tbuckley/cabot-search huggingface dataset:
The mutational landscape of the sensitivity of cancer to ionizing radiation.
Authors: Priyanka Gopal, Brian Yard, Aaron Petty, Jessica Castrillon, Jyoti D. Patel, Mohamed E. Abazeed
Journal: Journal of Clinical Oncology (2021)

3129 Background: The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well) profiling effort to identify gene mutations that alter cellular sensitivity to radiation and validated some of our findings using a clinical cohort of patients who received thoracic radiotherapy alone. Methods: Candidate mutations were prioritized on the basis of genotype-phenotype associations from our previously completed large-scale cancer cell line irradiation profiling study (doi: 10.1038/ncomms11428), location within conserved protein domains, and functional impact (MutationAssessor). We used site-directed mutagenesis to generate mutant clones (2 clones per variant) and transferred the ORFs into lentiviral vectors in SV40 lung primary immortalized cells (BEAS2B). For clinical validation, an IRB-approved study was used to identify patients treated with lung radiotherapy alone. 197 patients with primary (stage I–IV) or recurrent lung cancer and patients with other cancer types and solitary metastases or oligometastases to the lung were included. Death without evidence of local failure was treated as a competing event, and Fine and Gray regression modeling was used to examine potential predictors of local failure. Results: Over 600 cancer variants were tested in ̃1200 experimental replicates, comprising 91 genes. We identified known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Variants that conferred resistance in BEAS2B cells were significantly more likely to confer resistance in TERT-HU1 and NCI-H520 cells, suggesting that most functional variants are cellular context indifferent. Variants under somatic oncogenic selection (hotspot mutants) were significantly more likely to confer resistance to radiation. Several infrequent cancer variants ( &lt; 1% prevalence in cancer), including those in ERBB3, SMAD4, TGFBR1, VHL, CTNNB1, and MAP2K1, conferred radiation resistance. Some genes (e.g. KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g. CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. KRAS (resistant; HR 2.23; P= 0.02) and CTNNB1 exon 3 (sensitive; HR 0.3; P = 0.04) mutants conferred resistance and sensitivity, respectively, to radiotherapy in our clinical cohort. Conclusions: We report on a large-scale profiling effort to identify mutant alleles that govern radiation survival. Our results reveal new insights into potentially actionable determinants of tumor sensitivity to radiotherapy and accelerate clinical validation of common and rare gene mutations that impact radiation sensitivity.
Evaluation of somatic and germline mutations in Chinese patients with gallbladder carcinoma reveals clinically actionable targets.
Authors: Wenhui Yang, Si Liu, Xiaomo Li, Hongjian Gao, Tonghui Ma, Rong Liu
Journal: Journal of Clinical Oncology (2021)

e16143 Background: Gallbladder cancer (GBC) is an aggressive gastrointestinal cancer and the median survival of GBC patients is less than one year. Given the rarity of this disease, there is no enough evidence to guide the precision therapy for GBC patients. Therefore, it is urgent to identify therapeutic targets in GBC to help physicians to enroll patients in clinical trials. In this study, we aimed to characterize clinically actionable mutations in a large cohort of patients with GBC. Methods: To characterize therapeutic targets in 118 Chinese GBC patients, a deep sequencing panel (OncoPanscan, Genetronhealth) was applied to explore somatic alterations including point mutations, indels, copy number alterations and gene fusions, as well as possible pathogenic germline variants respectively from their tumor tissues and matched genomic DNA sample. Results: Recurrent somatic mutations were identified in TP53 (65%), ERBB2 (18%), ARID2 (13%), ELF3 (13%), CDKN2A (12%), ARID1A (10%), KRAS (10%) and KMT2C (10%). Of the entire cohort, the most frequently mutated genes were in the ErbB pathway including EGFR, ERBB2, ERBB3, and ERBB4. For the patients with ERBB2 genetic aberrations, 67% (14/21) patients had gene amplification and 29% (6/21) patients had the oncogenic S310F/Y (n = 6) mutation which may be eligible for HER2-targeted therapy clinical trial. Importantly, 9% (10/118) patients carried activating PIK3CA mutations including P104L, E110del, E545K/Q/G, E542K, E726K and T1025S which may be targeted by PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 6), STK11 (n = 5) and PTEN (n = 2) can be respectively targeted with MEK inhibitor and mTOR inhibitor. Furthermore, patients with MET amplification (n = 3) may be eligible for clinical trials of MET inhibitor carbozantinib. There were four patients (3.4%) carried loss-of-function germline mutations in DNA repair genes ( BRCA1, BRCA2 and PALB2) and 19 patients (16%) harbored somatic loss-of-function mutations in BRCA1 (n = 2), BRCA2 (n = 2), ARID1A (n = 12) and ATM (n = 3). These patients may benefit from platinum chemotherapy or targeted therapy with PARP inhibitors. Interestingly, 13% (15/118) patients in our cohort carried ELF3 inactivating mutations which was reported as a potential GBC vaccine candidate. Taken together, at least 54 (46%) patients in our cohort had actionable genetic alterations. Conclusions: Our results indicated that activating mutations in the ErbB and PI3K signaling pathways are the major driving events of GBC. The results of genomic profiling can guide physicians to enroll a significant portion of GBC patients into genomically matched clinical trials.
RARE-18. NF1-MUTATED TUMORS EXHIBIT INCREASED SENSITIVITY TO AUTOPHAGY INHIBITION ALONE AND IN COMBINATION WITH MEK INHIBITION
Authors: Eliza Baird-Daniel, Shadi Zahedi, Andrew Morin, Michelle Desmarais, Kyle Williams, Rory Williams, Rajeev Vibhakar, Nicholas Foreman, Jean Mulcahy-Levy
Journal: Neuro-Oncology (2021)

Abstract Background Autophagy inhibition is a potential treatment for central nervous system (CNS) tumors. Autophagy, a heavily regulated process by which cellular waste is transferred to lysosomes for degradation and processing, is an integral part of tumor cell survival under stressful conditions including nutrient deprivation and chemotherapy. While the efficacy of autophagy inhibition has been demonstrated in CNS tumors with BRAFV600e mutations, it has yet to be explored in other CNS tumor types with MAPK pathway dysregulation including NF1-mutated tumors. Many tumors associated with the NF1 phenotype can be difficult to treat surgically thus development of further pharmacologic interventions is necessary. Methods A CRISPR/Cas9 mediated NF1 KO was derived from human immortalized Schwann cells and utilized as a tumor model. Autophagy inhibition was achieved pharmacologically by chloroquine (CQ) and genetically via shRNAi of ATG5 and ATG7. Trametinib was used for MEK inhibition. Cell growth and viability were determined by Incucyte, Cell Titer-Glo luminescent assay, and colony-formation assays. Protein expression was measured by western blot. Results We demonstrate increased autophagic activity in NF1 KO cell as compared to control lines both at baseline and in response to cellular stress. Furthermore, we describe that NF1 KO cells exhibit increased sensitivity to CQ alone, CQ in combination with trametinib, and shRNAi-mediated autophagy inhibition in combination with trametinib. Conclusion Here, we describe increased autophagic dependence of NF1 mutated tumors and demonstrate increased tumor sensitivity to autophagy inhibition both alone and in combination with MEK inhibition. These findings indicate that autophagy inhibition via CQ may be an effective adjunctive treatment for NF1 mutated tumors and suggests that diverse CNS tumor types with MAPK pathway dysregulation are susceptible to autophagy inhibition. Clinical investigation of combined MEK and autophagy inhibition has the potential to improve outcomes for NF1 patients with CNS tumors.
RARE-16. A PATIENT WITH MOSAIC POST-ZYGOTIC KRAS-G12D PATHOGENIC VARIANT PRESENTING WITH A SYMPTOMATIC SPINAL NEUROFIBROMA AND LARGE SEGMENTAL TRUNCAL CAFÉ AU LAIT SPOT
Authors: Dardan Demaliaj, Jianglin Ji, Matthew Deardorff, Peter Chiarelli, Benita Tamrazi, Debra Hawes, Jaclyn Biegel, Tena Rosser, Tom Davidson, Anat Erdreich-Epstein
Journal: Neuro-Oncology (2021)

Abstract An 11 year old boy presented with a three month history of progressive bilateral lower extremity weakness associated with recent intermittent incontinence. Spine MRI showed a right-sided T11-T12 paraspinal mass extending through the neural foramina into the epidural space and causing severe spinal cord compression. Skin showed a large macular lightly-hyperpigmented café au lait spot with irregular borders along the T10-T12 dermatome extending from the spine to approximately the anterior-axillary line. He was suspected to have segmental neurofibromatosis type 1 (NF1) as no additional clinical findings, radiographic features or family history of NF1 were identified. Patient underwent T10-12 laminectomy for resection of the epidural tumor component. Post-operative MRI showed resolution of the mass effect on the thecal sac and cord, with expected tumor residual lateral to the neural foramen. His residual spinal tumor and mild scoliosis remained stable over the two years of follow up to date. Pathological and molecular analysis of the resected tumor revealed a neurofibroma harboring an activating KRAS c.35G&amp;gt;A, p.Gly12Asp (KRAS-G12D) pathogenic variant at 27% variant allele frequency. Melanocytes cultured from two hyperpigmented skin biopsies showed the same KRAS-G12D pathogenic variant. This KRAS-G12D pathogenic variant was not found in leukocytes, indicating a post-zygotic origin. No NF1 pathogenic variant was identified in tumor tissue, melanocytes or leukocytes. The clinical findings were consistent with a mosaic KRASopathy due to a post zygotic KRAS-G12D pathogenic variant. The presence of the KRAS variant in the spinal neurofibroma and overlaying café au lait spot without an NF1 etiology in associated tissues demonstrates overlapping variability of presentations of RAS-MAPK pathway disorders. This case highlights the need for full clinical and genetic evaluation of patients presenting with segmental neurocutaneous disorders.
State variation in marijuana use among U.S. adults with cancer.
Authors: Min Jee Lee, Eric Adjei Boakye
Journal: Journal of Clinical Oncology (2021)

e24064 Background: The number of cancer survivors in the United States (U.S.) is projected to exceed 20 million by 2024. More and more U.S. states are legalizing marijuana use for both recreational and medicinal purposes. This study estimated the prevalence of marijuana use by state among adult cancer survivors. Methods: U.S nationally representative, cross-sectional data from the 2018-2019 Behavioral Risk Factor Surveillance System Survey (BRFSS) Marijuana Use module were used. A total of 13,174 cancer survivors in 17 states was included. Analyses were weighted to account for BRFSS’s complex survey design with results generalizable to 5.7 million cancer survivors. The outcome variable was marijuana use in the past 30 days. Weighted prevalence estimates were computed. Weighted, multivariable logistic regression model estimated the association between state and marijuana use, adjusting for sociodemographic, health, and healthcare factors. Analyses were performed in January 2021. Results: The prevalence of past-month marijuana use among adult cancer survivors in these states was 9.2%. States varied widely in terms of the prevalence of marijuana use. Marijuana use was higher among those who resided in Guam (15.9%), followed by New Hampshire (13.1%), and lowest for those in Puerto Rico (3.3%) ( p&lt; 0.0001). In the adjusted models, compared with the adult cancer survivors residing in California, those living in Maryland, Minnesota, North Dakota, Ohio, South Carolina, Tennessee, Utah, West Virginia, and Wyoming were significantly less likely to use marijuana. Conclusions: Nearly 9% of adult cancer survivors used marijuana, and those who resided in Guam, New Hampshire, Florida, and California are at higher risk for marijuana use. Given the increasing number of cancer survivors and the proliferation of marijuana legalization, identifying high-risk cancer survivors for marijuana use and informing physicians and patients about safe uses and doses and the potential adverse effects of marijuana use is critical.
CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
Authors: Anni Laine, Srikar G. Nagelli, Caroline Farrington, Umar Butt, Anna N. Cvrljevic, Julia P. Vainonen, Femke M. Feringa, Tove J. Grönroos, Prson Gautam, Sofia Khan, Harri Sihto, Xi Qiao, Karolina Pavic, Denise C. Connolly, Pauliina Kronqvist, Laura L. Elo, Jochen Maurer, Krister Wennerberg, Rene H. Medema, Heikki Joensuu, Emilia Peuhu, Karin de Visser, Goutham Narla, Jukka Westermarck
Journal: Cancer Research (2021)

Abstract Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.
Is HCV Infection a Risk Factor for Cardiac Complications in TM
Authors: Antonella Meloni, Laura Pistoia, Saveria Campisi, Francesco Massei, Sabrina Armari, Maurizio Caniglia, Roberta Renni, Giovanni Palazzi, Aurelio Maggio, Vincenzo Positano, Emanuele Grassedonio, Alessia Pepe
Journal: Blood (2017)
Patient-reported outcomes in cancer patients admitted during the COVID 19 pandemic in a tertiary Spanish hospital.
Authors: Veronica Velasco Durantez, Adán Rodríguez González, Maria Pilar Solis-Hernandez, Clara Iglesias Gomez, Alfonso Revuelta, Paula Jiménez-Fonseca, Luka Mihic Góngora, Debora Corina Contreras Toledo, Sena Valcárcel González, Sara Fernandez Arrojo, David Gómez, Jorge del Río Fernández, Marta Izquierdo, Carlos Alvarez-Fernandez, Noemí Villanueva, Emilio Esteban
Journal: Journal of Clinical Oncology (2021)

e24098 Background: Patient reported outcomes measures (PROMs) represent a tool to objectively assess the health of cancer patients. PROMs may complement oncological evaluations by adding patients’ perspectives on their care priorities. Aim: to address more accurately the management of tumor related symptoms or drug related toxicities to bring he therapies more accurately to bring patients the best quality of life possible. Methods: Data was collected from our electronic registry after proper authorization and corresponding anonymization. Patients were systematically asked for symptoms as fever, diarrhea, dyspnea, vomiting and nausea. These symptoms were graded according to their severity using the Common Toxicity Criteria v5.0. Results: 49 patients admitted to Medical Oncology Hospitalization were included from July of 2020 to January 2021, 80% in advanced disease. Median age 63yo, 32% above 70 yo. Baseline data showed that 27% patients (19% stage IV) had fever at admission, decreasing at 48h to 4%. Patients who had vomiting at admission were 33% (28% stage IV) median grade 2 becoming 20% and grade 1 at 48h. Nausea was present in 49% patients (35% stage IV) at the time of admission with a median grade 1.5, and it decreased to 16% at 48h with a median grade 2. Diarrhea was reported in 12% patients (6% stage IV) median grade 2 at baseline and it was reduced to 10% median grade 1 at 48h. The median severity of diarrhea at admission was 2 and only 1 at 48h. At admission, 33% (all stage IV) of patients presented dyspnea with a median grade 3, while at 48h it was present in 26% of patients and reduced to median grade 2. Conclusions: By systematically measuring symptoms, patients achieved better control of diarrhea, dyspnea, vomiting and nausea after admission. It should be noted that nausea was the variable that decreased the most at 48h, followed by fever, vomiting, dyspnea and diarrhea. All patients with stage IV disease had dyspnea and most of them had nausea and vomiting. These results reflect that these symptoms are more usual in patients with advanced disease compared to those with localized disease. PROMS also help us educate patients by teaching them how to manage treatments, thus improving therapeutic adherence.
Thirty day readmissions and outcomes following radical nephrectomy in renal cell carcinoma: A nationwide analysis.
Authors: Trilok Shrivastava, Miguel Salazar, Victor Prado, Estefania Gauto, Binav Baral, Shristi Upadhyay, Maha A.T. Elsebaie
Journal: Journal of Clinical Oncology (2021)

e16560 Background: Nephrectomy is one of the primary treatments of Stage I-III renal cell carcinoma (RCC), which is usually associated with low rates of serious morbidity and mortality. However, a fraction of patients gets readmitted after the surgery for numerous reasons which can impact their overall prognosis. Methods: We conducted a retrospective cohort study using the 2017 National Readmission Database of adult patients with RCC readmitted within 30 days after an index admission for nephrectomy. We aimed to identify the 30-day readmission rate, mortality, resource utilization, and independent predictors of readmission. Results: A total of 25,307 patients with RCC underwent nephrectomy. The 30-day readmission rate was 8.7%. The top five causes for readmission were sepsis, AKI, STEMI, surgical infections &amp; metastatic disease. Patients requiring readmission were less likely to be discharged home (56.5 vs 81.8%), have private insurance (27.2 vs 34.7), obesity (14.7 vs 20.6%), hypertension (30.9 vs 47.1%), and be admitted to a teaching hospital (75.8 vs 79.2%). They were more likely to be insured with Medicare (58.3 vs 53.3%), have lower income (28.7 vs 26.3%), type 2 diabetes (32.4 vs 26.7%), CKD (44.1 vs 20.7%), malnutrition (9.2 vs 2.1%), undergo chemotherapy (5.2 vs 1.9%). Readmission was associated with higher in-hospital mortality (1.5 vs. 0.1%), CVA (0.6 vs 0.3%), AKI (29.6 vs 16.9%) and pleural effusion (7.8 vs 1.8%). They were also more likely to require mechanical ventilation (3.5 vs 1.8%), parenteral nutrition (1.2 vs 0.4%) and hemodialysis (11.9 vs 4.5%). The in-hospital economic burden of readmission was $128 million in total charges and $31.8 million in total costs. Independent predictors of readmission were disposition to a short-term hospital or skilled nursing facility, length of stay, need for mechanical ventilation and transfusion of blood products, having type 1 diabetes, malnutrition, pleural effusion, and CKD. Younger age and private insurance were associated with preventing readmission. Conclusions: Readmissions after nephrectomy in patients with RCC are associated with increased in-hospital mortality rate and pose a high health care economic burden. We identified few risk factors and patient characteristics associated with post-surgical readmissions; however, further in-depth studies are needed to find preventable risk factors.[Table: see text]
Impact of a high emergency lung transplantation programme for cystic fibrosis in France: insight from a comparison with Canada
Authors: Adèle Coriati, Jenna Sykes, Lydie Lemonnier, Xiayi Ma, Sanja Stanojevic, Clémence Dehillotte, Nicolas Carlier, Anne L. Stephenson, Pierre-Régis Burgel
Journal: European Respiratory Journal (2021)

Background France implemented a high emergency lung transplantation (HELT) programme nationally in 2007. A similar programme does not exist in Canada. The objectives of our study were to compare health outcomes within France as well as between Canada and France before and after the HELT programme in a population with cystic fibrosis (CF). Methods This population-based cohort study utilised data from the French and Canadian CF registries. A cumulative incidence curve assessed time to transplant with death without transplant as competing risks. The Kaplan–Meier method was used to estimate post-transplant survival. Results Between 2002 and 2016, there were 1075 (13.0%) people with CF in France and 555 (10.2%) people with CF in Canada who underwent lung transplantation. The proportion of lung transplants increased in France after the HELT programme was initiated (4.5% versus 10.1%), whereas deaths pre-transplant decreased from 85.3% in the pre-HELT period to 57.1% in the post-HELT period. Between 2008 and 2016, people in France were significantly more likely to receive a transplant (hazard ratio (HR) 1.56, 95% CI 1.37–1.77; p&lt;0.001) than die (HR 0.55, 95% CI 0.46–0.66; p&lt;0.001) compared with Canada. Post-transplant survival was similar between the countries, and there was no difference in survival when comparing pre- and post-HELT periods in France. Conclusions Following the implementation of the HELT programme, people living with CF in France were more likely to receive a transplant than die. Post-transplant survival in the post-HELT period in France did not change compared with the pre-HELT period, despite potentially sicker patients being transplanted, and was comparable to Canada.