norway.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored and mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.
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http://dx.doi.org/10.3390/cells9010227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016771PMC
January 2020

Oncogene Mutations in Colorectal Polyps Identified in the Norwegian Colorectal Cancer Prevention (NORCCAP) Screening Study.

Clin Med Insights Pathol 2016 7;9:19-28. Epub 2016 Sep 7.

Department of Pathology, Oslo University Hospital, Oslo, Norway.

Data are limited on oncogene mutation frequencies in polyps from principally asymptomatic participants of population-based colorectal cancer screening studies. In this study, DNA from 204 polyps, 5 mm or larger, were collected from 176 participants of the NORCCAP screening study and analyzed for mutations in KRAS, BRAF, and PIK3CA including the rarely studied KRAS exons 3 and 4 mutations. KRAS mutations were identified in 23.0% of the lesions and were significantly associated with tubulovillous adenomas and large size. A significantly higher frequency of KRAS mutations in females was associated with mutations in codon 12. The KRAS exon 3 and 4 mutations constituted 23.4% of the KRAS positive lesions, which is a larger proportion compared to previous observations in colorectal cancer. BRAF mutations were identified in 11.3% and were associated with serrated polyps. None of the individuals were diagnosed with de novo or recurrent colorectal cancer during the follow-up time (median 11.2 years). Revealing differences in mutation-spectra according to gender and stages in tumorigenesis might be important for optimal use of oncogenes as therapeutic targets and biomarkers.
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http://dx.doi.org/10.4137/CPath.s40143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015815PMC
September 2016

Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients.

Am J Surg Pathol 2014 Dec;38(12):1588-602

*Department of Anatomical Pathology †Cancer Diagnosis and Pathology Research Group §§Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital ‡University of Sydney, Sydney ††Histopath Pathology ¶¶Douglass Hanly Moir Pathology, North Ryde ‡‡Department of Anatomical Pathology, St Vincents Hospital, Darlinghurst §§§Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool, NSW ∥∥Pathology Queensland, Gold Coast University Hospital, Qld ****Department of Anatomical Pathology, Royal Children's Hospital, Parkville, Vic., Australia §Department of Pathology, Medical Faculty and Charles University, Pilsen, Czech Republic ∥Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, Rotterdam ##Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands ¶Department of Pathology, Singapore General Hospital, Singapore, Singapore #Institute of Pathology, Friedrich-Alexander-University, Erlangen, Germany **Department of Pathology, Oslo University Hospital ***Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway †††Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH ¶¶¶Department of Pathology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI ††††Laboratory of Surgical Pathology, National Cancer Institute, Bethesda, MD ‡‡‡Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and University of Calgary, Calgary, AB, Canada ∥∥∥Department of Pathology, Hopital Cochin Université Paris Descartes, Paris, France ###Department of Molecular Pathology, University of Dundee, Ninewells Hospital, Dundee, UK.

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.
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http://dx.doi.org/10.1097/PAS.0000000000000292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229399PMC
December 2014

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.

Eur J Endocrinol 2014 Jan 22;170(1):1-12. Epub 2013 Nov 22.

Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.

Design And Methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.

Results: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.

Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.
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http://dx.doi.org/10.1530/EJE-13-0623DOI Listing
January 2014

Genome-wide association study identifies three new melanoma susceptibility loci.

Nat Genet 2011 Oct 9;43(11):1108-13. Epub 2011 Oct 9.

Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James’s University Hospital, Leeds, UK.

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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http://dx.doi.org/10.1038/ng.959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251256PMC
October 2011

Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.

J Med Genet 2010 Sep 28;47(9):579-85. Epub 2010 Jun 28.

Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway.

Background: Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.

Objective: To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.

Methods: Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria.

Results: Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations.

Conclusion: Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.
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http://dx.doi.org/10.1136/jmg.2010.077677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976029PMC
September 2010

APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations.

J Cancer Res Clin Oncol 2009 Oct 15;135(10):1463-70. Epub 2009 May 15.

Pathology Division, University Hospital of Oslo-Rikshospitalet, N0027 Oslo, Norway.

Introduction: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease caused by mutations in the adenomatous polyposis coli (APC) gene. Massive formation of colorectal adenomas, of which some will inevitably develop into adenocarcinomas, is the hallmark of the disease. Characterization of causative APC mutations allows presymptomatic diagnosis, close follow-up and prophylactic intervention in families. To date more than 900 different germline mutations have been characterized worldwide demonstrating allelic heterogeneity.

Purpose: The germline mutation spectrum of APC identified in 69 apparently unrelated Norwegian FAP families are presented and discussed with reference to clinical phenotype and novel mutation rate.

Methods: Different methods have been used over the years. However, all mutations were confirmed detectable by an implemented denaturing high-performance liquid chromatography screening approach. Multiplex ligation-dependent probe amplification analysis was employed for potential gross rearrangements.

Results: Fifty-three distinctive mutations were detected, of which 22 have been detected in Norway exclusively. Except for two major deletion mutations encompassing the entire APC, all mutations resulted in premature truncation of translation caused by non-sense (31%) or change in reading frame (69%).

Conclusion: A high ratio of novel APC mutations continues to contribute to APC mutation heterogeneity causing FAP. This is the first comprehensive report of APC germline mutation spectrum in Norway.
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http://dx.doi.org/10.1007/s00432-009-0594-4DOI Listing
October 2009

Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas.

Genes Chromosomes Cancer 2008 Feb;47(2):175-84

Department of Dermatology, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.
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http://dx.doi.org/10.1002/gcc.20518DOI Listing
February 2008

Gene symbol: APC.

Hum Genet 2007 Apr;121(2):288

Rikshospitalet-Radiumhospitalet Medical Center, Department of Pathology Clinic, Sognsvannsv. 20, 0027, OSLO, Norway.

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April 2007

Human polyomavirus type 1 (BK virus) agnoprotein is abundantly expressed but immunologically ignored.

Clin Vaccine Immunol 2007 Aug 30;14(8):959-68. Epub 2007 May 30.

Transplantation Virology, Institute for Medical Microbiology, Department of Clinical and Biological Sciences, University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.

Impaired BK virus (BKV)-specific immunity is a key risk factor of polyomavirus-associated nephropathy. We hypothesized that BKV agnoprotein might constitute an important immune target, as it is highly expressed after infection in vitro. We demonstrate abundant expression of BKV agnoprotein in vivo by immunostaining of kidney transplant (KT) biopsy specimens. Antibody responses to the recombinant affinity-purified BKV agnoprotein, large tumor (LT), and VP1 antigens in 146 sera from 38 KT patients and in 19 sera from 16 healthy donors (HD) were compared by enzyme immunoassay. In HD, low titers of anti-agnoprotein immunoglobulin G (IgG) were found in 15% of sera, compared to 41% for anti-LT antigen and 63% for anti-VP1. No anti-BKV IgM was detectable. In KT patients, anti-agnoprotein IgG and IgM were found in 8% and 3.6% of sera, compared to 63% and 18% for anti-LT IgG and IgM and 80% and 41% for anti-VP1 IgG and IgM, respectively. Anti-LT antigen and anti-VP1, but not anti-agnoprotein, activities increased during and after BKV viremia in KT patients. To investigate specific cellular immune responses, we compared levels of gamma interferon production in peripheral blood mononuclear cells (PBMC) of 10 HD and 30 KT patients by enzyme-linked immunospot assay. In HD, the median numbers of gamma interferon spot-forming units per million PBMC for the agnoprotein, LT antigen, and VP1 peptides were 1, 23, and 25, respectively, whereas the responses in KT patients were 2, 24, and 99, respectively. We conclude that BKV agnoprotein, though abundantly expressed in vivo, is poorly recognized immunologically.
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http://dx.doi.org/10.1128/CVI.00123-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2044487PMC
August 2007

Chromosomal 20q gain in the DNA diploid component of aneuploid colorectal carcinomas.

Int J Cancer 2007 Jun;120(12):2734-8

The Pathology Clinic, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, 0027 Oslo, Norway.

The order of appearance of different genetic aberrations during the shift from diploidy/near-diploidy to aneuploidy in colorectal cancers is not yet clear. We studied genetic alterations in flow cytometrically-sorted DNA diploid and corresponding aneuploid epithelial cell populations from each of 20 colorectal tumors using comparative genomic hybridization, FISH, and PCR. Analysis of the 19 cases in which aberrations were found in the flow-sorted diploid population indicated that large-scale aneuploidization in colorectal cancer was preceded by amplification of oncogene(s) localized to chromosome 20q13.2 and by KRAS mutations, but not by TP53 deletions or losses of large chromosomal regions such as 4q, 8p and 18q.
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http://dx.doi.org/10.1002/ijc.22537DOI Listing
June 2007

Fluorescence in situ hybridization (FISH) on touch preparations: a reliable method for detecting loss of heterozygosity at 1p and 19q in oligodendroglial tumors.

Am J Surg Pathol 2006 Jul;30(7):828-37

The Pathology Clinic, Department of Pathology, Rikshospitalet-Radiumhospitalet Medical Center, 0027 Oslo, Norway.

Combined loss of heterozygosity (LOH) on 1p and 19q is reported in 50% to 90% of oligodendroglial tumors and has emerged as a strong and favorable prognostic factor. Fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are the most widely used techniques. The aim of this study was to evaluate the reliability of FISH to predict LOH at 1p and 19q when performed on touch preparations from 40 oligodendroglial tumors, even if the majority of the nuclei showed chromosomal imbalance. PCR was used as the gold standard. The presence of none or one target signal was reported as FISH-LOH, whereas all other losses were defined as FISH-imbalance. The sum of nuclei with FISH-LOH and imbalance was calculated in each case (FISH-sum) and cut-off values were defined as the mean FISH-sum value in controls plus 3 standard deviations; 27.7% for 1p and 33.2% for 19q. These corresponded well with the optimal cut-off values for our data, calculated using the minimum error rate classification procedure (35.6% for 1p and 33.1% for 19q). Concurrent FISH and PCR results were encountered in 95% for 1p and 87.5% for 19q. FISH-sum was the best and simplest discriminating variable for correct classification of LOH status. Under these conditions, even a dominant population of nuclei showing FISH-imbalance represented an LOH status in the tumor cells. FISH on touch preparations is a quick and reliable method for 1p/19q testing, does not require normal DNA and can be easily performed in an immunohistochemistry unit.
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http://dx.doi.org/10.1097/01.pas.0000213250.44822.2eDOI Listing
July 2006

Genetic variability in BK Virus regulatory regions in urine and kidney biopsies from renal-transplant patients.

J Med Virol 2006 Mar;78(3):384-93

Department of Microbiology and Virology, Faculty of Medicine, University of Tromsø, Tromsø, Norway.

The human Polyomavirus BK (BKV) contains a hypervariable non-coding control region (NCCR), which regulates DNA replication and RNA transcription. The aim of this study was to characterize BKV NCCR-variants in kidney biopsies and urine samples from renal-transplant patients and to see whether there is any association between NCCR variability and BKV-nephropathy. Kidney biopsies and urine samples were examined from 11 patients with elevated serum creatinine and >5,000 genomic BKV copies per ml of urine. BKV-nephropathy was diagnosed in seven patients. Using PCR, BKV NCCR was amplified from urine from all BKV-nephropathy patients. The dominant NCCR corresponded to the archetype (WWT). In addition, a total of 14 non-archetype NCCR-variants were detected. Thirteen of these NCCR-variants were found in urine from one single BKV-nephropathy patient also suffering from hepatitis C. The NCCR of BKV was amplified from kidney biopsies of six BKV-nephropathy patients. Three patients demonstrated WWT NCCR, while three other patients harbored rearranged NCCR variants. The WWT NCCR was also detected in urine from control patients, except for one patient who harbored two non-archetypal NCCR variants. However, these variants were not resulting from complex rearrangements but instead had a linear NCCR anatomy with deletion(s) in the P-block. No BKV DNA was detected in biopsies from control patients. The results indicate that rearranged BKV NCCR is associated with BKV-nephropathy.
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http://dx.doi.org/10.1002/jmv.20551DOI Listing
March 2006

MUTYH Mutations Do Not Cause HNPCC or Late Onset Familial Colorectal Cancer.

Hered Cancer Clin Pract 2006 May 15;4(2):90-3. Epub 2006 May 15.

Section for Inherited Cancer, Department for Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.

Recently, carriers of biallelic mutations in the base excision repair gene MUTYH, have been demonstrated to have a predisposition for multiple adenomas and colorectal cancer. Still, many questions remain unanswered concerning MUTYH. We have addressed the following: Do biallelic MUTYH mutation carriers invariably demonstrate FAP, and may MUTYH be a gene causing HNPCC, HNPCC-like or dominantly inherited late onset colorectal cancer? We examined affecteds from our total series of HNPCC, HNPCC-like and dominantly inherited late onset colorectal cancer kindreds not demonstrated to have any MMR mutations. Bloodsamples from 96 patients were subjected to sequencing of exon 7 and exon 13 in the MUTYH gene. Two heterozygotes and one homozygote for the European founder mutations were found. The homozygous carrier did not meet criteria for FAP/AFAP. We conclude that MUTYH, when mutated, causes a rare recessively inherited disorder including colorectal- and duodenal cancers. It is not verified that heterozygous carriers of MUTYH mutations have an increased risk of cancer, and they do not explain the occurrence of familial colorectal cancer in the population.
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http://dx.doi.org/10.1186/1897-4287-4-2-90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837291PMC
May 2006

Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease.

Clin Gastroenterol Hepatol 2005 Sep;3(9):875-85

Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology, University of Oslo, Oslo, Norway.

Background & Aims: Patients with celiac disease (CD) who do not improve or exhibit villous atrophy on a gluten-free diet may have type 1 refractory CD (RCD) with a polyclonal mucosal T-cell infiltrate, or type 2 RCD with a monoclonal infiltrate, also termed cryptic T-cell lymphoma. Both conditions are difficult to treat. Here we describe the effects of a nonimmunogenic elemental diet on clinical symptoms and mucosal immunopathology in type 1 RCD.

Methods: Ten CD patients on a strict gluten-free diet were diagnosed with type 1 RCD after extensive clinical evaluation in a tertiary referral hospital. A 4-week amino-acid-based liquid elemental diet regimen was given with no other treatment, except in 1 patient who also received methotrexate. Duodenal biopsy specimens were obtained before and after treatment for histologic assessment, immunophenotyping of intraepithelial lymphocytes, T-cell receptor clonality, mucosal interleukin (IL)-15 expression, flow-cytometric analysis of interferon (IFN)-gamma-secreting T cells, and whole biopsy specimen IFN-gamma messenger RNA determination.

Results: Nine patients completed the treatment; however, 1 patient did not tolerate the diet. Histologic improvement and reduced epithelial IL-15 were seen in 8 patients, whereas IFN-gamma-secreting mucosal T cells and IFN-gamma messenger RNA levels decreased in 4 and 7 patients, respectively. Clinical improvement was noted in 6 patients, with 1 patient showing normalization of hypoalbuminemia. Three patients could discontinue their total parenteral nutrition.

Conclusions: Persistent mucosal IFN-gamma and IL-15 production often occurs in type 1 RCD despite conventional treatment. Elemental diet is a therapeutic option that can provide long-term immunopathologic and clinical improvement of this difficult condition.
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http://dx.doi.org/10.1016/s1542-3565(05)00295-8DOI Listing
September 2005
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