POT1 mutation

We recognize the POT1 mutation may have been discovered incidentally in this case. Further research into an association between POT1 and ependymomas is needed to advance our understanding.

No abstract available

POT1b, but not POT1a, was able to unfold G-quadruplex present in hyper-elongated telomeres to repress the DNA damage response. Our findings demonstrate that the repression of the RPA-ATR DDR is conserved between POT1b and human POT1, suggesting that similar mechanisms may underly the phenotypes observed in human cancers harboring human POT1 mutations.

Our results highlight the presence of KDR mutations in primary CAS that have been reported predominantly in primary breast AS in previous studies. Primary CAS is characterized by POT1 mutations, which have previously been reported only in CAS in Li-Fraumeni like families. We are limited by the small number of samples with RNAseq data to derive inferences about the immune profile of CAS, which is also confounded by chemotherapy administered to the patients prior to surgical resection.

POT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).

Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

Interestingly, Ki-67 index was significantly higher in dogs harboring POT1 mutations compared to wild-type ones. These results suggest that POT1 mutations may exert their pathogenic role in cDLBCL by promoting cellular proliferation.

As in human Li-Fraumeni patients, heterozygous Pot1a+/ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a+/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations.

Genomic profiling of peripheral blood samples can be applied to dynamically monitor disease progression. The reduction in ctDNA concentration during treatment implied DCBs.

Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.

Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Based on these results, we conclude that SF3B1, EGR2, XPO1 and BIRC3 mutations independently predicted short TTFT and should be considered for extended molecular testing in CLL. However, considering the different impact of gene mutations in M-CLL and U-CLL, the IGHV mutation status must be taken into account when constructing future prognostic models including recurrent gene mutations.

Furthermore, hESC lines with caPOT1 mutations showed no detectable telomere damage response while showing consistent telomere elongation. Thus, caPOT1 mutations are likely selected for during cancer progression because of their ability to elongate telomeres and extend the proliferative capacity of the incipient cancer cells.

Similar sex-dependent trends were observed in human gliomas that had low expression of POT1. Together, our studies demonstrate context-dependent functions for POT1 mutation or loss in driving progenitor proliferation in the developing brain and sexual dimorphism in glioma.