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1. Clinicogenomic associations in childhood Langerhans cell histiocytosis:an international cohort study

Author

Kemps, Paul G., Zondag, Timo C.E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A.M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, van Halteren, Astrid G.S., Kemps, Paul G., Zondag, Timo C.E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A.M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, and van Halteren, Astrid G.S.

Abstract

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ~80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)–risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Published
2023

2. QPOLE:A Quick, Simple, and Cheap Alternative for POLE Sequencing in Endometrial Cancer by Multiplex Genotyping Quantitative Polymerase Chain Reaction

Author

Van den Heerik, Anne Sophie V.M., Ter Haar, Natalja T., Vermij, Lisa, Jobsen, Jan J., Brinkhuis, Mariel, Roothaan, Suzan M., Leon-Castillo, Alicia, Ortoft, Gitte, Hogdall, Estrid, Hogdall, Claus, Van Wezel, Tom, Lutgens, Ludy C.H.W., Haverkort, Marie A.D., Khattra, Jas, McAlpine, Jessica N., Creutzberg, Carien L., Smit, Vincent T.H.B.M., Gilks, C. Blake, Horeweg, Nanda, Bosse, Tjalling, Van den Heerik, Anne Sophie V.M., Ter Haar, Natalja T., Vermij, Lisa, Jobsen, Jan J., Brinkhuis, Mariel, Roothaan, Suzan M., Leon-Castillo, Alicia, Ortoft, Gitte, Hogdall, Estrid, Hogdall, Claus, Van Wezel, Tom, Lutgens, Ludy C.H.W., Haverkort, Marie A.D., Khattra, Jas, McAlpine, Jessica N., Creutzberg, Carien L., Smit, Vincent T.H.B.M., Gilks, C. Blake, Horeweg, Nanda, and Bosse, Tjalling

Abstract

PURPOSE: Detection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and personnel. This may hamper the implementation of POLE-testing in clinical practice. To overcome this, we developed and validated a rapid, low-cost POLE hotspot test by a quantitative polymerase chain reaction (qPCR) assay, QPOLE. MATERIALS AND METHODS: Primer and fluorescence-labeled 5'-nuclease probe sequences of the 11 established pathogenic POLE mutations were designed. Three assays, QPOLE-frequent for the most common mutations and QPOLE-rare-1 and QPOLE-rare-2 for the rare variants, were developed and optimized using DNA extracted from formalin-fixed paraffin-embedded tumor tissues. The simplicity of the design enables POLE status assessment within 4-6 hours after DNA isolation. An interlaboratory external validation study was performed to determine the practical feasibility of this assay. RESULTS: Cutoffs for POLE wild-type, POLE-mutant, equivocal, and failed results were predefined on the basis of a subset of POLE mutants and POLE wild-types for the internal and external validation. For equivocal cases, additional DNA sequencing is recommended. Performance in 282 EC cases, of which 99 were POLE-mutated, demonstrated an overall accuracy of 98.6% (95% CI, 97.2 to 99.9), a sensitivity of 95.2% (95% CI, 90.7 to 99.8), and a specificity of 100%. After DNA sequencing of 8.8% equivocal cases, the final sensitivity and specificity were 96.0% (95% CI, 92.1 to 99.8) and 100%. External validation confirmed feasibility and accuracy. CONCLUSION: QPOLE is a qPCR assay that is a quick, simple, and reliable alternative for DNA sequencing. QPOLE detects all pathogenic variants in the exonuclease domain of the POLE gene. QPOLE will

Published
2023

3. Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome–Associated Colorectal Carcinomas

Author

Helderman, Noah c., Van Der Werf-’T Lam, Anne Sophie, Terlouw, Diantha, Bajwa-ten Broeke, Sanne W., Rodríguez-Girondo, Mar, van Egmond, Demi, Langers, Alexandra M.J., van Leerdam, Monique E., Rayner, Emily, van Asperen, Christi J., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bleeker, Fonnet E., Gomez Garcìa, Encarna B., Suerink, Manon, Tops, Carli M., de Wind, Niels, Morreau, Hans, Boot, Arnoud, Van Wezel, Tom, Nielsen, Maartje, Helderman, Noah c., Van Der Werf-’T Lam, Anne Sophie, Terlouw, Diantha, Bajwa-ten Broeke, Sanne W., Rodríguez-Girondo, Mar, van Egmond, Demi, Langers, Alexandra M.J., van Leerdam, Monique E., Rayner, Emily, van Asperen, Christi J., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bleeker, Fonnet E., Gomez Garcìa, Encarna B., Suerink, Manon, Tops, Carli M., de Wind, Niels, Morreau, Hans, Boot, Arnoud, Van Wezel, Tom, and Nielsen, Maartje

Published
2023

4. Clinicogenomic associations in childhood Langerhans cell histiocytosis:an international cohort study

Author

Kemps, Paul G., Zondag, Timo C.E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A.M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, van Halteren, Astrid G.S., Kemps, Paul G., Zondag, Timo C.E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A.M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, and van Halteren, Astrid G.S.

Abstract

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ~80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)–risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Published
2023

5. QPOLE:A Quick, Simple, and Cheap Alternative for POLE Sequencing in Endometrial Cancer by Multiplex Genotyping Quantitative Polymerase Chain Reaction

Author

Van den Heerik, Anne Sophie V.M., Ter Haar, Natalja T., Vermij, Lisa, Jobsen, Jan J., Brinkhuis, Mariel, Roothaan, Suzan M., Leon-Castillo, Alicia, Ortoft, Gitte, Hogdall, Estrid, Hogdall, Claus, Van Wezel, Tom, Lutgens, Ludy C.H.W., Haverkort, Marie A.D., Khattra, Jas, McAlpine, Jessica N., Creutzberg, Carien L., Smit, Vincent T.H.B.M., Gilks, C. Blake, Horeweg, Nanda, Bosse, Tjalling, Van den Heerik, Anne Sophie V.M., Ter Haar, Natalja T., Vermij, Lisa, Jobsen, Jan J., Brinkhuis, Mariel, Roothaan, Suzan M., Leon-Castillo, Alicia, Ortoft, Gitte, Hogdall, Estrid, Hogdall, Claus, Van Wezel, Tom, Lutgens, Ludy C.H.W., Haverkort, Marie A.D., Khattra, Jas, McAlpine, Jessica N., Creutzberg, Carien L., Smit, Vincent T.H.B.M., Gilks, C. Blake, Horeweg, Nanda, and Bosse, Tjalling

Abstract

PURPOSE: Detection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and personnel. This may hamper the implementation of POLE-testing in clinical practice. To overcome this, we developed and validated a rapid, low-cost POLE hotspot test by a quantitative polymerase chain reaction (qPCR) assay, QPOLE. MATERIALS AND METHODS: Primer and fluorescence-labeled 5'-nuclease probe sequences of the 11 established pathogenic POLE mutations were designed. Three assays, QPOLE-frequent for the most common mutations and QPOLE-rare-1 and QPOLE-rare-2 for the rare variants, were developed and optimized using DNA extracted from formalin-fixed paraffin-embedded tumor tissues. The simplicity of the design enables POLE status assessment within 4-6 hours after DNA isolation. An interlaboratory external validation study was performed to determine the practical feasibility of this assay. RESULTS: Cutoffs for POLE wild-type, POLE-mutant, equivocal, and failed results were predefined on the basis of a subset of POLE mutants and POLE wild-types for the internal and external validation. For equivocal cases, additional DNA sequencing is recommended. Performance in 282 EC cases, of which 99 were POLE-mutated, demonstrated an overall accuracy of 98.6% (95% CI, 97.2 to 99.9), a sensitivity of 95.2% (95% CI, 90.7 to 99.8), and a specificity of 100%. After DNA sequencing of 8.8% equivocal cases, the final sensitivity and specificity were 96.0% (95% CI, 92.1 to 99.8) and 100%. External validation confirmed feasibility and accuracy. CONCLUSION: QPOLE is a qPCR assay that is a quick, simple, and reliable alternative for DNA sequencing. QPOLE detects all pathogenic variants in the exonuclease domain of the POLE gene. QPOLE will

Published
2023

6. Specific (sialyl-)Lewis core 2 O-glycans differentiate colorectal cancer from healthy colon epithelium

Author

Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Madunić, Katarina, Mayboroda, Oleg A., Zhang, Tao, Weber, Julia, Boons, Geert Jan, Morreau, Hans, van Vlierberghe, Ronald, van Wezel, Tom, Lageveen-Kammeijer, Guinevere S.M., Wuhrer, Manfred, Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Madunić, Katarina, Mayboroda, Oleg A., Zhang, Tao, Weber, Julia, Boons, Geert Jan, Morreau, Hans, van Vlierberghe, Ronald, van Wezel, Tom, Lageveen-Kammeijer, Guinevere S.M., and Wuhrer, Manfred

Published
2022

7. Specific (sialyl-)Lewis core 2 O-glycans differentiate colorectal cancer from healthy colon epithelium

Author

Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Madunić, Katarina, Mayboroda, Oleg A., Zhang, Tao, Weber, Julia, Boons, Geert Jan, Morreau, Hans, van Vlierberghe, Ronald, van Wezel, Tom, Lageveen-Kammeijer, Guinevere S.M., Wuhrer, Manfred, Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Madunić, Katarina, Mayboroda, Oleg A., Zhang, Tao, Weber, Julia, Boons, Geert Jan, Morreau, Hans, van Vlierberghe, Ronald, van Wezel, Tom, Lageveen-Kammeijer, Guinevere S.M., and Wuhrer, Manfred

Published
2022

8. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, Claire, West, Hannah D., Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Palles, Claire, West, Hannah D., Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, and Lopez-Bigas, Nuria

Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

9. Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk

Author

Boonen, Rick A C M, Wiegant, Wouter W, Celosse, Nandi, Vroling, Bas, Heijl, Stephan; https://orcid.org/0000-0001-8920-4293, Kote-Jarai, Zsofia, Mijuskovic, Martina, Cristea, Simona, Solleveld-Westerink, Nienke, van Wezel, Tom; https://orcid.org/0000-0001-5773-7730, Beerenwinkel, Niko, Eeles, Rosalind; https://orcid.org/0000-0002-3698-6241, Devilee, Peter; https://orcid.org/0000-0002-8023-2009, Vreeswijk, Maaike P G; https://orcid.org/0000-0003-4068-9271, Marra, Giancarlo; https://orcid.org/0000-0003-1080-4320, van Attikum, Haico; https://orcid.org/0000-0001-8590-0240, Boonen, Rick A C M, Wiegant, Wouter W, Celosse, Nandi, Vroling, Bas, Heijl, Stephan; https://orcid.org/0000-0001-8920-4293, Kote-Jarai, Zsofia, Mijuskovic, Martina, Cristea, Simona, Solleveld-Westerink, Nienke, van Wezel, Tom; https://orcid.org/0000-0001-5773-7730, Beerenwinkel, Niko, Eeles, Rosalind; https://orcid.org/0000-0002-3698-6241, Devilee, Peter; https://orcid.org/0000-0002-8023-2009, Vreeswijk, Maaike P G; https://orcid.org/0000-0003-4068-9271, Marra, Giancarlo; https://orcid.org/0000-0003-1080-4320, and van Attikum, Haico; https://orcid.org/0000-0001-8590-0240

Abstract

Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a similar extent as truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group [OR 2.23; 95% confidence interval (CI), 1.62-3.07; P < 0.0001] and intermediate variants (OR 1.63; 95% CI, 1.21-2.20; P = 0.0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1.13; 95% CI, 0.87-1.46; P = 0.378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which cosegregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer. Significance: Quantitative assessment of the functional consequences of CHEK2 variants of uncertain significance identifies damaging variants associated with increased cancer risk, which may aid in the clinical management of patients and carriers.

Published
2022

10. Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing

Author

Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W J, van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C, Hijmering, Nathalie J, Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S J, de Vree, Paula J P, Verstegen, Marjon J A M, Krijger, Peter H L, Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, de Laat, Wouter, Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W J, van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C, Hijmering, Nathalie J, Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S J, de Vree, Paula J P, Verstegen, Marjon J A M, Krijger, Peter H L, Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, and de Laat, Wouter

Abstract

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Published
2021

11. Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing

Author

Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W J, van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C, Hijmering, Nathalie J, Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S J, de Vree, Paula J P, Verstegen, Marjon J A M, Krijger, Peter H L, Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, de Laat, Wouter, Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W J, van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C, Hijmering, Nathalie J, Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S J, de Vree, Paula J P, Verstegen, Marjon J A M, Krijger, Peter H L, Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, and de Laat, Wouter

Abstract

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Published
2021

13. Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC

Author

Hondelink, Liesbeth M., Jebbink, Merel, von der Thüsen, Jan H., Cohen, Danielle, Dubbink, Hendrikus J., Paats, Marthe S., Dingemans, Anne Marie C., de Langen, Adrianus J., Boelens, Mirjam C., Smit, Egbert F., Postmus, Pieter E., van Wezel, Tom, Monkhorst, Kim, Hondelink, Liesbeth M., Jebbink, Merel, von der Thüsen, Jan H., Cohen, Danielle, Dubbink, Hendrikus J., Paats, Marthe S., Dingemans, Anne Marie C., de Langen, Adrianus J., Boelens, Mirjam C., Smit, Egbert F., Postmus, Pieter E., van Wezel, Tom, and Monkhorst, Kim

Abstract

Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important—and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting. Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI–treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC). Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity. Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as—although rare—multiple acquired resistance mechanisms may occur.

Published
2021

14. Comedonecrosis Gleason pattern 5 is associated with worse clinical outcome in operated prostate cancer patients

Author

Hansum, Tim, Hollemans, Eva, Verhoef, Esther I., Bangma, Chris H., Rietbergen, John, Osanto, Susanne, Pelger, Rob C.M., van Wezel, Tom, van der Poel, Henk, Bekers, Elise, Helleman, Jozien, Remmers, Sebastiaan, van Leenders, Geert J.L.H., Hansum, Tim, Hollemans, Eva, Verhoef, Esther I., Bangma, Chris H., Rietbergen, John, Osanto, Susanne, Pelger, Rob C.M., van Wezel, Tom, van der Poel, Henk, Bekers, Elise, Helleman, Jozien, Remmers, Sebastiaan, and van Leenders, Geert J.L.H.

Abstract

Individual growth patterns and cribriform architecture are increasingly considered in risk stratification and clinical decision-making in men with prostate cancer. Our objective was to establish the prognostic value of individual Gleason 5 patterns in a radical prostatectomy (RP) cohort. We reviewed 1064 RPs and recorded Grade Group (GG), pT-stage, surgical margin status, Gleason 4 and 5 growth patterns as well as intraductal carcinoma. The clinical endpoints were biochemical recurrence and post-operative distant metastasis. Gleason pattern 5 was present in 339 (31.9%) RPs, of which 47 (4.4%) presented as primary, 166 (15.6%) as secondary, and 126 (11.8%) as tertiary pattern. Single cells/cords were present in 321 (94.7%) tumors with Gleason pattern 5, solid fields in 90 (26.5%), and comedonecrosis in invasive carcinoma in 32 (9.4%) tumors. Solid fields demonstrated either a small nested morphology (n = 50, 14.7%) or medium to large solid fields (n = 61, 18.0%). Cribriform architecture was present in 568 (53.4%) RPs. Medium to large solid fields and comedonecrosis coincided with cribriform architecture in all specimens, and were not observed in cribriform-negative cases. In multivariable analysis adjusted for Prostate-Specific Antigen, pT-stage, GG, surgical margin status and lymph node metastases, cribriform architecture (Hazard Ratio (HR) 9.9; 95% Confidence Interval (CI) 3.9–25.5, P < 0.001) and comedonecrosis (HR 2.1, 95% CI 1.2–3.7, P = 0.01) were independent predictors for metastasis-free survival, while single cells/cords (HR 1.2; 95% CI 0.7–1.8, P = 0.55) and medium to large solid fields (HR 1.6, 95% CI 0.9–2.7, P = 0.09) were not. In conclusion, comedonecrosis in invasive carcinoma is an independent prognostic Gleason 5 pattern for metastasis-free survival after RP. These data support the current recommendations to routinely include cribriform pattern in pathology reports and indicate that comedonecrosis should also be commented on.

Published
2021

15. Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing

Author

CMM Groep De Ridder, Cancer, CMM Groep Kloosterman, Pathologie Pathologen staf, Pathologie Moleculair, CMM Onderwijs, Pathologie Moleculair Path., CMM Groep Burgering, Genetica, Hubrecht Institute with UMC, Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G. Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W.J., van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C., Hijmering, Nathalie J., Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S.J., de Vree, Paula J.P., Verstegen, Marjon J.A.M., Krijger, Peter H.L., Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, de Laat, Wouter, CMM Groep De Ridder, Cancer, CMM Groep Kloosterman, Pathologie Pathologen staf, Pathologie Moleculair, CMM Onderwijs, Pathologie Moleculair Path., CMM Groep Burgering, Genetica, Hubrecht Institute with UMC, Allahyar, Amin, Pieterse, Mark, Swennenhuis, Joost, Los-de Vries, G. Tjitske, Yilmaz, Mehmet, Leguit, Roos, Meijers, Ruud W.J., van der Geize, Robert, Vermaat, Joost, Cleven, Arjen, van Wezel, Tom, Diepstra, Arjan, van Kempen, Léon C., Hijmering, Nathalie J., Stathi, Phylicia, Sharma, Milan, Melquiond, Adrien S.J., de Vree, Paula J.P., Verstegen, Marjon J.A.M., Krijger, Peter H.L., Hajo, Karima, Simonis, Marieke, Rakszewska, Agata, van Min, Max, de Jong, Daphne, Ylstra, Bauke, Feitsma, Harma, Splinter, Erik, and de Laat, Wouter

Published
2021

16. Multicenter comparison of Molecular Tumor Boards in the Netherlands: definition, composition, methods and targeted therapy recommendations

Author

Pathologie Stafondersteuning, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Longziekten, Infection & Immunity, Koopman, Bart, Groen, Harry J M, Ligtenberg, Marjolijn J L, Grünberg, Katrien, Monkhorst, Kim, de Langen, Adrianus J, Boelens, Mirjam C, Paats, Marthe S, von der Thüsen, Jan H, Dinjens, Winand N M, Solleveld, Nienke, van Wezel, Tom, Gelderblom, Hans, Hendriks, Lizza E, Speel, Ernst Jan M, Theunissen, Tom E, Kroeze, Leonie I, Mehra, Niven, Piet, Berber, van der Wekken, Anthonie J, Ter Elst, Arja, Timens, Wim, Willems, Stefan M, Meijers, Ruud W J, de Leng, Wendy W J, van Lindert, Anne S R, Radonic, Teodora, Hashemi, Sayed M S, Heideman, Daniëlle A M, Schuuring, Ed, van Kempen, Léon C, Pathologie Stafondersteuning, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Longziekten, Infection & Immunity, Koopman, Bart, Groen, Harry J M, Ligtenberg, Marjolijn J L, Grünberg, Katrien, Monkhorst, Kim, de Langen, Adrianus J, Boelens, Mirjam C, Paats, Marthe S, von der Thüsen, Jan H, Dinjens, Winand N M, Solleveld, Nienke, van Wezel, Tom, Gelderblom, Hans, Hendriks, Lizza E, Speel, Ernst Jan M, Theunissen, Tom E, Kroeze, Leonie I, Mehra, Niven, Piet, Berber, van der Wekken, Anthonie J, Ter Elst, Arja, Timens, Wim, Willems, Stefan M, Meijers, Ruud W J, de Leng, Wendy W J, van Lindert, Anne S R, Radonic, Teodora, Hashemi, Sayed M S, Heideman, Daniëlle A M, Schuuring, Ed, and van Kempen, Léon C

Published
2021

17. Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Author

Kemps, Paul G., Zondag, Timo C., Steenwijk, Eline C., Andriessen, Quirine, Borst, Jelske, Vloemans, Sandra, Roelen, Dave L., Voortman, Lenard M., Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Hawkins, Cynthia, Lang, Veronica, de Ru, Arnoud H., Janssen, George M.C., Haasnoot, Geert W., Franken, Kees L.M.C., van Eijk, Ronald, Solleveld-Westerink, Nienke, van Wezel, Tom, Egeler, R. Maarten, Beishuizen, Auke, van Laar, Jan A.M., Abla, Oussama, van den Bos, Cor, van Veelen, Peter A., van Halteren, Astrid G.S., Kemps, Paul G., Zondag, Timo C., Steenwijk, Eline C., Andriessen, Quirine, Borst, Jelske, Vloemans, Sandra, Roelen, Dave L., Voortman, Lenard M., Verdijk, Robert M., van Noesel, Carel J.M., Cleven, Arjen H.G., Hawkins, Cynthia, Lang, Veronica, de Ru, Arnoud H., Janssen, George M.C., Haasnoot, Geert W., Franken, Kees L.M.C., van Eijk, Ronald, Solleveld-Westerink, Nienke, van Wezel, Tom, Egeler, R. Maarten, Beishuizen, Auke, van Laar, Jan A.M., Abla, Oussama, van den Bos, Cor, van Veelen, Peter A., and van Halteren, Astrid G.S.

Abstract

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the H

Published
2020

18. Multicenter Comparison of Molecular Tumor Boards in The Netherlands:Definition, Composition, Methods, and Targeted Therapy Recommendations

Author

Koopman, Bart, Groen, Harry J.M., Ligtenberg, Marjolijn J.L., Grünberg, Katrien, Monkhorst, Kim, de Langen, Adrianus J., Boelens, Mirjam C., Paats, Marthe S., von der Thüsen, Jan H., Dinjens, Winand N.M., Solleveld, Nienke, van Wezel, Tom, Gelderblom, Hans, Hendriks, Lizza E., Speel, Ernst Jan M., Theunissen, Tom E., Kroeze, Leonie I., Mehra, Niven, Piet, Berber, van der Wekken, Anthonie J., ter Elst, Arja, Timens, Wim, Willems, Stefan M., Meijers, Ruud W.J., de Leng, Wendy W.J., van Lindert, Anne S.R., Radonic, Teodora, Hashemi, Sayed M.S., Heideman, Daniëlle A.M., Schuuring, Ed, van Kempen, Léon C., Koopman, Bart, Groen, Harry J.M., Ligtenberg, Marjolijn J.L., Grünberg, Katrien, Monkhorst, Kim, de Langen, Adrianus J., Boelens, Mirjam C., Paats, Marthe S., von der Thüsen, Jan H., Dinjens, Winand N.M., Solleveld, Nienke, van Wezel, Tom, Gelderblom, Hans, Hendriks, Lizza E., Speel, Ernst Jan M., Theunissen, Tom E., Kroeze, Leonie I., Mehra, Niven, Piet, Berber, van der Wekken, Anthonie J., ter Elst, Arja, Timens, Wim, Willems, Stefan M., Meijers, Ruud W.J., de Leng, Wendy W.J., van Lindert, Anne S.R., Radonic, Teodora, Hashemi, Sayed M.S., Heideman, Daniëlle A.M., Schuuring, Ed, and van Kempen, Léon C.

Abstract

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming

Published
2020

19. Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Author

Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, Ligtenberg, Marjolijn J L, Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, and Ligtenberg, Marjolijn J L

Published
2019

20. Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Author

Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, Ligtenberg, Marjolijn J L, Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, and Ligtenberg, Marjolijn J L

Published
2019

21. Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Author

Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, Ligtenberg, Marjolijn J L, Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, and Ligtenberg, Marjolijn J L

Published
2019

22. Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Author

Pathologie Laboratorium diagnostiek, Pathologie Pathologen staf, Cancer, Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, Ligtenberg, Marjolijn J L, Pathologie Laboratorium diagnostiek, Pathologie Pathologen staf, Cancer, Eijkelenboom, Astrid, Tops, Bastiaan B J, van den Berg, Anke, van den Brule, Adrianus J C, Dinjens, Winand N M, Dubbink, Hendrikus J, Ter Elst, Arja, Geurts-Giele, Willemina R R, Groenen, Patricia J T A, Groenendijk, Floris H, Heideman, Daniëlle A M, Huibers, Manon M H, Huijsmans, Cornelis J J, Jeuken, Judith W M, van Kempen, Léon C, Korpershoek, Esther, Kroeze, Leonie I, de Leng, Wendy W J, van Noesel, Carel J M, Speel, Ernst-Jan M, Vogel, Maartje J, van Wezel, Tom, Nederlof, Petra M, Schuuring, Ed, and Ligtenberg, Marjolijn J L

Published
2019

23. Clinical and Molecular Characteristics May Alter Treatment Strategies of Thyroid Malignancies in DICER1-syndrome

Author

Genetica Klinische Genetica, Cancer, van der Tuin, Karin, de Kock, Leanne, Kamping, Eveline J, Hannema, Sabine E, Pouwels, Marie-Jose M, Niedziela, Marek, van Wezel, Tom, Hes, Frederik J, Jongmans, Marjolijn C, Foulkes, William D, Morreau, Hans, Genetica Klinische Genetica, Cancer, van der Tuin, Karin, de Kock, Leanne, Kamping, Eveline J, Hannema, Sabine E, Pouwels, Marie-Jose M, Niedziela, Marek, van Wezel, Tom, Hes, Frederik J, Jongmans, Marjolijn C, Foulkes, William D, and Morreau, Hans

Published
2019

24. SNP association study in PMS2-associated Lynch syndrome

Author

Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, Nielsen, Maartje, Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, and Nielsen, Maartje

Published
2018

25. Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

Author

Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, Morreau, Hans, Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, and Morreau, Hans

Published
2018

26. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2

Author

ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, Nielsen, Maartje, ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, and Nielsen, Maartje

Published
2018

27. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2

Author

ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, Nielsen, Maartje, ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, and Nielsen, Maartje

Published
2018

28. SNP association study in PMS2-associated Lynch syndrome

Author

Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, Nielsen, Maartje, Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, and Nielsen, Maartje

Published
2018

29. Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

Author

Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, Morreau, Hans, Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, and Morreau, Hans

Published
2018

30. Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

Author

Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, Morreau, Hans, Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, and Morreau, Hans

Published
2018

31. SNP association study in PMS2-associated Lynch syndrome

Author

Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, Nielsen, Maartje, Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, and Nielsen, Maartje

Published
2018

32. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2

Author

ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, Nielsen, Maartje, ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, and Nielsen, Maartje

Published
2018

33. Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

Author

Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, Morreau, Hans, Crobach, Stijn, Jansen, Anne M L, Ligtenberg, Marjolein J.L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N M, van Wezel, Tom, and Morreau, Hans

Published
2018

34. SNP association study in PMS2-associated Lynch syndrome

Author

UMC Utrecht, Genetica Klinische Genetica, Child Health, Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, Nielsen, Maartje, UMC Utrecht, Genetica Klinische Genetica, Child Health, Ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J W, Garcia, Encarna Gomez, Gille, Hans J J P, van Hest, Liselot P., Letteboer, Tom G.W., Van Der Kolk, Lizet E., Mensenkamp, Arjen R., Van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J W, Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, Ewout W., Tops, Carli M J, van Wezel, Tom, and Nielsen, Maartje

Published
2018

35. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2

Author

Genetica Klinische Genetica, Child Health, ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, Nielsen, Maartje, Genetica Klinische Genetica, Child Health, ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, and Nielsen, Maartje

Published
2018

36. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Author

Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam, Grolleman, Judith E, van Wezel, Tom, Nik-Zainal, Serena, Kuiper, Roland P, Cuppen, Edwin, Clevers, Hans, Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam, Grolleman, Judith E, van Wezel, Tom, Nik-Zainal, Serena, Kuiper, Roland P, Cuppen, Edwin, and Clevers, Hans

Abstract

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.

Published
2017

37. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Author

Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam, Grolleman, Judith E, van Wezel, Tom, Nik-Zainal, Serena, Kuiper, Roland P, Cuppen, Edwin, Clevers, Hans, Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam, Grolleman, Judith E, van Wezel, Tom, Nik-Zainal, Serena, Kuiper, Roland P, Cuppen, Edwin, and Clevers, Hans

Abstract

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.

Published
2017

38. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

39. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

40. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, Wijnen, Juul T, Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, and Wijnen, Juul T

Published
2016

41. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

42. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, Wijnen, Juul T, Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, and Wijnen, Juul T

Published
2016

43. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Genetica Sectie Oncogenetica, Child Health, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Genetica Sectie Oncogenetica, Child Health, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

44. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

Genetica Sectie Oncogenetica, Child Health, Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, Wijnen, Juul T, Genetica Sectie Oncogenetica, Child Health, Jansen, Anne M L, Geilenkirchen, Marije A, van Wezel, Tom, Jagmohan-Changur, Shantie C, Ruano, Dina, van der Klift, Heleen M, van den Akker, Brendy E W M, Laros, Jeroen F J, van Galen, Michiel, Wagner, Anja, Letteboer, Tom G W, Gómez-García, Encarna B, Tops, Carli M J, Vasen, Hans F, Devilee, Peter, Hes, Frederik J, Morreau, Hans, and Wijnen, Juul T

Published
2016

45. Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2

Author

de Miranda, Noel F. C. C., van Dinther, Maarten, van den Akker, Brendy E. W. M., van Wezel, Tom, ten Dijke, Peter, Morreau, Hans, de Miranda, Noel F. C. C., van Dinther, Maarten, van den Akker, Brendy E. W. M., van Wezel, Tom, ten Dijke, Peter, and Morreau, Hans

Abstract

BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGF beta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGF beta. We investigated how TGF beta signaling might continue in MSI-H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGF beta signaling was detected by SMAD2 phosphorylation and through use of a TGF beta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGF beta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGF beta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGF beta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability sh

Published
2015
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46. The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Author

Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, Castellví-Bel, Sergi, Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, and Castellví-Bel, Sergi

Abstract

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

Published
2014

47. Association between CASP8-652 6N Del Polymorphism (rs3834129) and Colorectal Cancer Risk: Results from a Multi-Centric Study

Author

Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, EPICOLON Consortium, Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, and EPICOLON Consortium

Abstract

The common 2652 6N del variant in the CASP8 promoter (rs3834129) has been described as a putative low-penetrance risk factor for different cancer types. In particular, some studies suggested that the deleted allele (del) was inversely associated with CRC risk while other analyses failed to confirm this. Hence, to better understand the role of this variant in the risk of developing CRC, we performed a multi-centric case-control study. In the study, the variant 2652 6N del was genotyped in a total of 6,733 CRC cases and 7,576 controls recruited by six different centers located in Spain, Italy, USA, England, Czech Republic and the Netherlands collaborating to the international consortium COGENT (COlorectal cancer GENeTics). Our analysis indicated that rs3834129 was not associated with CRC risk in the full data set. However, the del allele was under-represented in one set of cases with a family history of CRC (per allele model OR = 0.79, 95% CI = 0.69-0.90) suggesting this allele might be a protective factor versus familial CRC. Since this multi-centric case-control study was performed on a very large sample size, it provided robust clarification of the effect of rs3834129 on the risk of developing CRC in Caucasians.

Published
2014

48. The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Author

Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, Castellví-Bel, Sergi, Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, and Castellví-Bel, Sergi

Abstract

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

Published
2014

49. Association between CASP8-652 6N Del Polymorphism (rs3834129) and Colorectal Cancer Risk: Results from a Multi-Centric Study

Author

Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, EPICOLON Consortium, Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, and EPICOLON Consortium

Abstract

The common 2652 6N del variant in the CASP8 promoter (rs3834129) has been described as a putative low-penetrance risk factor for different cancer types. In particular, some studies suggested that the deleted allele (del) was inversely associated with CRC risk while other analyses failed to confirm this. Hence, to better understand the role of this variant in the risk of developing CRC, we performed a multi-centric case-control study. In the study, the variant 2652 6N del was genotyped in a total of 6,733 CRC cases and 7,576 controls recruited by six different centers located in Spain, Italy, USA, England, Czech Republic and the Netherlands collaborating to the international consortium COGENT (COlorectal cancer GENeTics). Our analysis indicated that rs3834129 was not associated with CRC risk in the full data set. However, the del allele was under-represented in one set of cases with a family history of CRC (per allele model OR = 0.79, 95% CI = 0.69-0.90) suggesting this allele might be a protective factor versus familial CRC. Since this multi-centric case-control study was performed on a very large sample size, it provided robust clarification of the effect of rs3834129 on the risk of developing CRC in Caucasians.

Published
2014

50. The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Author

Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, Castellví-Bel, Sergi, Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, and Castellví-Bel, Sergi

Abstract

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

Published
2014

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