221 results on '"Schackert HK"'
Search Results
2. Langzeitergebnisse der chemopräventiven rektalen Sulindac-Therapie gegen Rektum-Adenome bei kolektomierten FAP-Patienten unter Berücksichtigung des Einfluss der APC- oder MUTYH-Gen Mutation
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Bruenjes, S, Aretz, S, Schackert, HK, Schmid, KW, and Winde, G
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Einleitung: 29 (17w, 12 m) FAP-Patienten wurden 65-306 Monate (durchschnittlich 193) mit dem NSAR Sulindac im Rahmen einer nicht randomisierten Pilotstudie behandelt. Ziel war, die Auswirkungen der Sulindac-Langzeittherapie und den Einfluss der APC-Gen-Mutation auf die Polypenausprägung und die[zum vollständigen Text gelangen Sie über die oben angegebene URL], 133. Kongress der Deutschen Gesellschaft für Chirurgie
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- 2016
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3. Ein Vergleich von fünf verschiedenen statistischen Modellen zur Vorhersage von Keimbahn-mutationen in Mismatch-Repair-Genen bei Familien mit Verdacht auf Lynch-Syndrom
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Zachariae, S, Wetzler, M, Holinski-Feder, E, Schackert, HK, Schmiegel, W, Royer-Pokora, B, Möslein, G, von Knebel Doeberitz, M, Büttner, R, Propping, P, Löffler, M, and Engel, C
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Lynch-Syndrom ,ddc: 610 ,Risikomodelle ,HNPCC ,610 Medical sciences ,Medicine ,Erblicher Darmkrebs - Abstract
Hintergrund: Das Lynch-Syndrom ist die häufigste Form des erblich bedingten Darmkrebses. Ursache für die Erkrankung sind Keimbahnmutationen im DNA-Mismatch-Reparatur-(MMR)-System, vor allem in den MMR-Genen MSH2 und MLH1, seltener in den Genen MSH6 und PMS2. Charakteristisch für das Syndrom[for full text, please go to the a.m. URL], Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi)
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- 2011
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4. Genexpressionsanalyse von mikrodisseziertem Stroma von duktalen Pankreaskarzinomen und chronischer Pankreatitis
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Grützmann, R, Sipos, B, Ammerpohl, O, Kalthoff, H, Klöppel, G, Schackert, HK, Pilarsky, C, and Saeger, HD
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ddc: 610 - Published
- 2008
5. PHOX2B-Mutationen im Neuroblastom: Analyse von 69 Patienten
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Serra, A, Häberle, B, Kappler, R, Schackert, HK, Roesner, D, and Fitze, G
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ddc: 610 - Published
- 2008
6. Die Sequenzvarianten Arg72Pro des Tumorsuppressorgens p53 und Arg462Gln des Prostatakarzinom-Suszeptibilitätsgens RNASEL haben einen additiven Effekt auf das Erkrankungsalter von HNPCC-Patienten
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Krüger, S, Engel, C, Bier, A, Silber, AS, Görgens, H, Mangold, E, Pagenstecher, C, and Schackert, HK
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ddc: 610 - Published
- 2007
7. Assoziation von regulatorischen Varainten des RET-Protoonkogens mit dem Morbus Hirschsprung (HSCR)
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von Kannen, S, Görgens, H, König, IR, Ziegler, A, Schackert, HK, and Fitze, G
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ddc: 610 - Published
- 2007
8. The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in hereditary nonpolyposis colorectal cancer (HNPCC) patients with pathogenic germline mutations in MSH2/MLH1
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Schackert, HK, Engel, C, Bier, A, Silber, AS, Görgens, H, Mangold, E, Pagenstecher, C, Holinski-Feder, E, von Knebel Doeberitz, M, Möslein, G, Dechant, S, Pox, C, Rahner, N, Müller, A, and Krüger, S
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ddc: 610 - Published
- 2006
9. Induzierung von Differenzierungsmechanismen von murinen neuralen Stammzellen durch Konfrontation von regenerierendem Blastemgewebe des Axolotlsalamanders
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Kirsch, M, Niesche, M, Kilian, B, Schackert, G, Schackert, HK, and Tanaka, E
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Ambystoma mexicanum ,Axolotl ,ddc: 610 ,regeneration ,neurale Stammzellen ,neural stem cells - Published
- 2006
10. Methylierung der Promotorregion der Zellzyklus inhibierenden Tumorsuppressorgene p16INK4a, p14ARF, p18INK4c und des Retinoblastomgens
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Kirsch, M, Mörz, M, Pinzer, T, Schackert, HK, and Schackert, G
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promoter ,ddc: 610 ,methylierung ,promotor ,pituitary adenoma ,methylation ,hypophysenadenom - Published
- 2006
11. Deletions- und Promotoranalyse der Mismatch Repair Gene MSH2 und MLH1 bei Bethesda-positiven Patienten
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Görgens, H, Höhl, R, Plaschke, J, Krüger, S, and Schackert, HK
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ddc: 610 - Published
- 2006
12. Die Bedeutung des NAT2 Acetylatortyps für die Entwicklung und das Erkrankungsalter bei Patienten mit HNPCC-assoziierten bzw. Mikrosatelliten-stabilen kolorektalen Karzinomen
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Pistorius, S, Görgens, H, Krüger, S, Engel, C, Mangold, E, Holinski-Feder, E, Möslein, G, Saeger, HD, and Schackert, HK
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ddc: 610 - Published
- 2006
13. Genetische Varianten in Genen, die für Enzyme der extrazellulären Matrix kodieren, in der Pathogenese von intrakraniellen Aneurysmen
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Krex, D, Fortun, S, König, IR, Ziegler, A, Schackert, HK, and Schackert, G
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ddc: 610 - Published
- 2005
14. Beeinflussung von Migration und Differenzierung neuraler Vorläuferzellen durch anti-angiogenetische Substanzen
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Kirsch, M, Senenko, L, Knaute, C, Heese, O, Schackert, G, and Schackert, HK
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ddc: 610 - Published
- 2005
15. Assoziation funktioneller Haplotypen des RET-Protoonkogen Promotors mit dem Morbus Hirschsprung
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Fitze, G, Luksch, H, König, IR, Görgens, H, Stein, U, Walther, W, Gossen, M, Ziegler, A, and Schackert, HK
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ddc: 610 - Published
- 2004
16. ADAM9 als prognostischer Marker beim human duktalen Pankreaskarzinom
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Grützmann, R, Lüttges, J, Alldinger, I, Kersting, S, Ammerpohl, O, Schackert, HK, Saeger, HD, Klöppel, G, and Pilarsky, CH
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ddc: 610 - Published
- 2004
17. Unterschiedliches molekulargenetisches Profil von Riesenzell-GBMs im Vergleich zu Standard-GBMs
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Martinez, R, Schackert, HK, Klein, R, Roggendorf, W, and Schackert, G
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ddc: 610 - Published
- 2004
18. Genetische Varianten von Matrix-Metalloproteinasen bei Patienten mit intrakraniellen Aneurysmen
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Krex, D, Kotteck, K, König, IR, Ziegler, A, Schackert, HK, and Schackert, G
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ddc: 610 - Published
- 2004
19. Ambystoma mexicanum oder der Axolotl: ein neuartiges Nervenregenerationsmodell
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Krishnan, KG, Jung, R, Schackert, HK, and Schackert, G
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ddc: 610 - Published
- 2004
20. Single nucleotide polymorphism (SNPs) in der kodierenden Region von MMP-9 in einer europäischen Population mit intrakraniellen Aneurysmen
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Krex, D, Kotteck, K, König, IR, Ziegler, A, Schackert, HK, and Schackert, G
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ddc: 610 - Published
- 2004
21. TLR4 and IL-18 gene variants in aggressive periodontitis.
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Noack B, Görgens H, Lorenz K, Ziegler A, Hoffmann T, and Schackert HK
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Aim: We aimed to assess the association of different genotypes with increased aggressive periodontitis susceptibility by studying functional relevant variants in the pathogen-recognition receptor Toll-like receptor 4 (TLR4) and variants in the promoter region of the pro-inflammatory cytokine interleukin-18 (IL-18). Material and Methods: One hundred and eleven patients with aggressive periodontitis and 80 periodontally healthy controls were genotyped for four functional variants in the TLR4 gene (c.896A>G and c.1196C>T) and in the IL-18 promoter (c.-368G>C and c.-838C>A). The genotype and allele frequencies, as well as the frequency of combined genotypes were compared between study groups. Results: There were no statistical differences in genotype and allele frequencies within the four variants between the groups. All study subjects were further classified into carriers and non-carriers of at least one variant of both genes. The logistic regression analysis adjusted for gender and smoking showed no association between carrier status of at least one variant of both genes and periodontal status (OR=1.41, 95% CI: 0.43-4.70). Conclusions: Our results reject the hypothesis that functionally relevant IL-18 and TLR4 gene mutations have a major effect on aggressive periodontitis susceptibility alone or in combination. [ABSTRACT FROM AUTHOR]
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- 2008
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22. Functional Cathepsin C mutations cause different Papillon-Lefèvre syndrome phenotypes.
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Noack B, Görgens H, Schacher B, Puklo M, Eickholz P, Hoffmann T, and Schackert HK
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AIM: The autosomal-recessive Papillon-Lefèvre syndrome (PLS) is characterized by severe aggressive periodontitis, combined with palmoplantar hyperkeratosis, and is caused by mutations in the Cathepsin C (CTSC) gene. This study aimed to identify CTSC mutations in different PLS phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PAP). MATERIAL AND METHODS: Thirteen families with different phenotypes were analysed by direct sequencing of the entire coding region and the regulatory regions of CTSC. The function of novel mutations was tested with enzyme activity measurements. RESULTS: In 11 of 13 families, 12 different pathogenic CTSC mutations were found in 10 typical PLS patients, three atypical cases and one PAP patient. Out of four novel mutations, three result in protein truncation and are thus considered to be pathogenic. The homozygous c.854C>T nucleotide exchange (p.P285L) was associated with an almost complete loss of enzyme activity. The observed phenotypic heterogeneity could not be associated with specific genotypes. CONCLUSIONS: The phenotypic variability of the PLS associated with an identical genetic background may reflect the influence of additional genetic or environmental factors on disease characteristics. CTSC mutation analyses should be considered for differential diagnosis in all children suffering from severe aggressive periodontitis. [ABSTRACT FROM AUTHOR]
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- 2008
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23. CARD15 gene variants in aggressive periodontitis.
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Noack B, Görgens H, Hoffmann T, and Schackert HK
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OBJECTIVE: The CARD15 gene encodes a protein that acts as an intracellular receptor of bacterial products, thus playing an important role in the innate immune response. Recently, CARD15 gene variants have been identified as a cause of increased susceptibility to Crohn's disease. The present study aimed to examine a potential association of CARD15 gene variants with aggressive periodontitis susceptibility. MATERIAL AND METHODS: The three main known CARD15 gene variants (p.R702W, p.G908R, and p.L1007fsX1008) were analysed by direct sequencing of exon 4, 8, and 11 of the gene in a total of 86 generalized aggressive periodontitis patients in comparison with 67 healthy controls. RESULTS: The mutant allele frequencies of the CARD15 variants were low in the generalized aggressive periodontitis group as well as in the control group and not significantly different (R702W: 3.5% versus 5.2%; G908R: 1.7% versus 1.5%; L1007fsX1008: 5.2% versus 4.5%). Two rare variants (A755V and R791Q), previously described only in patients with other inflammatory diseases, were observed in three patients having aggressive periodontitis but not in controls. CONCLUSIONS: Unlike in Crohn's disease, our results did not show an association between the three main CARD15 mutations and aggressive periodontitis. The role of rare variants remains unclear. [ABSTRACT FROM AUTHOR]
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- 2006
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24. Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.
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Ladigan-Badura S, Vangala DB, Engel C, Bucksch K, Hueneburg R, Perne C, Nattermann J, Steinke-Lange V, Rahner N, Schackert HK, Weitz J, Kloor M, Kuhlkamp J, Nguyen HP, Moeslein G, Strassburg C, Morak M, Holinski-Feder E, Buettner R, Aretz S, Loeffler M, Schmiegel W, Pox C, and Schulmann K
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- Adult, Age Factors, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Early Detection of Cancer standards, Early Detection of Cancer statistics & numerical data, Evaluation Studies as Topic, Gastric Mucosa diagnostic imaging, Gastric Mucosa pathology, Gastroscopy standards, Genetic Predisposition to Disease, Germany epidemiology, Humans, Male, Middle Aged, MutL Protein Homolog 1 genetics, MutS Homolog 2 Protein genetics, Mutation, Neoplasm Staging, Patient Compliance statistics & numerical data, Practice Guidelines as Topic, Prospective Studies, Stomach Neoplasms epidemiology, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Colorectal Neoplasms, Hereditary Nonpolyposis complications, Early Detection of Cancer methods, Gastroscopy statistics & numerical data, Stomach Neoplasms diagnosis
- Abstract
In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)
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- 2021
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25. Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.
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Bläker H, Haupt S, Morak M, Holinski-Feder E, Arnold A, Horst D, Sieber-Frank J, Seidler F, von Winterfeld M, Alwers E, Chang-Claude J, Brenner H, Roth W, Engel C, Löffler M, Möslein G, Schackert HK, Weitz J, Perne C, Aretz S, Hüneburg R, Schmiegel W, Vangala D, Rahner N, Steinke-Lange V, Heuveline V, von Knebel Doeberitz M, Ahadova A, Hoffmeister M, and Kloor M
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- Age Factors, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Female, Humans, Male, Microsatellite Instability, Middle Aged, Mutation Rate, Sensitivity and Specificity, Amino Acid Substitution, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Early Detection of Cancer methods, Genetic Markers, Proto-Oncogene Proteins B-raf genetics
- Abstract
BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6%) harbored BRAF mutations. Six of seven LS patients with BRAF-mutant CRC and reported age were <50 years. Among 339 of 756 (44.8%) of BRAF mutations detected in unselected MSI CRC, only 2 of 339 (0.6%) BRAF mutations were detected in patients <50 years. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age <50 years. BRAF testing in patients <50 years carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without BRAF testing., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)
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- 2020
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26. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.
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Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, and Møller P
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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27. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.
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Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, and Møller P
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- Adult, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis mortality, DNA Mismatch Repair, Databases, Genetic, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Penetrance, Prospective Studies, Risk Assessment, Sex Characteristics, Survival Analysis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins economics, Mismatch Repair Endonuclease PMS2 genetics, MutL Protein Homolog 1 genetics, MutS Homolog 2 Protein genetics, Mutation
- Abstract
Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer., Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years., Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer., Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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- 2020
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28. The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.
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Ten Broeke SW, Rodríguez-Girondo M, Suerink M, Aretz S, Bernstein I, Capellá G, Engel C, Gomez-Garcia EB, van Hest LP, von Knebel Doeberitz M, Lagerstedt-Robinson K, Letteboer TGW, Moller P, van Os TA, Pineda M, Rahner N, Olderode-Berends MJW, von Salomé J, Schackert HK, Spruijt L, Steinke-Lange V, Wagner A, Tops CMJ, and Nielsen M
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- Age of Onset, Aged, Cohort Effect, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, DNA Mismatch Repair, Female, Humans, Male, Middle Aged, Models, Statistical, Netherlands epidemiology, Pedigree, Penetrance, Proportional Hazards Models, Anticipation, Genetic, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Mismatch Repair Endonuclease PMS2 genetics, Mutation
- Abstract
Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families., Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias., Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]., Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome., Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition., (©2019 American Association for Cancer Research.)
- Published
- 2019
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29. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.
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Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, Ligtenberg MJL, Vos JR, Ten Broeke SW, de Miranda NFCC, Kuiper RA, Kamping EJ, Jansen EAM, Vink-Börger ME, Popp I, Lang A, Spier I, Hüneburg R, James PA, Li N, Staninova M, Lindsay H, Cockburn D, Spasic-Boskovic O, Clendenning M, Sweet K, Capellá G, Sjursen W, Høberg-Vetti H, Jongmans MC, Neveling K, Geurts van Kessel A, Morreau H, Hes FJ, Sijmons RH, Schackert HK, Ruiz-Ponte C, Dymerska D, Lubinski J, Rivera B, Foulkes WD, Tomlinson IP, Valle L, Buchanan DD, Kenwrick S, Adlard J, Dimovski AJ, Campbell IG, Aretz S, Schindler D, van Wezel T, Hoogerbrugge N, and Kuiper RP
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- Adult, Aged, Biomarkers, Tumor deficiency, DNA Repair genetics, Deoxyribonuclease (Pyrimidine Dimer) deficiency, Europe, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Heredity, Humans, Male, Middle Aged, Neoplastic Syndromes, Hereditary enzymology, Neoplastic Syndromes, Hereditary pathology, Pedigree, Phenotype, Risk Assessment, Risk Factors, Young Adult, Biomarkers, Tumor genetics, DNA Mutational Analysis, Deoxyribonuclease (Pyrimidine Dimer) genetics, Gene Expression Profiling, Germ-Line Mutation, Neoplastic Syndromes, Hereditary genetics, Transcriptome
- Abstract
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2019
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30. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes.
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Kayser K, Degenhardt F, Holzapfel S, Horpaopan S, Peters S, Spier I, Morak M, Vangala D, Rahner N, von Knebel-Doeberitz M, Schackert HK, Engel C, Büttner R, Wijnen J, Doerks T, Bork P, Moebus S, Herms S, Fischer S, Hoffmann P, Aretz S, and Steinke-Lange V
- Subjects
- Adult, Colorectal Neoplasms genetics, DNA Mismatch Repair genetics, Female, Genotype, Germ-Line Mutation genetics, High-Throughput Nucleotide Sequencing methods, Humans, Male, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Copy Number Variations genetics
- Abstract
In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings., (© 2018 UICC.)
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- 2018
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31. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.
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Engel C, Vasen HF, Seppälä T, Aretz S, Bigirwamungu-Bargeman M, de Boer SY, Bucksch K, Büttner R, Holinski-Feder E, Holzapfel S, Hüneburg R, Jacobs MAJM, Järvinen H, Kloor M, von Knebel Doeberitz M, Koornstra JJ, van Kouwen M, Langers AM, van de Meeberg PC, Morak M, Möslein G, Nagengast FM, Pylvänäinen K, Rahner N, Renkonen-Sinisalo L, Sanduleanu S, Schackert HK, Schmiegel W, Schulmann K, Steinke-Lange V, Strassburg CP, Vecht J, Verhulst ML, de Vos Tot Nederveen Cappel W, Zachariae S, Mecklin JP, and Loeffler M
- Subjects
- Adult, Colorectal Neoplasms epidemiology, Colorectal Neoplasms pathology, Female, Humans, Incidence, Male, Middle Aged, Neoplasm Staging, Proportional Hazards Models, Colonoscopy, Colorectal Neoplasms diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis
- Abstract
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., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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- 2018
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32. Cancer Risks for PMS2-Associated Lynch Syndrome.
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Ten Broeke SW, van der Klift HM, Tops CMJ, Aretz S, Bernstein I, Buchanan DD, de la Chapelle A, Capella G, Clendenning M, Engel C, Gallinger S, Gomez Garcia E, Figueiredo JC, Haile R, Hampel HL, Hopper JL, Hoogerbrugge N, von Knebel Doeberitz M, Le Marchand L, Letteboer TGW, Jenkins MA, Lindblom A, Lindor NM, Mensenkamp AR, Møller P, Newcomb PA, van Os TAM, Pearlman R, Pineda M, Rahner N, Redeker EJW, Olderode-Berends MJW, Rosty C, Schackert HK, Scott R, Senter L, Spruijt L, Steinke-Lange V, Suerink M, Thibodeau S, Vos YJ, Wagner A, Winship I, Hes FJ, Vasen HFA, Wijnen JT, Nielsen M, and Win AK
- Subjects
- Adult, Aged, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Mismatch Repair Endonuclease PMS2 genetics, Neoplasms epidemiology, Neoplasms genetics, Penetrance
- Abstract
Purpose: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants., Methods: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance., Results: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer., Conclusion: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
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- 2018
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33. Role of germline aberrations affecting CTNNA1 , MAP3K6 and MYD88 in gastric cancer susceptibility.
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Weren RDA, van der Post RS, Vogelaar IP, van Krieken JH, Spruijt L, Lubinski J, Jakubowska A, Teodorczyk U, Aalfs CM, van Hest LP, Oliveira C, Kamping EJ, Schackert HK, Ranzani GN, Gómez García EB, Hes FJ, Holinski-Feder E, Genuardi M, Ausems MGEM, Sijmons RH, Wagner A, van der Kolk LE, Cats A, Bjørnevoll I, Hoogerbrugge N, and Ligtenberg MJL
- Subjects
- Adult, Aged, Cohort Studies, Europe, Female, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Sequence Analysis, DNA, Young Adult, Antigens, CD genetics, Cadherins genetics, MAP Kinase Kinase Kinases genetics, Myeloid Differentiation Factor 88 genetics, Stomach Neoplasms genetics, alpha Catenin genetics
- Abstract
Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1 , MAP3K6 or MYD88 ., Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1 germline mutation for germline variants affecting CTNNA1 , MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes., Results: Predicted deleterious germline variants were not encountered in MYD88 , but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1 , deleterious variants in MAP3K6 also occur frequently in the general population., Conclusions: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2018
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34. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.
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Vogelaar IP, van der Post RS, van Krieken JHJ, Spruijt L, van Zelst-Stams WA, Kets CM, Lubinski J, Jakubowska A, Teodorczyk U, Aalfs CM, van Hest LP, Pinheiro H, Oliveira C, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, de Ligt J, Vissers LELM, Hoischen A, Gilissen C, van de Vorst M, Goeman JJ, Schackert HK, Ranzani GN, Molinaro V, Gómez García EB, Hes FJ, Holinski-Feder E, Genuardi M, Ausems MGEM, Sijmons RH, Wagner A, van der Kolk LE, Bjørnevoll I, Høberg-Vetti H, van Kessel AG, Kuiper RP, Ligtenberg MJL, and Hoogerbrugge N
- Subjects
- Adult, Aged, Antigens, CD, Cadherins genetics, Early Detection of Cancer methods, Female, Humans, Male, Middle Aged, Sequence Analysis, DNA methods, Stomach Neoplasms diagnosis, Exome, Genetic Predisposition to Disease, Genetic Testing methods, Germ-Line Mutation, Stomach Neoplasms genetics
- Abstract
Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
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- 2017
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35. Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6.
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Morak M, Käsbauer S, Kerscher M, Laner A, Nissen AM, Benet-Pagès A, Schackert HK, Keller G, Massdorf T, and Holinski-Feder E
- Subjects
- DNA-Binding Proteins metabolism, Female, Heterozygote, Humans, Loss of Heterozygosity, Male, MutS Homolog 2 Protein metabolism, MutS Homolog 3 Protein metabolism, Pedigree, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, MutS Homolog 2 Protein genetics, MutS Homolog 3 Protein genetics
- Abstract
Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.
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- 2017
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36. Prevalence of germline mutations in the spindle assembly checkpoint gene BUB1B in individuals with early-onset colorectal cancer.
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Hahn MM, Vreede L, Bemelmans SA, van der Looij E, van Kessel AG, Schackert HK, Ligtenberg MJ, Hoogerbrugge N, Kuiper RP, and de Voer RM
- Subjects
- Adolescent, Adult, Age of Onset, Alleles, Animals, Colorectal Neoplasms pathology, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, M Phase Cell Cycle Checkpoints genetics, Male, Mice, Middle Aged, Cell Cycle Proteins genetics, Colorectal Neoplasms genetics, Germ-Line Mutation genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (≤50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild-type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumors. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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37. An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis.
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Pistorius S, Klink B, Pablik J, Rump A, Aust D, Garzarolli M, Schröck E, and Schackert HK
- Abstract
Background: Ganglioneuromatous polyposis (GP) is a very rare disorder which may be associated with other clinical manifestations and syndromes, such as Cowden syndrome, multiple endocrine neoplasia (MEN) type II and neurofibromatosis (NF) 1. The risk for malignant transformation of ganglioneuromas is unknown, and the combination of GP with colon cancer has been only very seldom reported., Methods and Results: We report the case of a 60-year old male patient with adenocarcinoma, adenomas and lipomas of the colon and multiple gastroduodenal lesions combined with generalised lipomatosis and macrocephaly. Based on the initial endoscopic and histological findings, a (restorative) proctocolectomy was recommended but declined by the patient. Instead, a colectomy was performed. The histological examination revealed an unforeseen GP in addition to the colon cancer. Extensive molecular diagnostics allowed for the differential diagnosis of the causes of the clinical manifestations, and the clinical suspicion of Cowden syndrome could not be confirmed using Sanger Sequencing and MLPA for the analysis of PTEN. Finally, a pathogenic germline mutation in PTEN (heterozygous stop mutation in exon 2: NM_000314 (PTEN):c.138C > A; p.Tyr46*) could be detected by next-generation sequencing (NGS), confirming an unusual presentation of Cowden syndrome with GP., Conclusions: Cowden syndrome should be considered in cases of GP with extracolonic manifestation and verified by combined clinical and molecular diagnostics. Because GP may represent a premalignant condition, a surgical-oncological prophylactic procedure should be considered. Based on our experience, we recommend early implementation of Panel NGS rather than classical Sanger sequencing for genetic diagnostics, especially if various diagnoses are considered.
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- 2016
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38. Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility.
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de Voer RM, Hahn MM, Weren RD, Mensenkamp AR, Gilissen C, van Zelst-Stams WA, Spruijt L, Kets CM, Zhang J, Venselaar H, Vreede L, Schubert N, Tychon M, Derks R, Schackert HK, Geurts van Kessel A, Hoogerbrugge N, Ligtenberg MJ, and Kuiper RP
- Subjects
- Age of Onset, Amino Acid Sequence, Chromosome Segregation genetics, Cohort Studies, Colorectal Neoplasms enzymology, DNA Mismatch Repair genetics, Exome genetics, Genes, Neoplasm, Humans, Molecular Sequence Data, Mutation, Missense genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 12 chemistry, Protein Tyrosine Phosphatase, Non-Receptor Type 12 genetics, Sequence Analysis, DNA, Signal Transduction genetics, Wnt Proteins metabolism, Colorectal Neoplasms genetics, Genetic Association Studies, Genetic Predisposition to Disease
- Abstract
Approximately 25-30% of colorectal cancer (CRC) cases are expected to result from a genetic predisposition, but in only 5-10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55) with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤ 0.001) with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age), and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC.
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- 2016
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39. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer.
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de Voer RM, Hahn MM, Mensenkamp AR, Hoischen A, Gilissen C, Henkes A, Spruijt L, van Zelst-Stams WA, Kets CM, Verwiel ET, Nagtegaal ID, Schackert HK, van Kessel AG, Hoogerbrugge N, Ligtenberg MJ, and Kuiper RP
- Subjects
- Adult, Age of Onset, Case-Control Studies, Datasets as Topic, Exome, Female, Gene Frequency, Genome-Wide Association Study, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Loss of Heterozygosity, Male, Mutation Rate, Pedigree, Population Surveillance, Risk, Colorectal Neoplasms epidemiology, Colorectal Neoplasms genetics, Germ-Line Mutation, RecQ Helicases genetics
- Abstract
Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.
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- 2015
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40. Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.
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Weren RD, Venkatachalam R, Cazier JB, Farin HF, Kets CM, de Voer RM, Vreede L, Verwiel ET, van Asseldonk M, Kamping EJ, Kiemeney LA, Neveling K, Aben KK, Carvajal-Carmona L, Nagtegaal ID, Schackert HK, Clevers H, van de Wetering M, Tomlinson IP, Ligtenberg MJ, Hoogerbrugge N, Geurts van Kessel A, and Kuiper RP
- Subjects
- Adenomatous Polyposis Coli metabolism, Adult, Case-Control Studies, Chromosomes, Human, Pair 9 genetics, Colorectal Neoplasms metabolism, DNA Copy Number Variations genetics, Epithelial Cells metabolism, Female, Gene Expression Regulation, Neoplastic genetics, Heterozygote, Humans, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Open Reading Frames genetics, Tumor Suppressor Proteins metabolism, Adenomatous Polyposis Coli genetics, Colorectal Neoplasms genetics, Gene Deletion, Germ-Line Mutation genetics, Tumor Suppressor Proteins genetics
- Abstract
Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC., (© 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)
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- 2015
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41. Analysis of gastrin-releasing peptide gene and gastrin-releasing peptide receptor gene in patients with agoraphobia.
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Zimmermann K, Görgens H, Bräuer D, Einsle F, Noack B, von Kannen S, Grossmann M, Hoyer J, Strobel A, Köllner V, Weidner K, Ziegler A, Hemmelmann C, and Schackert HK
- Subjects
- Case-Control Studies, Humans, Agoraphobia genetics, Gastrin-Releasing Peptide genetics, Genetic Predisposition to Disease, Receptors, Bombesin genetics
- Abstract
A gastrin-releasing peptide receptor (GRPR) knock-out mouse model provided evidence that the gastrin-releasing peptide (GRP) and its neural circuitry operate as a negative feedback-loop regulating fear, suggesting a novel candidate mechanism contributing to individual differences in fear-conditioning and associated psychiatric disorders such as agoraphobia with/without panic disorder. Studies in humans, however, provided inconclusive evidence on the association of GRP and GRPR variations in agoraphobia with/without panic disorder. Based on these findings, we investigated whether GRP and GRPR variants are associated with agoraphobia. Mental disorders were assessed via the Munich-Composite International Diagnostic Interview (M-CIDI) in 95 patients with agoraphobia with/without panic disorder and 119 controls without any mental disorders. A complete sequence analysis of GRP and GRPR was performed in all participants. We found no association of 16 GRP and 7 GRPR variants with agoraphobia with/without panic disorder.
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- 2014
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42. Complete homozygous deletion of CTSC in an Iranian family with Papillon-Lefèvre syndrome.
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Schackert HK, Agha-Hosseini F, Görgens H, Jatzwauk M, von Kannen S, Noack B, Eckelt U, Hoffmann P, Shabestari SB, and Mehdipour P
- Subjects
- Adult, DNA Mutational Analysis, Female, Homozygote, Humans, Iran, Male, Pedigree, Young Adult, Base Sequence, Cathepsin C genetics, Chromosomes, Human, Pair 11 genetics, Papillon-Lefevre Disease genetics, Sequence Deletion
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- 2014
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43. Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.
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Steinke V, Holzapfel S, Loeffler M, Holinski-Feder E, Morak M, Schackert HK, Görgens H, Pox C, Royer-Pokora B, von Knebel-Doeberitz M, Büttner R, Propping P, and Engel C
- Subjects
- Adenosine Triphosphatases genetics, Adult, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, DNA Mismatch Repair genetics, DNA Mutational Analysis, DNA Repair Enzymes genetics, DNA-Binding Proteins genetics, Female, Germ-Line Mutation, Humans, Male, Microsatellite Instability, Middle Aged, Mismatch Repair Endonuclease PMS2, MutL Protein Homolog 1, Adaptor Proteins, Signal Transducing genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, MutS Homolog 2 Protein genetics, Nuclear Proteins genetics
- Abstract
Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome., (© 2013 UICC.)
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- 2014
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44. Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3.
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Yang R, Chen B, Pfütze K, Buch S, Steinke V, Holinski-Feder E, Stöcker S, von Schönfels W, Becker T, Schackert HK, Royer-Pokora B, Kloor M, Schmiegel WH, Büttner R, Engel C, Lascorz Puertolas J, Försti A, Kunkel N, Bugert P, Schreiber S, Krawczak M, Schafmayer C, Propping P, Hampe J, Hemminki K, and Burwinkel B
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, GTP Phosphohydrolases genetics, Gene Rearrangement, Humans, Male, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Risk Factors, Young Adult, Biomarkers, Tumor genetics, Chromosomes, Human, Pair 12 chemistry, Chromosomes, Human, Pair 12 genetics, Colorectal Neoplasms genetics, DNA Copy Number Variations, Genome, Human, Genome-Wide Association Study
- Abstract
Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the 'missing heritability' of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls (P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
- Published
- 2014
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45. Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer.
- Author
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de Voer RM, Geurts van Kessel A, Weren RD, Ligtenberg MJ, Smeets D, Fu L, Vreede L, Kamping EJ, Verwiel ET, Hahn MM, Ariaans M, Spruijt L, van Essen T, Houge G, Schackert HK, Sheng JQ, Venselaar H, van Ravenswaaij-Arts CM, van Krieken JH, Hoogerbrugge N, and Kuiper RP
- Subjects
- Adult, Biomarkers, Tumor metabolism, Case-Control Studies, Cell Cycle Proteins metabolism, Colorectal Neoplasms metabolism, Genome-Wide Association Study, Humans, Poly-ADP-Ribose Binding Proteins, Protein Serine-Threonine Kinases metabolism, Risk Factors, Biomarkers, Tumor genetics, Cell Cycle Proteins genetics, Colorectal Neoplasms genetics, Germ-Line Mutation, Protein Serine-Threonine Kinases genetics
- Abstract
The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
46. Analysis of Stathmin gene variation in patients with panic disorder and agoraphobia.
- Author
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Bräuer D, Görgens H, Einsle F, Zimmermann K, Noack B, von Kannen S, Hoyer J, Strobel A, Weidner K, Jatzwauk M, Ziegler A, Hemmelmann C, Köllner V, and Schackert HK
- Subjects
- Case-Control Studies, Female, Gene Frequency genetics, Humans, Male, Agoraphobia genetics, Genetic Predisposition to Disease, Panic Disorder genetics, Polymorphism, Single Nucleotide genetics, Stathmin genetics
- Published
- 2013
- Full Text
- View/download PDF
47. Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome.
- Author
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Steinke V, Engel C, Büttner R, Schackert HK, Schmiegel WH, and Propping P
- Subjects
- Diagnosis, Differential, Humans, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Genetic Counseling methods, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Genetic Testing methods, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Hereditary nonpolyposis colorectal cancer HNPCC, Lynch syndrome) is a genetic disease of autosomal dominant inheritance. It is caused by a mutation in one of four genes of the DNA mismatch repair system and confers a markedly increased risk for various types of cancer, particularly of the colon and the endometrium. Its prevalence in the general population is about 1 in 500, and it causes about 2% to 3% of all colorectal cancers. Lynch syndrome is diagnosed in two steps: If it is suspected (because a patient develops cancer at an unusually young age or because of familial clustering), the tumor tissue is analyzed for evidence of deficient mismatch repair (microsatellite instability, loss of mismatch repair protein expression). If such evidence is found, a genetic mutation is sought. The identification of a pathogenic mutation confirms the diagnosis in the patient and enables predictive testing of other family members. Diagnostic evaluations for Lynch syndrome should be carried out with appropriate genetic counseling., Method: Selective literature review., Results: Prospective cohort studies from Germany, Finland and the Netherlands have shown that colorectal cancers detected by systematic colonoscopic surveillance tend to be at an earlier stage than those that are discovered after the patients present with symptoms. The Finnish study also showed an overall reduction in cancer risk from colonoscopic polypectomy at regular intervals., Conclusion: The studies conducted so far have not yet clearly documented the putative benefit of an individualized, risk-adapted surveillance strategy. Until this is done, patients with Lynch syndrome and healthy carriers of causative mutations should be monitored with annual colonoscopy and (for women) annual gynecological examination.
- Published
- 2013
- Full Text
- View/download PDF
48. Risks of less common cancers in proven mutation carriers with lynch syndrome.
- Author
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Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, Schackert HK, Goergens H, von Knebel Doeberitz M, Goecke TO, Schmiegel W, Buettner R, Moeslein G, Letteboer TG, Gómez García E, Hes FJ, Hoogerbrugge N, Menko FH, van Os TA, Sijmons RH, Wagner A, Kluijt I, Propping P, and Vasen HF
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Cohort Studies, DNA-Binding Proteins genetics, Female, Germany epidemiology, Humans, Male, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein genetics, Mutation, Netherlands epidemiology, Nuclear Proteins genetics, Registries, Retrospective Studies, Risk Factors, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplasms epidemiology, Neoplasms genetics
- Abstract
Purpose: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6., Patients and Methods: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk., Results: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers., Conclusion: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
- Published
- 2012
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- View/download PDF
49. Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer.
- Author
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Kast K, Neuhann TM, Görgens H, Becker K, Keller K, Klink B, Aust D, Distler W, Schröck E, and Schackert HK
- Subjects
- Age of Onset, Chromatography, High Pressure Liquid, Female, Germ-Line Mutation, Humans, Middle Aged, Pedigree, DNA-Binding Proteins genetics, Endometrial Neoplasms genetics, Genetic Predisposition to Disease genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Background: Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare., Case Presentation: We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years., Conclusions: Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.
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- 2012
- Full Text
- View/download PDF
50. Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability.
- Author
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Plaschke J, Preußler M, Ziegler A, and Schackert HK
- Subjects
- Adult, Aged, Aged, 80 and over, Base Sequence, Colorectal Neoplasms pathology, Female, Humans, Immunohistochemistry, Male, Middle Aged, Molecular Sequence Data, MutS Homolog 3 Protein, Phenotype, Sequence Analysis, DNA, Colorectal Neoplasms genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Loss of Heterozygosity genetics, Microsatellite Instability
- Abstract
Purpose: High level of microsatellite instability (MSI-H) in colorectal cancer (CRC) is caused by the inactivation of mismatch repair (MMR) genes; however, it is unknown for tumors with low level MSI (MSI-L). The protein complex involving MSH3 preferentially recognizes insertion/deletion loops (IDLs) of two to eight bases and di- and tetranucleotide repeats are affected in the majority of MSI-L CRC., Methods: We selected 10 and eight MSI-L CRCs from 228 and 204 patients with sporadic and hereditary disease, respectively. The tumors were analyzed for protein expression of MSH3, MSH2, MSH6, MLH1, and PMS2, and for mutations and loss of heterozygosity (LOH) in MSH3., Results: Four tumors showed a markedly reduced MSH3 expression, whereas all 18 tumors had normal expression of the remaining MMR proteins. Twenty-five different sequence variants were identified. None of these results in a truncated protein, though L902W represents the first constitutional missense mutation in MSH3 predicted to be functional based on conservation among mutS homologues. All variants have also been found in normal DNA of the patients and in controls. LOH intragenic to MSH3 was evident for 12 of 16 (75%) informative tumors., Conclusions: Occurrence of sequence variants in normal DNA of the patients and in controls excludes somatic mutations and mutations specific to the CRC patient population, respectively. In contrast, the high frequency of LOH as well as the aberrant protein expression in some tumors indicates an involvement of MSH3 impairment in MSI-L CRC.
- Published
- 2012
- Full Text
- View/download PDF
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