Review
Biochemistry & Molecular Biology
Cristina Carrato, Carolina Sanz, Ana Maria Munoz-Marmol, Ignacio Blanco, Marta Pineda, Jesus Del Valle, Estela Damaso, Manel Esteller, Eva Musulen
Summary: Biallelic germline mismatch repair gene mutations causing constitutional mismatch repair deficiency syndrome are rare and often present with pediatric malignant brain tumors. Immunohistochemical assessment of MMR protein expression is essential for diagnosis, while MSI analysis may be less reliable in brain tumors. Early diagnosis is crucial to identify cases of CMMRD for appropriate treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Gastroenterology & Hepatology
Keinosuke Hizuka, Shin-ichiro Hagiwara, Takatoshi Maeyama, Hitoshi Honma, Masanobu Kawai, Kiwamu Akagi, Michiko Yasuhara, Naohiro Tomita, Yuri Etani
Summary: We report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers. This patient developed colorectal cancer in childhood and exhibited symptoms resembling NF1. Physicians should be familiar with CMMRD clinical phenotypes for early cancer screening and detection.
BMC GASTROENTEROLOGY
(2021)
Review
Oncology
Asima Abidi, Mark A. J. Gorris, Evan Brennan, Marjolijn C. J. Jongmans, Dilys D. Weijers, Roland P. Kuiper, Richarda M. de Voer, Nicoline Hoogerbrugge, Gerty Schreibelt, I. Jolanda M. de Vries
Summary: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterized by a significantly increased risk of cancer development due to germline mutations in DNA repair genes. Although the high mutation load in tumors of these patients may generate neoantigens for immune therapies, challenges such as tumor heterogeneity and resistance to immune checkpoint therapy need to be addressed. New approaches, including precise HLA binding algorithms and additional therapies to counter immune evasion, are warranted to optimize neoantigen targeting strategies.
Article
Oncology
Elvan C. Citak, Fatih Sagcan, Begumhan D. Gundugan, Sevcan T. Bozdogan, Eda B. Yilmaz, Emel Avci, Yuksel Balci, Yasemin Y. Karabulut
Summary: Constitutional mismatch repair deficiency (CMMRD) is a childhood cancer predisposition syndrome caused by biallelic germline mutations in key DNA mismatch repair genes, leading to a high risk of developing central nervous system tumors, hematologic, and intestinal tract tumors. A patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia was found to have a novel homozygous mutation in MSH6. CMMRD should be considered in patients with cutaneous features similar to NF1, tumor types different from NF tumors, early onset cancer, and strong family history of cancer.
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
(2021)
Article
Genetics & Heredity
Ying L. Liu, Karen A. Cadoo, Anna Maio, Zalak Patel, Yelena Kemel, Erin Salo-Mullen, Amanda Catchings, Megha Ranganathan, Sarah Kane, Robert Soslow, Ozge Ceyhan-Birsoy, Diana Mandelker, Maria I. Carlo, Michael F. Walsh, Jinru Shia, Arnold J. Markowitz, Kenneth Of, Alicia Latham
Summary: This study aimed to characterize MSH6/PMS2-associated mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors. It found that patients with germline MSH6/PMS2 pathogenic/likely pathogenic variants are at risk for a broad spectrum of cancers, with CRC and EC being the most common. The study also highlighted the occurrence of MMR-D/MSI-H CRC and EC at younger ages.
GENETICS IN MEDICINE
(2022)
Article
Oncology
Joseph Chao, Charles S. Fuchs, Kohei Shitara, Josep Tabernero, Kei Muro, Eric Van Cutsem, Yung-Jue Bang, Ferdinando De Vita, Gregory Landers, Chia-Jui Yen, Ian Chau, Anneli Elme, Jeeyun Lee, Mustafa Ozguroglu, Daniel Catenacci, Harry H. Yoon, Erluo Chen, David Adelberg, Chie-Schin Shih, Sukrut Shah, Pooja Bhagia, Zev A. Wainberg
Summary: This study indicates that MSI-H status may serve as a biomarker for pembrolizumab therapy in advanced G/GEJ cancer patients regardless of the line of therapy.
Article
Genetics & Heredity
Astrid Sehested, Julia Meade, David Scheie, Olga Ostrup, Birgitte Bertelsen, Maria Anna Misiakou, Tomasz Sarosiek, Elena Kessler, Linea C. Melchior, Helga Fibiger Munch-Petersen, Reetesh K. Pai, Matthias Schmuth, Hendrik Gottschling, Johannes Zschocke, Richard Gallon, Katharina Wimmer
Summary: Heterozygous POLE or POLD1 germline pathogenic variants cause PPAP, while bi-allelic PVs affecting one of four MMR genes lead to CMMRD, with similar clinical features but potentially different effects. Monitoring patients with severe polymerase proofreading deficiencies is important due to the underlying replication error repair defect and similar tumor spectrum.
Article
Oncology
Venu Thatikonda, S. M. Ashiqul Islam, Robert J. Autry, Barbara C. Jones, Susanne N. Groebner, Gregor Warsow, Barbara Hutter, Daniel Huebschmann, Stefan Froehling, Marcel Kool, Mirjam Blattner-Johnson, David T. W. Jones, Ludmil B. Alexandrov, Stefan M. Pfister, Natalie Jaeger
Summary: Jager and colleagues analyzed the mutational patterns in pediatric cancers and found marked differences compared to adult cancers, providing insights into molecular mechanisms. They identified a small number of mutational signatures specific to pediatric cancers and discovered a previously unreported indel signature in pediatric leukemias. This study provides a systematic overview of mutational signatures in pediatric cancers, which is highly relevant for understanding tumor biology and developing biomarkers for treatment response.
Article
Multidisciplinary Sciences
Bernard C. H. Lee, Philip S. Robinson, Tim H. H. Coorens, Helen H. N. Yan, Sigurgeir Olafsson, Henry Lee-Six, Mathijs A. Sanders, Hoi Cheong Siu, James Hewinson, Sarah S. K. Yue, Wai Yin Tsui, Annie S. Y. Chan, Anthony K. W. Chan, Siu Lun Ho, Peter J. Campbell, Inigo Martincorena, Simon J. A. Buczacki, Siu Tsan Yuen, Suet Yi Leung, Michael R. Stratton
Summary: The study shows that normal tissues in Lynch Syndrome (LS) patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution. This highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Katja Kratz, Mariela Artola-Boran, Saho Kobayashi-Era, Gene Koh, Goncalo Oliveira, Shunsuke Kobayashi, Andreia Oliveira, Xueqing Zou, Julia Richter, Masataka Tsuda, Hiroyuki Sasanuma, Shunichi Takeda, Joanna Loizou, Alessandro A. Sartori, Serena Nik-Zainal, Josef Jiricny
Summary: A study revealed a new exonuclease, FAN1, which can efficiently substitute for EXO1 in the mismatch repair process, with its functional complementation modulated by its interaction with MLH1. Loss of FAN1 exacerbates the mutational profile of EXO1-deficient cells, suggesting redundant action of these two nucleases in the same antimutagenic pathway.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Oncology
Di Wu, Qingshan Chen, Jian Chen
Summary: This study presents a case of two siblings diagnosed with brain tumors. Whole-genome sequencing analysis revealed high somatic mutation loads in the tumor samples, along with pigmentation on the skin of one patient. Further investigation identified a causal link between the brain tumors and a biallelic mutation of the MSH6 gene, which is involved in DNA mismatch repair.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yuan Zhuang, Jiangle Liu, Hao Wu, Qingguo Zhu, Yongchang Yan, Haowei Meng, Peng R. Chen, Chengqi Yi
Summary: The HOPE method utilizes paired pegRNAs encoding the same edits to achieve high editing efficiency in human embryonic kidney and colorectal carcinoma cells, showing improved product purity compared to the original PE3 system. This enhanced tool has the potential to broaden both fundamental research and therapeutic applications of prime editing.
NATURE CHEMICAL BIOLOGY
(2022)
Review
Oncology
Richard Gallon, Peter Gawthorpe, Rachel L. Phelps, Christine Hayes, Gillian M. Borthwick, Mauro Santibanez-Koref, Michael S. Jackson, John Burn
Summary: The article discusses international guidelines for the diagnosis of Lynch syndrome (LS), barriers and limitations, as well as new screening opportunities. It also proposes additional LS screening strategies.
Article
Multidisciplinary Sciences
Yunbeom Lee, Ji Ae Lee, Hye Eun Park, Hyojun Han, Yuhnam Kim, Jeong Mo Bae, Jung Ho Kim, Nam-Yun Cho, Hwang-Phill Kim, Tae-You Kim, Gyeong Hoon Kang
Summary: A new computational method and microsatellite marker panels were developed to assess and detect microsatellite instability in CRC, which does not require paired normal tissues. It showed good sensitivity and specificity for different types of samples.
Article
Cell Biology
Nigel Scott, Nick P. West, Alison Cairns, Olorunda Rotimi
Summary: Medullary carcinoma of the colon is often mistaken for poorly differentiated adenocarcinoma NOS and occasionally for neuroendocrine or metastatic carcinoma. Greater familiarity with morphological criteria and use of mismatch repair protein staining should improve diagnosis. Most medullary carcinomas exhibit mismatch repair deficiency, are located in ascending colon and caecum and have a lower rate of vascular channel invasion and lymph node metastasis compared to poorly differentiated adenocarcinoma.
Review
Oncology
M. Suerink, K. Wimmer, L. Brugieres, C. Colas, R. Gallon, T. Ripperger, P. R. Benusiglio, E. M. A. Bleiker, Z. Ghorbanoghli, Y. Goldberg, J. C. H. Hardwick, M. Kloor, M. le Mentec, M. Muleris, M. Pineda, C. Ruiz-Ponte, H. F. A. Vasen
Correction
Oncology
Tim Ripperger, D. Gareth Evans, David Malkin, Christian P. Kratz
Letter
Oncology
Tim Ripperger, DGareth Evans, David Malkin, Christian P. Kratz
Letter
Oncology
Greta Winter, Renate Kirschner-Schwabe, Stefanie Groeneveld-Krentz, Gabriele Escherich, Anja Moericke, Arend von Stackelberg, Martin Stanulla, Simon Bailey, Lisa Richter, Doris Steinemann, Tim Ripperger, Adela Escudero, Roula Farah, Olli Lohi, Karin Wadt, Marjolijn Jongmans, Nienke van Engelen, Cornelia Eckert, Christian Peter Kratz
Letter
Oncology
Melanie Decker, Tim Lammens, Alina Ferster, Miriam Erlacher, Ayami Yoshimi, Charlotte M. Niemeyer, Martijn P. T. Ernst, Marc H. G. P. Raaijmakers, Nicolas Duployez, Andreas Flaum, Doris Steinemann, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger
Article
Cell & Tissue Engineering
Benjamin Dannenmann, Maksim Klimiankou, Benedikt Oswald, Anna Solovyeva, Jehan Mardan, Masoud Nasri, Malte Ritter, Azadeh Zahabi, Patricia Arreba-Tutusaus, Perihan Mir, Frederic Stein, Siarhei Kandabarau, Nico Lachmann, Thomas Moritz, Tatsuya Morishima, Martina Konantz, Claudia Lengerke, Tim Ripperger, Doris Steinemann, Miriam Erlacher, Charlotte M. Niemeyer, Cornelia Zeidler, Karl Welte, Julia Skokowa
Summary: By editing CN patient-derived iPSCs using CRISPR-Cas9, this study established a model of stepwise leukemogenesis in CN/AML and identified the upregulation of BAALC and phosphorylation of MK2a as key events in leukemogenesis. Deleting BAALC or using a selective inhibitor of MK2a phosphorylation, CMPD1, can prevent cell proliferation and induce differentiation of CN/AML cells.
Article
Oncology
Judith Penkert, Andre Maertens, Martin Seifert, Bernd Auber, Katja Derlin, Ursula Hille-Betz, Philipp Hoermann, Norman Klopp, Jana Prokein, Lisa Schlicker, Frank Wacker, Hannah Wallaschek, Brigitte Schlegelberger, Karsten Hiller, Tim Ripperger, Thomas Illig
Summary: Individuals with pathogenic germline variant in breast cancer predisposition gene BRCA1 are predisposed to developing breast cancer. This study found systemic metabolic differences in individuals carrying the BRCA1 variant, independent of cancer incidence.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Jette J. Bakhuizen, Helen Hanson, Karin van der Tuin, Fiona Lalloo, Marc Tischkowitz, Karin Wadt, Marjolijn C. J. Jongmans
Summary: DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging due to uncertainty about clinical efficacy and varying appraisal of potential benefits and harms. Current recommendations include annual clinical examinations, chest X-rays, and ultrasounds, with additional procedures for consideration based on patient needs and potential efficacy. Further evaluation is necessary to expand the evidence base for DICER1 surveillance protocols.
Letter
Hematology
Claire C. Homan, Sarah L. King-Smith, David M. Lawrence, Peer Arts, Jinghua Feng, James Andrews, Mark Armstrong, Thuong Ha, Julia Dobbins, Michael W. Drazer, Kai Yu, Csaba Bodor, Alan Cantor, Mario Cazzola, Erin Degelman, Courtney D. DiNardo, Nicolas Duployez, Remi Favier, Stefan Frohling, Jude Fitzgibbon, Jeffery M. Klco, Alwin Kramer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V. Morgan, Georges Natsoulis, Carolyn Owen, Keyur P. Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Paul Liu, Lucy A. Godley, Andreas W. Schreiber, Christopher N. Hahn, Hamish S. Scott, Anna L. Brown
Article
Urology & Nephrology
Christian Fuhrmann, Christoph P. Czerner, Tim Ripperger, Florian Imkamp
Summary: The study conducted a literature search on five important hereditary syndromes with kidney cancer association and summarized the results. Based on the data, a diagnostic workflow and treatment path were established. The results showed that hereditary kidney cancer, although rare, could present in significant numbers in high-volume centers. For doctors who have limited experience with these types of tumors, the acronym and workflow provided in this study could be a valuable asset for clinical diagnosis.
Article
Hematology
Melanie Decker, Anupriya Agarwal, Andreas Benneche, Jane Churpek, Nicolas Duployez, Adam Duvall, Martijn P. T. Ernst, Alisa Foerster, Hildegunn Hoberg-Vetti, Inga Hofmann, Michelle Nash, Marc H. G. P. Raaijmakers, Tor H. A. Tvedt, Adrianna Vlachos, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger
Summary: In this study, the applicability of transactivation assays to investigate variants of the RUNX1 protein was evaluated. It was found that C-terminal RUNX1 variants require the development of new assays. Two variants of unknown significance were reclassified as likely pathogenic, and the (likely) pathogenic classification of two other variants was supported. The functionality of four variants of unknown significance was demonstrated, but reclassification to (likely) benign was challenging, indicating the need for reevaluating current classification guidelines. The clinical utility of the assays was illustrated in the context of seven families.
Review
Oncology
Alisa Foerster, Melanie Decker, Brigitte Schlegelberger, Tim Ripperger
Summary: Pathogenic germline variants affecting RUNX1 are associated with platelet defects and hematologic malignancies. Somatic genetic alterations play a role in leukemic transformation, but the mechanism is not well understood. Through analyzing previously reported patients, we summarized the impact of RUNX1 variants on phenotype and somatic genetic alterations. Patients often harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These studies highlight the importance of somatic secondary events in the development of RUNX1-associated hematologic malignancies.
Article
Oncology
Kerstin Rhiem, Silke Zachariae, Anke Waha, Sabine Grill, Anna Hester, Michael Golatta, Marion van Mackelenbergh, Tanja Fehm, Tanja Schlaiss, Tim Ripperger, Susanne Ledig, Cornelia Meisel, Dorothee Speiser, Kristina Veselinovic, Christopher Schroeder, Isabell Witzel, Julia Gallwas, Bernhard H. F. Weber, Christine Solbach, Bariyhe Aktas, Eric Hahnen, Christoph Engel, Rita Schmutzler
Summary: In this study, we investigated the prevalence of cancer predisposition genes in patients with TNBC and found that in patients diagnosed with TNBC before the age of 50 without a family history of breast or ovarian cancer, the prevalence of these genes reached 10.6%. Logistic regression analysis revealed that the younger the age at diagnosis, the higher the prevalence.
Letter
Oncology
Christian P. Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jaeger, Sebastian M. Waszak, Anika Grosshennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M. Pfister, Holger Prokisch, Tim Ripperger, David Malkin
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2023)
Article
Oncology
Jelena Lazic, Oskar A. Haas, Ugur Ozbek, Tim Ripperger, Anna Byrjalsen, Geertruij te Kronnie
Summary: The European Union-funded LEGEND project explored the perception and handling of genetic predisposition in childhood leukemia through a questionnaire-based survey. The results showed a high overall awareness and presence of identification and treatment for common predisposition syndromes. However, there is a high demand for continuous education and routinely updated resources.
PEDIATRIC BLOOD & CANCER
(2023)