The landscape of RET alterations from 56,970 adult patients with cancer: Clinical implications.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3106-3106
Author(s):  
Alexander Andreev-Drakhlin ◽  
Jason Roszik ◽  
Vivek Subbiah
Keyword(s):  
Mapk Pathway ◽  
Functional Characterization ◽  
Great Promise ◽  
Precision Oncology ◽  
Missense Mutations ◽  
Variants Of Unknown Significance ◽  
Patients With Cancer ◽  
Unknown Significance ◽  
Cancer Types ◽  
The Impact

3106 Background: Activating receptor-tyrosine kinase rearranged during transfection ( RET) mutations and fusions have been recognized as potent drivers of oncogenesis. Recent identification of highly potent and selective RET inhibitors holds great promise in the management of RET-dependent tumors. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Methods: We analyzed 59,347 samples from 56,970 patients available from AACR Project GENIE (Cancer Discov. 2017) database for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types. Results: A total of 1414 RET alterations were detected, including 91 fusions (6.4%), 1166 missense mutations (82.5%), 136 truncating mutations (9.6%), and 21 in-frame mutations (1.5%). RET fusions were observed in 0.15% of tumor samples and were most commonly identified in non-small cell lung cancer, thyroid cancer, colorectal cancer, prostate cancer, and gastric cancer (62.6%, 18.6%, 5.5%, 4.4%, 3.3% of identified RET fusions, respectively). RET fusions were significantly co-altered with MAPK3/ERK1 (p=0.045), SETD2 (p=1.36E-07 ), and EIF4E (p=0.045), while there was a negative association between RET fusions and EGFR (p=0.009634) , TP53 (p=0.02267), and KRAS (p=2.53E-05) alterations. Most common RET gene upstream partners were KIF5B, CCDC6, and NCOA4 (42.9%, 24.2%, 7.7% of identified RET fusions, respectively). RET missense mutations were found in 2.0% of tumor samples; 136 (11.7%) of identified missense mutations, including 8 RET gatekeeper V804M/L mutations, were characterized as likely oncogenic, 12 (1.0%) as likely benign, and 1018 (87.3%) as variants of unknown significance using OncoKB database. RET amplifications occurred in 1.5% of tested samples. Conclusions: While RET fusions represent extremely rare events in multiple cancers, RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted. MAPK pathway co-alterations in patents with RET fusions may present a strategy for future therapeutic combinations.

Palliative care referral and associated outcomes among patients with cancer in the last 2 weeks of life

2015 ◽  
Vol 9 (1) ◽  
pp. e16-e16 ◽  
Author(s):  
Mathilde Ledoux ◽  
Wadih Rhondali ◽  
Véronique Lafumas ◽  
Julien Berthiller ◽  
Marion Teissere ◽  
...  
Keyword(s):  
Palliative Care ◽  
Advanced Cancer ◽  
Academic Medical Centre ◽  
Haematological Cancer ◽  
Patients With Cancer ◽  
Respiratory Cancer ◽  
Academic Medical ◽  
Cancer Types ◽  
The Impact

BackgroundPalliative care (PC) improves the quality of life of patients with advanced cancer. Our aim was to describe PC referral among patients with advanced cancer, and associated outcomes in an academic medical centre.MethodsWe reviewed the medical records of 536 inpatients with cancer who had died in 2010. Our retrospective study compared patients who accessed PC services with those who did not. Statistical analysis was conducted using non-parametric tests due to non-normal distribution. We also conducted a multivariate analysis using a logistic regression model including age, gender, type of cancer and metastatic status.ResultsOut of 536 patients, 239 (45%) had PC referral. The most common cancer types were respiratory (22%) and gastrointestinal (19%). Patients with breast cancer (OR 23.76; CI 6.12 to 92.18) and gynaecological cancer (OR 7.64; CI 2.61 to 22.35) had greater PC access than patients with respiratory or haematological cancer. Patients referred to PC had significantly less chemotherapy in the last 2 weeks of life than non-referred patients, with 22 patients (9%) vs 59 (19%; p<0.001). PC-referred patients had significantly fewer admissions to intensive care units in the last month of life than non-referred patients, with 14 (6%) vs 58 (20%; p<0.001).ConclusionsThere was a large variation in access to PC according to the type of cancer. There is a need to improve collaboration between the PC service and the respiratory, cancer and haematology specialists. Further research will be required to determine the modality and the impact of this collaboration.

Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 306-306 ◽  
Author(s):  
Malshundria Prophet ◽  
Kun Xiao ◽  
Theodore Stewart Gourdin ◽  
Rebecca J Nagy ◽  
Lesli Ann Kiedrowski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Driver Mutations ◽  
Genomic Profiling ◽  
Missense Mutations ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Variants Of Unknown Significance ◽  
Activating Mutations ◽  
Unknown Significance

306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.

scholarly journals Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna E. Patrick ◽  
Eden M. Lyons ◽  
Lisa Ishii ◽  
Alan S. Boyd ◽  
Joseph M. Choi ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Early Recognition ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Inflammatory Disorder ◽  
Laboratory Findings ◽  
Genetic Sequencing ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The Impact

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1β. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant’s diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

scholarly journals The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

2019 ◽  
Author(s):  
Burcu Aykac Fas ◽  
Mukesh Kumar ◽  
Valentina Sora ◽  
Maliha Mashkoor ◽  
Matteo Lambrughi ◽  
...  
Keyword(s):  
Physical Models ◽  
Missense Mutations ◽  
Cancer Types ◽  
Neutral Mutations ◽  
And Function ◽  
Cellular Components ◽  
The Impact ◽  
Pan Cancer ◽  
Structural Ensemble

AbstractAutophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.

scholarly journals Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

2019 ◽  
Author(s):  
Sathiya N. Manivannan ◽  
Sihem Darouich ◽  
Aida Masmoudi ◽  
David Gordon ◽  
Gloria Zender ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exome Sequencing ◽  
Rapid Screening ◽  
Functional Study ◽  
Ventricular Muscle ◽  
Loss Of Function ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The Impact

AbstractHypertrophic cardiomyopathy (HCM) is characterized by enlargement of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the C-terminal EF-hand (CEF) domain. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stopgain variants that lead to loss of the CEF domain are stably expressed. However, stopgain variants show impaired localization suggesting a functional role for the CEF domain. The degradation of the MYL2-fs can be rescued by inhibiting the cell’s proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither MYL2-fs nor MYL2:p.Gly162Arg supports regular cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathies.Author SummaryWe report a novel frameshift variant in MYL2 that is associated with a severe form of infantile-onset hypertrophic cardiomyopathy. The impact of the variant is only observed in the recessive form of the disease in the proband and not in the parents who are carriers of the variant. This is in contrast to other dominant variants in MYL2 that are associated with cardiomyopathies. We compared the stability of this variant to that of other cardiomyopathy associated MYL2 variants and found molecular differences in the disease pathology. We also show different protein domain requirement for stability and localization of MYL2 in cardiomyocytes. Further, we used a fly model to demonstrate functional deficits due to the variant in the developing heart. Overall, our study shows a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant. We highlight the use of exome sequencing and functional testing to assist in the diagnosis of rare forms of diseases where pathogenicity of the variant is not obvious. The new tools we developed for in vitro functional study and the fly fluorescent reporter analysis will permit rapid analysis of MYL2 variants of unknown significance.

scholarly journals Effects of the COVID-19 Pandemic on Cancer-Related Patient Encounters

2020 ◽  
pp. 657-665 ◽  
Author(s):  
Jack W. London ◽  
Elnara Fazio-Eynullayeva ◽  
Matvey B. Palchuk ◽  
Peter Sankey ◽  
Christopher McNair
Keyword(s):  
Breast Cancer ◽  
Cancer Screening ◽  
Research Network ◽  
Malignant Neoplasms ◽  
Patients With Cancer ◽  
Hematologic Cancer ◽  
Cancer Screenings ◽  
Number Of Patients ◽  
Cancer Types ◽  
The Impact

PURPOSE While there are studies under way to characterize the direct effects of the COVID-19 pandemic on the care of patients with cancer, there have been few quantitative reports of the impact that efforts to control the pandemic have had on the normal course of cancer diagnosis and treatment encounters. METHODS We used the TriNetX platform to analyze 20 health care institutions that have relevant, up-to-date encounter data. Using this COVID and Cancer Research Network (CCRN), we compared cancer cohorts identified by querying encounter data pre-COVID (January 2019-April 2019) and current (January 2020-April 2020). Cohorts were generated for all patients with neoplasms (malignant, benign, in situ, and of unspecified behavior), with new incidence neoplasms (first encounter), with exclusively malignant neoplasms, and with new incidence malignant neoplasms. Data from a UK institution were similarly analyzed. Additional analyses were performed on patients with selected cancers, as well as on those having had cancer screening. RESULTS Clear trends were identified that suggest a significant decline in all current cohorts explored, with April 2020 displaying the largest decrease in the number of patients with cancer having encounters. Of the cancer types analyzed, lung, colorectal, and hematologic cancer cohorts exhibited smaller decreases in size in April 2020 versus 2019 (−39.1%, −39.9%, −39.1%, respectively) compared with cohort size decreases for breast cancer, prostate cancer, and melanoma (−47.7%, −49.1%, −51.8%, respectively). In addition, cancer screenings declined drastically, with breast cancer screenings dropping by −89.2% and colorectal cancer screenings by −84.5%. CONCLUSION Trends seen in the CCRN clearly suggest a significant decrease in all cancer-related patient encounters as a result of the pandemic. The steep decreases in cancer screening and patients with a new incidence of cancer suggest the possibility of a future increase in patients with later-stage cancer being seen initially as well as an increased demand for cancer screening procedures as delayed tests are rescheduled.

scholarly journals A segregating human allele ofSPO11modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve

2019 ◽  
Author(s):  
Tina N. Tran ◽  
John C. Schimenti
Keyword(s):  
Variants Of Unknown Significance ◽  
Y Chromosomes ◽  
Sperm Counts ◽  
Meiotic Dsbs ◽  
Unknown Significance ◽  
Causes Of Disease ◽  
Underlying Causes ◽  
Timely Fashion ◽  
Difficult Challenge ◽  
The Impact

ABSTRACTA major challenge in medical genetics is to characterize variants of unknown significance (VUS), so as to better understand underlying causes of disease and design customized treatments. Infertility has presented an especially difficult challenge with respect to not only determining if a given patient has a genetic basis, but also to identify the causative genetic factor(s). Though genome sequencing can identify candidate variants, in silico predictions of causation are not always sufficiently reliable so as to be actionable. Thus, experimental validation is crucial. Here, we describe the phenotype of mice containing a nonsynonymous (proline-to-threonine at position 306) change inSpo11, corresponding to human SNP rs185545661. SPO11 is a topoisomerase-like protein that is essential for meiosis because it induces DNA double stranded breaks (DSBs) that stimulate pairing and recombination of homologous chromosomes.Although both male and femaleSpo11P306T/P306Tmice were fertile, they had reduced sperm and oocytes, respectively. Spermatocyte chromosomes exhibited synapsis defects (especially between the X and Y chromosomes), elevated apoptotic cells, persistent markers of DSBs, and most importantly, fewer Type 1 crossovers that causes some chromosomes to have none.Spo11P306T/−mice were sterile and made fewer meiotic DSBs thanSpo11+/−animals, suggesting that theSpo11P306Tallele is a hypomorph and likely is delayed in making sufficient DSBs in a timely fashion. If the consequences are recapitulated in humans, it would predict phenotypes of premature ovarian failure, reduced sperm counts, and possible increased number of aneuploid gametes. These results emphasize the importance of deep phenotyping in order to accurately assess the impact of VUSs in reproduction genes.

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