CLOCK mutation

Our study provides a comprehensive characterization of the genomic landscape and clonal evolution in OCCC within a substantial cohort. These findings unveil potentially actionable molecular alterations that could be leveraged to develop targeted therapies.

Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.

Furthermore, repair on TSs of thousands of genes was altered when the circadian clock is disrupted. These data contribute to a better understanding of the regulatory role of the circadian clock on nucleotide excision repair in mammals and may be invaluable toward the design of time-aware platinum-based interventions in cancer.

After treatment with first-line afatinib (44%) or erlotinib/gefitinib (56%), median progression-free survival and overall survival were 12.1 and 33.7 months, respectively. Extended molecular profiling with WES at initial diagnosis reveals several complex biomarkers associated with subsequent development of T790M resistance mutation in NSCLC patients receiving first-/second-generation TKIs as the first-line therapy. Larger prospective studies will be necessary to define a forecasting model.

Leveraging one of the largest series of diverse patients with WGS, and integrating genomic data with comprehensive ancestry information, AA MM emerged as biologically different in term of genomic drivers and mutational signatures, suggesting potential differences in etiology and genomic evolution over time. Further analysis will include molecular timing of clonal copy number gains, and reconstruction of phylogenetic trees, with view to improving our understanding of the etiology of MM development across patient genetic backgrounds. FIGURE: Genomic characteristics of myeloma across ancestries.

In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.

Lastly, we observed that the top identified driver genes, including NIRF-specific recurrently mutated genes, were selected based on a given mutational process, thus reflecting distinct natural disease histories.ConclusionOur results show that the NIRF OSCCs are likely driven by endogenous mutagenesis, with no apparent direct link to known exogenous exposures, and that these cancers have distinguishable disease histories. Our study provides a basis for more comprehensive future investigations of this emerging cancer subtype of unclear etiology and increasing incidence.

In cancer cells clock 3 is typically inactivated by loss of p53 as well as increased expression of telomerase. Taken together, aging in humans can be described by the ticking of three clocks: the clock that directs development, the accumulation of (epi-)mutations over time and the telomere clock that limits the number of cell divisions in normal stem and immune cells.

These data suggest that genetic driving aberrations may not be the only underlying mechanism of AML development in children. Noncoding drivers, epigenetic changes or environmental influences may play an important role in the final steps towards leukemogenesis.

These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.

Our data indicated that mutations in the clock genes were associated with higher TMB and improved clinical outcomes in NSCLC patients treated with ICIs, suggesting that these mutations might be a potential predictive biomarker for ICIs treatment in NSCLC. However, they did not have significant prognostic value.