POT1 mutation

CAS demonstrate unique genetic profile, distinct from non-cardiac angiosarcoma. This study highlights the role of germline POT1 burden on CAS development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported herein, germline genetic testing should be considered in patients diagnosed with CAS.

We demonstrate loss of function owing to the inability of the mutant POT1 protein to bind telomeric DNA compared to its wild-type counterpart. This study provides important functional validation of a novel POT1 variant in FM.

METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

In contrast, a substantial fraction of clinically-validated pathogenic mutations support normal cellular proliferation, but still drive ATR-dependent telomeric DNA damage signaling and ATR-independent telomere elongation. Moreover, this class of cancer-associated POT1 variants elongates telomeres more rapidly than POT1 frame-shifts, indicating they actively drive oncogenesis and are not simple loss-of-function mutations.

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.

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.