MBD4 mutation

Eight CRC patients carried rare homozygous or heterozygous germline variants in MBD4. The information gathered on mode of inheritance, variant nature, functional effect of the variant, and tumour mutational characteristics suggested that none of the patients included in the study had an MBD4-associated hereditary syndrome and that the heterozygous variants identified were not associated with the disease.

We further confirm the exquisite activity of gemcitabine in an MBD4-deficient co-clinical model as (i) it completely prevented the development of an MBD4-deficient uveal melanoma patient-derived xenograft and (ii) treatment in the corresponding patient resulted in an exceptional tumor response. These data suggest that patients harboring MBD4-deficient tumors may be treated efficiently by cytidine analogs.

Consequently, in agreement with our hypothesis, TET2WT cells with loss of MBD4 were significantly more sensitive to olaparib-mediated PARP1 inhibition...1C). Our findings pave the way for consideration of MBD4 as a potential actionable target to regulate DNA methylation in association with TET2 during leukemogenesis.

In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.

In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.

Genomic profiling of the normal and affected tissue identified germline bi-allelic loss of function mutation in MBD4 as initiator of methylation defect in key driver genes in tissue specific manner leading to carcinogenesis. This conserved path to mutagenesis is unique to this cancer predisposition syndrome and further biological studies are needed to fully understand the spectrum of cancers associated with this syndrome.

We advise that MBD4 should be included in germline mutation testing panels for polyposis and/or early-onset AML. Impact statement Germline biallelic loss of MBD4 predisposes to a rare recessive inherited syndrome characterised by colorectal polyposis and AML.

MBD4-proficient UM are stable at the nucleotide level without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse thus opening avenues for a new genetic prognostic classification of UMs.

All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

Thirty-nine patients had a treatment recommendation and 25 (64%) of them received a targeted therapy accordingly, based on off-label use of trametinib (14), selumetinib (2), crizotinib (7), cabozantinib (4), palbociclib (1), sorafenib+trametinib (1)...One patient with 459 somatic mutations and a MBD4 mutation had a partial durable response under Nivolumab...Legal entity responsible for the study: Charité Comprehensive Cancer Center, Berlin, Germany Max-Planck-Institut für molekulare Genetik, Berlin, Germany. Funding: Bundesministerium für Bildung und Forschung, Germany Max-Planck-Institut für Molekulare Genetik, Berlin, Germany Charité Comprehensive Cancer Center, Berlin, Germany.

Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.