Publications by authors named "Heikki Järvinen"

113 Publications

Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers.

Genet Med 2020 09 13;22(9):1524-1532. Epub 2020 May 13.

Institute for Medical Genetics and Pathology, University Hospital Basel, and Research Group Human Genomics, Department of Research, University of Basel, Basel, Switzerland.

Purpose: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases.

Methods: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature.

Results: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%).

Conclusion: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462743PMC
September 2020

Mobile road weather sensor calibration by sensor fusion and linear mixed models.

PLoS One 2019 7;14(2):e0211702. Epub 2019 Feb 7.

Infotech Oulu, University of Oulu, Oulu, Finland.

Mobile, vehicle-installed road weather sensors are becoming ubiquitous. While mobile sensors are often capable of making observations on a high frequency, their reliability and accuracy may vary. Large-scale road weather observation and forecasting are still mostly based on stationary road weather stations (RWS). Though expensive, sparsely located and making observations on a relatively low frequency, RWS' reliability and accuracy are well-known and accommodated for in the road weather forecasting models. Statistical analysis revealed that road weather conditions indeed have a great effect on how the observations of mobile and stationary road weather temperature sensors differ from each other. Consequently, we calibrated the observations of mobile sensors with a linear mixed model. The mixed model was fitted fusing ca. 20 000 pairs of mobile and RWS observations of the same location at the same time, following a rendezvous model of sensor calibration. The calibration nearly halved the MSE between the observations of the mobile and the RWS sensor types. Computationally very light, the calibration can be embedded directly in the sensors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366776PMC
November 2019

No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.

Gastroenterology 2018 11 29;155(5):1400-1409.e2. Epub 2018 Jul 29.

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

Background & Aims: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals).

Methods: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy).

Results: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy.

Conclusions: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2018.07.030DOI Listing
November 2018

Colorectal cancer incidence in carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

Hered Cancer Clin Pract 2017 10;15:18. Epub 2017 Oct 10.

Research Group Inherited Cancer, The Norwegian Radium Hospital, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Background: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic variants ) despite follow-up with colonoscopy including polypectomy.

Methods: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy ( = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently ( = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence.

Results: Cumulative CRC incidences in carriers of at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively ( > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05).

Conclusions: The hypothesis that the high incidence of CRC in carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13053-017-0078-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635542PMC
October 2017

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

Int J Cancer 2018 02 12;142(3):540-546. Epub 2017 Oct 12.

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

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.31076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383773PMC
February 2018

Subtotal Colectomy for Colon Cancer Reduces the Need for Subsequent Surgery in Lynch Syndrome.

Dis Colon Rectum 2017 Aug;60(8):792-799

1 Department of Gastrointestinal Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland 2 Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland 3 Department of Education and Science, Central Finland Health Care District, Jyväskylä Finland and University of Eastern Finland, Finland.

Background: The risk of metachronous colorectal cancer is high after surgical resection for first colon cancer in Lynch syndrome.

Objective: This study aimed to examine whether extended surgery decreases the risk of subsequent colorectal cancer and improves long-term survival.

Design: This was a retrospective study.

Setting: Data were collected from a nationwide registry.

Patients: Two hundred forty-two Lynch syndrome pathogenic variant carriers who underwent surgery for a first colon cancer from 1984 to 2009 were included.

Interventions: Patients underwent standard segmental colectomy (n = 144) or extended colectomy (n = 98) for colon cancer. Patients were followed a median of 14.6 up to 25 years.

Main Outcome Measures: Risk of subsequent colorectal cancer in either group, overall and disease-specific survival, and operative mortality were the primary outcomes measured.

Results: Subtotal colectomy decreased the risk of subsequent colorectal cancer (HR, 0.20; 95% CI, 0.08-0.52; p = 0.001), compared with segmental resection. Subsequent colorectal cancer decreased in MLH1 carriers. The MSH2 carriers showed no statistical difference, possibly because of their small number. Disease-specific and overall survival within 25 years did not differ between the standard and extended surgeries (82.7% vs 87.2%, p = 0.76 and 47.2% vs 41.4%, p = 0.83). The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. The cumulative risk of metachronous colorectal cancer was 7% within 25 years after subtotal colectomy with ileosigmoidal anastomosis. One patient died of postoperative septicemia within 30 days after segmental colectomy.

Limitations: Data on surgical procedures were primarily collected retrospectively.

Conclusions: Lynch syndrome pathogenic variant carriers may undergo subtotal colectomy to manage first colon cancer and avoid repetitive abdominal surgery and to reduce the remaining bowel to facilitate easier endoscopic surveillance. It provides no survival benefit, compared with segmental colon resection. See Video Abstract at http://links.lww.com/DCR/A319.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000000802DOI Listing
August 2017

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer.

Cancer Res 2017 08 13;77(15):4078-4088. Epub 2017 Jun 13.

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

Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase and the solute transporter Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-17-0682DOI Listing
August 2017

Multiple components of PKA and TGF-β pathways are mutated in pseudomyxoma peritonei.

PLoS One 2017 20;12(4):e0174898. Epub 2017 Apr 20.

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

Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma mainly restricted to the peritoneal cavity and most commonly originating from the appendix. The genetic background of PMP is poorly understood and no targeted treatments are currently available for this fatal disease. While RAS signaling pathway is affected in most if not all PMP cases and over half of them also have a mutation in the GNAS gene, other genetic alterations and affected pathways are, to a large degree, poorly known. In this study, we sequenced whole coding genome of nine PMP tumors and paired normal tissues in order to identify additional, commonly mutated genes and signaling pathways affected in PMP. These exome sequencing results were validated with an ultra-deep amplicon sequencing method, leading to 14 validated variants. The validated results contain seven genes that contribute to the protein kinase A (PKA) pathway. PKA pathway, which also contains GNAS, is a major player of overproduction of mucin, which is the characteristic feature of PMP. In addition to PKA pathway, we identified mutations in six genes that belong to the transforming growth factor beta (TGF-β) pathway, which is a key regulator of cell proliferation. Since either GNAS mutation or an alternative mutation in the PKA pathway was identified in 8/9 patients, inhibition of the PKA pathway might reduce mucin production in most of the PMP patients and potentially suppress disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174898PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398530PMC
September 2017

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.

Hum Mol Genet 2016 06 22;25(11):2349-2359. Epub 2016 Mar 22.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddw087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081051PMC
June 2016

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis.

Oncotarget 2016 Oct;7(43):70685-70698

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

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.12206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342583PMC
October 2016

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

Br J Cancer 2016 Jul 23;115(2):266-72. Epub 2016 Jun 23.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.

Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.

Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively.

Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2016.188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947703PMC
July 2016

The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription.

Gastroenterol Res Pract 2016 7;2016:6089658. Epub 2016 Mar 7.

Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.

All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2016/6089658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800109PMC
April 2016

Expression of CEA, CA19-9, CA125, and EpCAM in pseudomyxoma peritonei.

Hum Pathol 2016 08 30;54:47-54. Epub 2016 Mar 30.

Pathology, Research Programs Unit, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland; Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, 00029, Helsinki, Finland. Electronic address:

Pseudomyxoma peritonei is a fatal clinical syndrome with mucinous tumor cells disseminated into peritoneal cavity and secreting abundant mucinous ascites. The serum tumor markers CEA, CA19-9, and CA125 are used to monitor pseudomyxoma peritonei remission, but their expression at tissue level has not been well characterized. Herein, we analyzed expression of these proteins and the adenocarcinoma marker EpCAM in 92 appendix-derived pseudomyxoma peritonei tumors by immunohistochemistry. All tumors were found to ubiquitously express CEA and EpCAM. In the majority of the tumors (94.6%), CEA showed polarized immunostaining, but in 5 aggressive high-grade tumors containing numerous signet ring cells, a nonpolarized staining was detected. We found preoperative CEA serum values to correlate with peritoneal cancer index. However, the serum values of the advanced cases with nonpolarized staining pattern were normal, and the patients died within 5 years after diagnosis. Thus, serum CEA measurements did not reflect aggressiveness of these tumors. CA19-9 showed strong immunopositivity in most of the tumors (91.3%), and mutated enzyme FUT3 was demonstrated from the cases showing negative or weak staining. CA125 was infrequently expressed by tumor cells (focal staining in 6.5% of the cases), but in most of the cases (79.3%), adjacent nonneoplastic mesothelial cells showed immunopositivity. As a conclusion, CEA and EpCAM are invariably expressed by pseudomyxoma peritonei tumor cells and could be exploited to targeted therapies against this malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2016.02.022DOI Listing
August 2016

[Diagnosis and treatment of Lynch syndrome].

Duodecim 2016 ;132(3):233-40

Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years. This would allow the selection of patients to be referred for gene testing as well as identification of mutation carriers, for whom a regular colonoscopy follow-up is arranged at an interval of 2 to 3 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2016

Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms.

Prostate 2016 Jan 18;76(1):22-31. Epub 2015 Sep 18.

Genome-Scale Biology Research Program and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Background: Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer.

Methods: To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed.

Results: In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed.

Conclusions: Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.23092DOI Listing
January 2016

DNA hypermethylation appears early and shows increased frequency with dysplasia in Lynch syndrome-associated colorectal adenomas and carcinomas.

Clin Epigenetics 2015 22;7:71. Epub 2015 Jul 22.

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

Background: Lynch syndrome (LS) is associated with germline mutations in DNA mismatch repair (MMR) genes. The first "hit" to inactivate one allele of the predisposing MMR gene is present in every cell, contributing to accelerated tumorigenesis. Less information is available of the nature, timing, and order of other molecular "hits" required for tumor development. To this end, MMR protein expression and coordinated promoter methylation were examined in colorectal specimens prospectively collected from LS mutation carriers (n = 55) during colonoscopy surveillance (10/2011-5/2013), supplemented with retrospective specimens.

Results: Loss of MMR protein corresponding to the gene mutated in the germline increased with dysplasia, with frequency of 0 % in normal mucosa, 50-68 % in low-grade dysplasia adenomas, and 100 % in high-grade dysplasia adenomas and carcinomas. Promoter methylation as a putative "second hit" occurred in 1/56 (2 %) of tumors with silenced MMR protein. A general hypermethylation tendency was evaluated by two gene sets, eight CpG island methylator phenotype (CIMP) genes, and seven candidate tumor suppressor genes linked to colorectal carcinoma (CRC). Hypermethylation followed the same trend as MMR protein loss and was present in some low-grade dysplasia adenomas that still expressed MMR protein suggesting the absence of a "second hit." To assess prospectively collected normal mucosa for carcinogenic "fields," the specimen donors were stratified according to age at biopsy (50 years or below vs. above 50 years) and further according to the absence vs. presence of a (previous or concurrent) diagnosis of CRC. In mutation carriers over 50 years old, two markers from the candidate gene panel (SFRP1 and SLC5A8) revealed a significantly elevated average degree of methylation in individuals with CRC diagnosis vs. those without.

Conclusions: Our findings emphasize the importance and early appearance of epigenetic alterations in LS-associated tumorigenesis. The results serve early detection and assessment of progression of CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-015-0102-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511034PMC
July 2015

Human population dynamics in Europe over the Last Glacial Maximum.

Proc Natl Acad Sci U S A 2015 Jul 22;112(27):8232-7. Epub 2015 Jun 22.

Department of Geosciences and Geography, University of Helsinki, FI-00014 Helsinki, Finland;

The severe cooling and the expansion of the ice sheets during the Last Glacial Maximum (LGM), 27,000-19,000 y ago (27-19 ky ago) had a major impact on plant and animal populations, including humans. Changes in human population size and range have affected our genetic evolution, and recent modeling efforts have reaffirmed the importance of population dynamics in cultural and linguistic evolution, as well. However, in the absence of historical records, estimating past population levels has remained difficult. Here we show that it is possible to model spatially explicit human population dynamics from the pre-LGM at 30 ky ago through the LGM to the Late Glacial in Europe by using climate envelope modeling tools and modern ethnographic datasets to construct a population calibration model. The simulated range and size of the human population correspond significantly with spatiotemporal patterns in the archaeological data, suggesting that climate was a major driver of population dynamics 30-13 ky ago. The simulated population size declined from about 330,000 people at 30 ky ago to a minimum of 130,000 people at 23 ky ago. The Late Glacial population growth was fastest during Greenland interstadial 1, and by 13 ky ago, there were almost 410,000 people in Europe. Even during the coldest part of the LGM, the climatically suitable area for human habitation remained unfragmented and covered 36% of Europe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1503784112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500234PMC
July 2015

CTCF/cohesin-binding sites are frequently mutated in cancer.

Nat Genet 2015 Jul 8;47(7):818-21. Epub 2015 Jun 8.

1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3335DOI Listing
July 2015

3'-UTR poly(T/U) repeat of EWSR1 is altered in microsatellite unstable colorectal cancer with nearly perfect sensitivity.

Fam Cancer 2015 Sep;14(3):449-53

Medicum/Department of Medical and Clinical Genetics, University of Helsinki, 00014, Helsinki, Finland,

Approximately 15% of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5%) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-015-9804-1DOI Listing
September 2015

Systematic search for rare variants in Finnish early-onset colorectal cancer patients.

Cancer Genet 2015 Jan-Feb;208(1-2):35-40. Epub 2014 Dec 31.

Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland. Electronic address:

The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered variants with CRC. These findings, together with a lack of family history in 19 of 22 (86%) early-onset patients, suggest genetic heterogeneity in unexplained early-onset CRC patients, thus emphasizing the requirement for large sample sizes and careful study designs to elucidate the role of rare variants in CRC susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2014.12.004DOI Listing
May 2015

Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation.

Epigenetics 2014 Dec;9(12):1577-87

a Department of Medical Genetics; Biomedicum Helsinki ; University of Helsinki ; Helsinki , Finland.

Diagnosis and treatment of epithelial ovarian cancer is challenging due to the poor understanding of the pathogenesis of the disease. Our aim was to investigate epigenetic mechanisms in ovarian tumorigenesis and, especially, whether tumors with different histological subtypes or hereditary background (Lynch syndrome) exhibit differential susceptibility to epigenetic inactivation of growth regulatory genes. Gene candidates for epigenetic regulation were identified from the literature and by expression profiling of ovarian and endometrial cancer cell lines treated with demethylating agents. Thirteen genes were chosen for methylation-specific multiplex ligation-dependent probe amplification assays on 104 (85 sporadic and 19 Lynch syndrome-associated) ovarian carcinomas. Increased methylation (i.e., hypermethylation) of variable degree was characteristic of ovarian carcinomas relative to the corresponding normal tissues, and hypermethylation was consistently more prominent in non-serous than serous tumors for individual genes and gene sets investigated. Lynch syndrome-associated clear cell carcinomas showed the highest frequencies of hypermethylation. Among endometrioid ovarian carcinomas, lower levels of promoter methylation of RSK4, SPARC, and HOXA9 were significantly associated with higher tumor grade; thus, the methylation patterns showed a shift to the direction of high-grade serous tumors. In conclusion, we provide evidence of a frequent epigenetic inactivation of RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML, and MIR34B in the development of non-serous ovarian carcinomas of Lynch and sporadic origin, as compared to serous tumors. Our findings shed light on the role of epigenetic mechanisms in ovarian tumorigenesis and identify potential targets for translational applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/15592294.2014.983374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622692PMC
December 2014

Costs of colorectal cancer in different states of the disease.

Acta Oncol 2015 Apr 18;54(4):454-62. Epub 2014 Dec 18.

University of Helsinki, Department of Public Health , Helsinki , Finland.

Objectives: This cross-sectional study estimates the resource use and costs among prevalent colorectal cancer (CRC) patients in different states of the disease.

Methods: Altogether 508 Finnish CRC patients (aged 26-96; colon cancer 56%; female 47%) answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Furthermore, data on direct medical resource use and productivity costs were obtained from registries. Patients were divided into five mutually exclusive groups based on the disease state and the time from diagnosis: primary treatments (the first six months after the diagnosis), rehabilitation, remission, metastatic disease, and palliative care. The costs were calculated for a six-month period. Multivariate modeling was performed to find the cost drivers.

Results: The costs were highest during the primary treatment state and the advanced disease states. The total costs for the cross-sectional six-month period were €22 200 in the primary treatment state, €2106 in the rehabilitation state, €2812 in the remission state, €20 540 in the metastatic state, and €21 146 in the palliative state. Most of the costs were direct medical costs. The informal care cost was highest per patient in the palliative care state, amounting to 33% of the total costs. The productivity costs varied between disease states, constituting 19-40% of the total costs, and were highest in the primary treatment state.

Conclusions: The first six months after the diagnosis of CRC are resource intensive, but compared with the metastatic disease state, which lasts on average for 2-3 years, the costs are rather modest. Informal care constitutes a remarkable share of the total costs, especially in the palliative state. These results form a basis for the evaluation of the cost effectiveness of new treatments when allocating resources in CRC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/0284186X.2014.985797DOI Listing
April 2015

Reply: To PMID 24941021.

Gastroenterology 2015 Jan 22;148(1):259. Epub 2014 Nov 22.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2014.11.028DOI Listing
January 2015

Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry.

Int J Cancer 2015 Mar 13;136(5):E282-9. Epub 2014 Oct 13.

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

Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared with low-grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.29245DOI Listing
March 2015

Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas.

Hum Mutat 2014 Sep 21;35(9):1136-41. Epub 2014 Jul 21.

Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.

Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22612DOI Listing
September 2014

Comparison of serial debulking and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei of appendiceal origin.

Int J Colorectal Dis 2014 Aug 26;29(8):999-1007. Epub 2014 Jun 26.

Department of Surgery, Meilahti Hospital, Helsinki University Central Hospital, Haartmaninkatu 4, FI-00029, Helsinki, Finland,

Purpose: Patients with pseudomyxoma peritonei (PMP) benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reports on this modality usually have included only patients with successful HIPEC treatment, which can potentially cause biased results. We report the survival of a PMP population treated by CRS and HIPEC, including patients who were not eligible for HIPEC.

Methods: The outcome of the whole population of 87 patients with PMP treated by CRS and HIPEC in Helsinki University Central Hospital between 2008 and 2011 was evaluated. The results of treatment were compared with 33 patients treated by serial debulking in our unit between 1984 and 2008.

Results: Of the 87 patients in the HIPEC-era group, 56 received HIPEC, 12 were treated non-radically in an attempt at HIPEC, 9 were debulked and 10 were referred back or transferred to palliative care without surgery. The 5-year overall survival for the debulking-era group and the HIPEC-era group were 67 and 69 %, respectively. The number of patients with no evidence of disease was higher in the HIPEC-era group (47/87) than that in the debulking-era group (8/33) at the end of the follow-up. Overall survival for patients who underwent successful CRS and HIPEC at 2 and 5 years was 95 and 93 %, respectively.

Conclusions: The improved survival from using the CRS and HIPEC was not apparent after 5-year follow-up, when the whole patient population was included in the analysis. Even so, patients successfully treated by CRS and HIPEC manage well.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00384-014-1933-8DOI Listing
August 2014

Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.

Genes Chromosomes Cancer 2014 Oct 20;53(10):857-64. Epub 2014 Jun 20.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Laboratorio de Citogenética y Mutagénesis, Instituto Multidisciplinario de Biología Celular (IMBICE-CONICET-CICPBA), La Plata, Argentina.

n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22197DOI Listing
October 2014

Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency.

Gastroenterology 2014 Sep 15;147(3):595-598.e5. Epub 2014 Jun 15.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.

Little is known about the genetic factors that contribute to familial colorectal cancer type X (FCCX), characterized by hereditary nonpolyposis colorectal carcinoma with no mismatch repair defects. Genetic linkage analysis, exome sequencing, tumor studies, and functional investigations of 4 generations of a FCCX family led to the identification of a truncating germline mutation in RPS20, which encodes a component (S20) of the small ribosomal subunit and is a new colon cancer predisposition gene. The mutation was associated with a defect in pre-ribosomal RNA maturation. Our findings show that mutations in a gene encoding a ribosomal protein can predispose individuals to microsatellite-stable colon cancer. Evaluation of additional FCCX families for mutations in RPS20 and other ribosome-associated genes is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2014.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155505PMC
September 2014

Endoscopic papillectomy, single-centre experience.

Surg Endosc 2014 Nov 14;28(11):3234-9. Epub 2014 Jun 14.

Department of Gastrointestinal and General Surgery, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS, Helsinki, Finland.

Background: Endoscopic removal of benign tumours of papilla is increasing. Our aim was to evaluate the outcome of endoscopic resection of papillary tumours.

Methods: In the years 2000-2012, 61 papillectomies were performed in Helsinki University Central Hospital. The cases were analysed retrospectively.

Results: There were 35 patients with benign tumour of papilla without familial adenomatous polyposis (FAP), 16 patients with FAP and 10 patients with ampullary cancer. Jaundice and bile duct dilation were risk factors for malignancy (p < 0.001). In benign tumours, the recurrence rate was 25.5 %. In 5/51 benign tumour cases (9.8 %), a pancreaticoduodenectomy was performed. The remaining cases were treated endoscopically. Neither tumour size, resection in one piece or piecemeal technique, nor coagulation of resection margins had an effect on the development of residual tumour. The total complication rate was 24.6 %. Pancreatitis developed in six patients (9.8 %, 3 mild and 3 moderate). In benign tumour cases, pancreatic stent decreased pancreatitis rate (p = 0.045). In cases where only a pancreatic sphincterotomy was performed, the risk of pancreatitis was high 4/7 (57 %). Bleeding was the most common complication (18 %). Only one patient was operated due to complication, a post-papillectomy bleeding. In six out of seven non-operated cancer patients, the disease progressed.

Conclusion: Endoscopic papillectomy is an effective procedure for treating benign papillary tumours. Jaundice and bile duct dilation are more common in malignant tumours. Pancreatic stent decreases the risk of post-papillectomy pancreatitis. Pancreatic sphincterotomy without stenting carries a high risk of pancreatitis. For papillary cancer, surgery is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00464-014-3596-5DOI Listing
November 2014

Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer.

Int J Cancer 2014 Aug 13;135(3):611-23. Epub 2014 Jan 13.

Department of Medical Genetics Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.

ARID1A has been identified as a novel tumor suppressor gene in ovarian cancer and subsequently in various other tumor types. ARID1A belongs to the ARID domain containing gene family, which comprises of 15 genes involved, for example, in transcriptional regulation, proliferation and chromatin remodeling. In this study, we used exome sequencing data to analyze the mutation frequency of all the ARID domain containing genes in 25 microsatellite unstable (MSI) colorectal cancers (CRCs) as a first systematic effort to characterize the mutation pattern of the whole ARID gene family. Genes which fulfilled the selection criteria in this discovery set (mutations in at least 4/25 [16%] samples, including at least one nonsense or splice site mutation) were chosen for further analysis in an independent validation set of 21 MSI CRCs. We found that in addition to ARID1A, which was mutated in 39% of the tumors (18/46), also ARID1B (13%, 6/46), ARID2 (13%, 6/46) and ARID4A (20%, 9/46) were frequently mutated. In all these genes, the mutations were distributed along the entire length of the gene, thus distinguishing them from typical MSI target genes previously described. Our results indicate that in addition to ARID1A, other members of the ARID gene family may play a role in MSI CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.28705DOI Listing
August 2014