Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Context.— Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy. Objective.— To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC. Design.— Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage. Results.— The 20 patients with MPBC had a median age of 62 years (range, 42–86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1–11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing–based copy-number assessment. Conclusions.— Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p \u3c 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p \u3c 0.0001), KMT2D (1% vs. 16%, p \u3c 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p \u3c 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas

significantly enriched for genomic alterations (GAs) causing inactivation of DNA repair genes (45%); these GAs have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable GAs in the majority of PACCs, and provide a rationale for using personalized therapies in this disease. Statement of Significance PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two-thirds of these tumors

Using observational data to emulate a randomized trial of dynamic treatment switching strategies

BACKGROUND: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy).METHODS: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting.RESULTS: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death.CONCLUSIONS: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses

Constraints on dark matter to dark radiation conversion in the late universe with DES-Y1 and external data

84siWe study a class of decaying dark matter models as a possible resolution to the observed discrepancies between early- and late-time probes of the universe. This class of models, dubbed DDM, characterizes the evolution of comoving dark matter density with two extra parameters. We investigate how DDM affects key cosmological observables such as the CMB temperature and matter power spectra. Combining 3x2pt data from Year 1 of the Dark Energy Survey,Planck-2018 CMB temperature and polarization data, Supernova (SN) Type Ia data from Pantheon, and BAO data from BOSS DR12, MGS and 6dFGS, we place new constraints on the amount of dark matter that has decayed and the rate with which it converts to dark radiation. The fraction of the decayed dark matter in units of the current amount of dark matter, $zeta$, is constrained at 68% confidence level to be <0.32 for DES-Y1 3x2pt data, <0.030 for CMB+SN+BAO data, and <0.037 for the combined dataset. The probability that the DES and CMB+SN+BAO datasets are concordant increases from 4% for the $Lambda$CDM model to 8% (less tension) for DDM. Moreover, tension in $S_8=sigma_8sqrt{Omega_m/0.3}$ between DES-Y1 3x2pt and CMB+SN+BAO is reduced from 2.3$sigma$ to 1.9$sigma$. We find no reduction in the Hubble tension when the combined data is compared to distance-ladder measurements in the DDM model. The maximum-posterior goodness-of-fit statistics of DDM and $Lambda$CDM are comparable, indicating no preference for the DDM cosmology over $Lambda$CDM....partially_openopenChen, Angela; Huterer, Dragan; Lee, Sujeong; Ferté, Agnès; Weaverdyck, Noah; Alonso Alves, Otavio; Leonard, C. Danielle; MacCrann, Niall; Raveri, Marco; Porredon, Anna; Di Valentino, Eleonora; Muir, Jessica; Lemos, Pablo; Liddle, Andrew; Blazek, Jonathan; Campos, Andresa; Cawthon, Ross; Choi, Ami; Dodelson, Scott; Elvin-Poole, Jack; Gruen, Daniel; Ross, Ashley; Secco, Lucas F.; Sevilla, Ignacio; Sheldon, Erin; Troxel, Michael A.; Zuntz, Joe; Abbott, Tim; Aguena, Michel; Allam, Sahar; Annis, James; Avila, Santiago; Bertin, Emmanuel; Bhargava, Sunayana; Bridle, Sarah; Brooks, David; Carnero Rosell, Aurelio; Carrasco Kind, Matias; Carretero, Jorge; Costanzi, Matteo; Crocce, Martin; da Costa, Luiz; Elidaiana da Silva Pereira, Maria; Davis, Tamara; Doel, Peter; Eifler, Tim; Ferrero, Ismael; Fosalba, Pablo; Frieman, Josh; Garcia-Bellido, Juan; Gaztanaga, Enrique; Gerdes, David; Gruendl, Robert; Gschwend, Julia; Gutierrez, Gaston; Hinton, Samuel; Hollowood, Devon L.; Honscheid, Klaus; Hoyle, Ben; James, David; Jarvis, Mike; Kuehn, Kyler; Lahav, Ofer; Maia, Marcio; Marshall, Jennifer; Menanteau, Felipe; Miquel, Ramon; Morgan, Robert; Palmese, Antonella; Paz-Chinchon, Francisco; Plazas Malagón, Andrés; Roodman, Aaron; Sanchez, Eusebio; Scarpine, Vic; Schubnell, Michael; Serrano, Santiago; Smith, Mathew; Suchyta, Eric; Tarle, Gregory; Thomas, Daniel; To, Chun-Hao; Varga, Tamas Norbert; Weller, Jochen; Wilkinson, ReeseChen, Angela; Huterer, Dragan; Lee, Sujeong; Ferté, Agnès; Weaverdyck, Noah; Alonso Alves, Otavio; Leonard, C. Danielle; Maccrann, Niall; Raveri, Marco; Porredon, Anna; Di Valentino, Eleonora; Muir, Jessica; Lemos, Pablo; Liddle, Andrew; Blazek, Jonathan; Campos, Andresa; Cawthon, Ross; Choi, Ami; Dodelson, Scott; Elvin-Poole, Jack; Gruen, Daniel; Ross, Ashley; Secco, Lucas F.; Sevilla, Ignacio; Sheldon, Erin; Troxel, Michael A.; Zuntz, Joe; Abbott, Tim; Aguena, Michel; Allam, Sahar; Annis, James; Avila, Santiago; Bertin, Emmanuel; Bhargava, Sunayana; Bridle, Sarah; Brooks, David; Carnero Rosell, Aurelio; Carrasco Kind, Matias; Carretero, Jorge; Costanzi, Matteo; Crocce, Martin; da Costa, Luiz; Elidaiana da Silva Pereira, Maria; Davis, Tamara; Doel, Peter; Eifler, Tim; Ferrero, Ismael; Fosalba, Pablo; Frieman, Josh; Garcia-Bellido, Juan; Gaztanaga, Enrique; Gerdes, David; Gruendl, Robert; Gschwend, Julia; Gutierrez, Gaston; Hinton, Samuel; Hollowood, Devon L.; Honscheid, Klaus; Hoyle, Ben; James, David; Jarvis, Mike; Kuehn, Kyler; Lahav, Ofer; Maia, Marcio; Marshall, Jennifer; Menanteau, Felipe; Miquel, Ramon; Morgan, Robert; Palmese, Antonella; Paz-Chinchon, Francisco; Plazas Malagón, Andrés; Roodman, Aaron; Sanchez, Eusebio; Scarpine, Vic; Schubnell, Michael; Serrano, Santiago; Smith, Mathew; Suchyta, Eric; Tarle, Gregory; Thomas, Daniel; Chun-Hao, To; Varga, Tamas Norbert; Weller, Jochen; Wilkinson, Rees

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Comprehensive genomic profiling (CGP) of ovarian clear cell carcinomas (OCCC) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options

• MTOR pathway genes are often mutated in ovarian clear cell carcinomas (OCCC). • 11.2% of OCCC have targetable alterations only in the mTOR pathway. • MTOR pathway mutations in OCCC can underlie robust, lasting responses to everolimus