After a prolonged response, an anaplastic thyroid cancer developed resistance to mammalian target of rapamycin (mTOR) inhibition by somatic mutation of mTOR at the everolimus binding site. The mutant ...enzyme retained in vitro responsiveness to an mTOR kinase inhibitor.
A better understanding of the mechanisms of sensitivity and resistance to anticancer therapies may improve patient selection and allow the development of rational treatment designs. One approach involves studying paired biopsy samples of pretreatment and drug-resistant tumors obtained from patients with exquisite sensitivity or unusually durable responses to therapy.
Everolimus is a Food and Drug Administration–approved oral allosteric inhibitor of mTOR. Tumors that exhibit a dependency on the mTOR pathway might have enhanced sensitivity to mTOR inhibition. Inactivating mutations in the tumor-suppressor genes
TSC1, TSC2,
and
STK11
result in mTOR-pathway activation and are targetable by TOR inhibitors in hamartoma syndromes . . .
Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing ...of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.
Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35) have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have ...yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA). Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML), in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs ...spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.
Acute myeloid leukemia (AML) is a heterogeneous malignancy with the most common genomic alterations in NPM1, DNMT3A, and FLT3. Midostaurin was the first FLT3 inhibitor FDA approved for AML and is ...standard of care for FLT3 mutant patients undergoing induction chemotherapy 1, 2. As there is a spectrum of response, we hypothesized that biological factors beyond FLT3 could play a role in drug sensitivity and that select FLT3-ITD negative samples may also demonstrate sensitivity. Thus, we aimed to identify features that would predict response to midostaurin in FLT3 mutant and wild-type samples. We performed an
drug sensitivity screen on primary and relapsed AML samples with corresponding targeted sequencing and RNA sequencing. We observed a correlation between FLT3-ITD mutations and midostaurin sensitivity as expected and observed KRAS and TP53 mutations correlating with midostaurin resistance in FLT3-ITD negative samples. Further, we identified genes differentially expressed in sensitive vs. resistant samples independent of FLT3-ITD status. Within FLT3-ITD mutant samples, over-expression of RGL4, oncogene and regulator of the Ras-Raf-MEK-ERK cascade, distinguished resistant from sensitive samples. Overall, this study highlights the complexity underlying midostaurin response. And, our results suggest that therapies that target both FLT3 and MAPK/ERK signaling may help circumvent some cases of resistance.
Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several ...years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .
The aim of this cross-sectional, descriptive study was to characterize the impact of modifiable activities on older adult mental health during the COVID-19 pandemic and to understand the interaction ...between older adult behaviors and the mental health of their informal caregivers.
This study leveraged the National Health and Aging Trends Study and associated Family and Friends survey completed 2020-2021. Participants included 3,257 community dwelling older adults and 2,062 associated unpaid caregivers, weighted sample sizes 26,074,143 and 21,871,408, respectively.
Older adult engagement in volunteering, religious, or group activities was associated with decreased older adult depression, as was increased walking or vigorous activity. However, online compared to in-person participation correlated with greater loneliness in older adults and anxiety for their caregivers. Finally, increased appreciation by the care recipient correlated with decreased caregiver depression.
Overall, a close interaction exists between caregiver and older adult behavior and psychiatric symptoms. Online activities are not an equivalent substitute for in-person activities during required social isolation; however, they remain superior to no participation. Further, increased walking and caregiver appreciation may ameliorate some of the harms of isolation. Health care providers should continue to promote engagement, exercise, and appreciation as ways to improve older adult and informal caregiver mental health.
The Philadelphia chromosome (Ph) resulting from the t(9;22) translocation generates the oncogenic BCR::ABL1 fusion protein that is most commonly associated with chronic myeloid leukemia (CML) and ...Ph-positive (Ph+) acute lymphoblastic leukemia (ALL). There are also rare instances of patients (≤1%) with newly diagnosed acute myeloid leukemia (AML) that harbor this translocation (Paietta et al.,
1881 1998; Keung et al.,
579 2004; Soupir et al.,
642 2007). AML with BCR::ABL has only recently been provisionally classified by the World Health Organization as a diagnostically distinct subtype of AML. Discernment from the extremely close differential diagnosis of myeloid blast crisis CML is challenging, largely relying on medical history rather than clinical characteristics (Arber et al.,
2391 2016). To gain insight into the genomic features underlying the evolution of AML with BCR::ABL, we identified a patient presenting with a high-risk myelodysplastic syndrome that acquired a BCR::ABL alteration after a peripheral blood stem cell transplant. Serial samples were collected and analyzed using whole-exome sequencing, RNA-seq, and ex vivo functional drug screens. Persistent subclones were identified, both at diagnosis and at relapse, including an
p.Lys700Glu mutation that later cooccurred with an
p.Gly12Cys mutation. Functional ex vivo drug screening performed on primary patient cells suggested that combination therapies of ABL1 with RAS or PI3K pathway inhibitors could have augmented the patient's response throughout the course of disease. Together, our findings argue for the importance of genomic profiling and the potential value of ABL1 inhibitor-inclusive combination treatment strategies in patients with this rare disease.
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