Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Palles, Claire; West, Hannah; 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.; Biezen, Simone A M van der; Christie, Michael; Clendenning, Mark; Thomas, Laura E.; Deltas, Constantinos; Dimovski, Aleksandar; Dymerska, Dagmara; Lubiński, Jan; Mahmood, Khalid; Post, Rachel S. van der; Sanders, Mathijs A.; Weitz, Jürgen; Taylor, Jenny C; Turnbull, Clare; Vreede, Lilian; Wezel, Tom van; Whalley, Celina M.; Arnedo-Pac, Claudia; Caravagna, Giulio; Cross, William; Chubb, Daniel; Frangou, Anna; Gruber, Andreas J.; Kinnersley, Ben; Noyvert, Boris; Church, David N.; Graham, Trevor A.; Houlston, Richard S.; López‐Bigas, Núria; Sottoriva, Andrea; Wedge, David C.; Jenkins, Mark A.; Kuiper, Roland P.; Roberts, Andrew W.; Cheadle, Jeremy P.; Ligtenberg, Marjolijn J. L.; Hoogerbrugge, Nicoline; Koelzer, Viktor H.; Rivas, Andrés Dacal; Winship, Ingrid; Ponte, Clara Ruiz; Buchanan, Daniel D.; Power, Derek G.; Green, Andrew; Tomlinson, Ian; Sampson, Julian R.; Majewski, Ian J.; Voer, Richarda M. de

doi:10.1016/j.ajhg.2022.03.018

Cited by 37 publications

(24 citation statements)

References 20 publications

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“…Next to the typical mutations, UMs with rare driver mutations that are associated with metastatic risk are reported. For example, deleterious MBD4 mutations are associated with a higher tumor mutation burden and a hypermutator phenotype [ 34 ]. UMs with MBD4 deficiency are interesting, as these tumors respond to immune checkpoint inhibitors [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Bruyn

Bongaerts

Bonte

et al. 2023

IJMS

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Uveal melanomas (UM) are detected earlier. Consequently, tumors are smaller, allowing for novel eye-preserving treatments. This reduces tumor tissue available for genomic profiling. Additionally, these small tumors can be hard to differentiate from nevi, creating the need for minimally invasive detection and prognostication. Metabolites show promise as minimally invasive detection by resembling the biological phenotype. In this pilot study, we determined metabolite patterns in the peripheral blood of UM patients (n = 113) and controls (n = 46) using untargeted metabolomics. Using a random forest classifier (RFC) and leave-one-out cross-validation, we confirmed discriminatory metabolite patterns in UM patients compared to controls with an area under the curve of the receiver operating characteristic of 0.99 in both positive and negative ion modes. The RFC and leave-one-out cross-validation did not reveal discriminatory metabolite patterns in high-risk versus low-risk of metastasizing in UM patients. Ten-time repeated analyses of the RFC and LOOCV using 50% randomly distributed samples showed similar results for UM patients versus controls and prognostic groups. Pathway analysis using annotated metabolites indicated dysregulation of several processes associated with malignancies. Consequently, minimally invasive metabolomics could potentially allow for screening as it distinguishes metabolite patterns that are putatively associated with oncogenic processes in the peripheral blood plasma of UM patients from controls at the time of diagnosis.

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Section: Discussionmentioning

confidence: 99%

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Bruyn

Bongaerts

Bonte

et al. 2023

IJMS

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“…In the four target panel sequenced patients where we have detailed clinical information, three had received a kidney or kidney and pancreas transplant, and the other had a lung transplant. Meanwhile, our two patients both received HSCT [ 7 , 8 ]. This suggests that GCV treatment induces mutations across a range of transplant protocols.…”

Section: Discussionmentioning

confidence: 99%

“…This mutational signature was found in blood progenitor cells of patients after HSCT and in two patients from a survey of 3668 solid whole cancer genomes [ 6 ]. Furthermore, we had previously observed two individuals (H015 and WEHI-2) with a shared history of acute myeloid leukaemia, HSCT, and colorectal cancer (CRC) carrying the same CA > AA enriched mutational signature [ 7 , 8 ]. Both patients had received GCV as part of their treatment following HSCT (Additional file 1 : Table S1).…”

Section: Introductionmentioning

confidence: 99%

Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies

Yan

Bilardi

et al. 2022

Genome Med

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Background Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

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“…Although germline predisposition testing is recommended for those diagnosed at particularly young ages as noted above, such testing should be considered in all patients with HMs regardless of age ( 14 , 15 ). Certain cytogenetic and molecular abnormalities detected in tumor cells may also provide clues as to an underlying germline predisposition, including (i) the presence of two mutations within a gene known to confer inherited risk, such as RUNX1 or CEBPA , one of which is actually a germline mutation; (ii) the presence of monosomy 7, which may suggest a deleterious germline variant in SAMD9/SAMD9L or GATA2 ; or (iii) a hypermutator tumor phenotype, which may indicate a germline alteration in a mismatch repair gene ( 16 ) or MBD4 ( 17 , 18 ).…”

Section: Germline Predisposition Testing For Patients With Hematopoie...mentioning

confidence: 99%

Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies

Godley

2023

Front. Oncol.

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Germline predisposition to hematopoietic malignancies is more common than previously appreciated, with several clinical guidelines advocating for cancer risk testing in an expanding pool of patients. As molecular profiling of tumor cells becomes a standard practice for prognostication and defining options for targeted therapies, recognition that germline variants are present in all cells and can be identified by such testing becomes paramount. Although not to be substituted for proper germline cancer risk testing, tumor-based profiling can help prioritize DNA variants likely to be of germline origin, especially when they are present on sequential samples and persist into remission. Performing germline genetic testing as early during patient work-up as possible allows time to plan allogeneic stem cell transplantation using appropriate donors and optimize post-transplant prophylaxis. Health care providers need to be attentive to the differences between molecular profiling of tumor cells and germline genetic testing regarding ideal sample types, platform designs, capabilities, and limitations, to allow testing data to be interpreted as comprehensively as possible. The myriad of mutation types and growing number of genes involved in germline predisposition to hematopoietic malignancies makes reliance on detection of deleterious alleles using tumor-based testing alone very difficult and makes understanding how to ensure adequate testing of appropriate patients paramount.

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Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Cited by 37 publications

References 20 publications

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies

Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies

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