This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from August 1through August 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Blood
Genetic Events Associated with Venetoclax Resistance in CLL Identified by Whole-Exome Sequencing of Patient Samples
Khalsa JK, Cha J, Naeem A, Murali I, Kuang Y, Vasquez K, Li L, Tyekucheva S, Fernandes SM, Sasi BK, Wang Z, Machado JH, Bai H, Alasfour M, Danysh BP, Slowik K, Jacobs RA, Davids MS, Paweletz CP, Leshchiner I, Getz G, Brown JR
Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point. We found the previously described acquired BCL2-G101V mutation in only 4 of 11 patients, with 2 patients showing a very low variant allele fraction (0.03%-4.68%). Whole-exome sequencing revealed acquired loss(8p) in 4 of 11 patients, of which 2 patients also had gain (1q21.2-21.3) in the same cells affecting the MCL1 gene. In vitro experiments showed that CLL cells from the 4 patients with loss(8p) were more resistant to venetoclax than cells from those without it, with the cells from 2 patients also carrying gain (1q21.2-21.3) showing increased sensitivity to MCL1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to the combination of MCL1 inhibitor and venetoclax. Differential gene expression analysis comparing bulk RNA sequencing data from pretreatment and progression time points of all patients showed upregulation of proliferation, B-cell receptor (BCR), and NF-κB gene sets including MAPK genes. Cells from progression time points
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Gastroenterology
Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma
Kumar S, Zhao J, Talluri S, Buon L, Mu S, Potluri LB, Liao C, Shi J, Chakraborty C, Gonzalez GB, Tai YT, Patel J, Pal J, Mashimo H, Samur MK, Munshi NC, Shammas MA
BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors.
METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization.
RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process.
CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.
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Journal of Clinical Oncology
Germline EGFR Mutations and Familial Lung Cancer
Oxnard GR, Chen R, Pharr JC, Koeller DR, Bertram AA, Dahlberg SE, Rainville I, Sholl LM, Jänne PA, Garber JE
BACKGROUND: The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs).
METHODS: The INHERIT study (NCT01754025) enrolled lung cancer patients whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in-person or remotely, providing germline testing and follow-up.
RESULTS: 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon prior genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, consistent with a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver co-mutation. Among 36 germline carriers without a cancer diagnosis, 15 had CT imaging and 9 had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the Southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1 Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.
CONCLUSIONS: In this first prospective description of familial EGFR-mutant lung cancer, we identify a recent founder germline EGFR T790M variant enriched in the US Southeast. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.
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Journal of Clinical Oncology
Reply to Z. Mai et al
D'Amico AV
We thank Mai et al for giving us the opportunity to provide clarification on our recently published article. We agree that the preradical prostatectomy prostate-specific antigen (PSA) level (>20, 10-20, <4 v 4-10 ng/mL [reference]), prostatectomy Gleason score (8-10, 7 v 6 [reference]), tumor category (T3b/4, T3a v T2 [reference]), and margin status (positive v negative [reference]) are all important predictors of both prostate cancer-specific and all-cause mortalities (PCSM, ACM). We mention in the statistical methods section that the model was adjusted for known prostate cancer prognostic factors, which included these factors. These adjustments were made to account for any differences that may exist between treatment groups as noted in Table 1 (Distribution of patient characteristics stratified by treatment). We did perform the same analyses evaluating for the end point of PCSM as mentioned in the results section. We found a very similar adjusted hazard ratio for PCSM as we did for ACM when comparing treatment initiating salvage radiation therapy at a PSA level of >0.25 ng/mL with 0.25 ng/mL or less. Specifically, these respective adjusted hazard ratios and 95% CIs were 1.43 (95% CI, 0.80 to 2.55) and 1.49 (95% CI, 1.11 to 2.00), but given a smaller number of prostate cancer as compared with all-cause deaths being 109 versus 1,269, respectively, the 95% CI for the adjusted hazard ratio for PCSM included 1.0. However, ACM is the most robust end point given that it is not subject to the potential for misclassification or ascertainment bias, which can exist when specifying a specific cause of death.
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Journal of Clinical Oncology
Reply to Z.R. McCaw et al
Matulonis UA
We thank McCaw et al for their thoughtful comments and interest in our study. We acknowledge that constructing a concurrent response curve over time to calculate a mean duration of response (DOR) can be one way to represent efficacy in an intent-to-treat population. Time-to-event analyses such as event-free survival and progression-free survival (PFS) are others that account for time on therapy for both responders and nonresponders. In the context of the single-arm SORAYA trial which tested the antibody-drug conjugate mirvetuximab soravtansine in patients with folate receptor alpha–positive platinum-resistant recurrent ovarian cancer, the efficacy and safety profile of mirvetuximab soravtansine in this population led the US Food and Drug Administrative (FDA) to grant this agent accelerated approval on November 14, 2022, with regular approval pending review of the confirmatory MIRASOL trial (ClinicalTrials.gov identifier: NCT04209855). The regulatory granting of an accelerated approval by the FDA is dependent on several factors which have been updated in agency documents. In a single-arm study, efficacy is defined by confirmed objective response rate and DOR. The DOR is defined as the time from initial complete or partial response until progressive disease or death, as assessed by the investigator (or blinded independent review) per RECIST v1.1. Time to response is not considered in this metric. The Kaplan-Meier curve for DOR provides the distribution of responses and contextualizes the point estimate of median DOR. To give context to clinical benefit, the agency considers the DOR seen among the fraction of patients achieving objective response from standardized assessment guidelines, such as RECIST v1.1, as well as other factors such as time-dependent end points, including PFS and safety.
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Lancet
Author Gender Representation of Journal Reviews and Editorials on Lymphoma
LaCasce A
Gender inequity in academic medicine is a well recognised problem that marginalises a crucial talent pool and ultimately diminishes innovation, collaboration, and progress. The international Women in Lymphoma (WiL) alliance, founded in 2019, consists of over 930 members globally from more than 50 countries. WiL is led by a steering committee of 23 members representing nine countries from five global regions. Recognising gender parity in lymphoma practice despite the under-representation of women in lymphoma leadership, WiL is committed to advocacy and promotion of equal gender representation in all lymphoma academic and clinical leadership settings. A key priority is to analyse gender data related to academic presentations and publishing.
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Molecular Cell
UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Stability
Tsai JM, Li YD, Brown J, Sandoval B, Rutter JC, Cutler JA, Zou C, Donovan KA, Lumpkin RJ, Park PMC, Sievers Q, Hatton C, Ener E, Regalado BD, Sperling MT, Słabicki M, Kim J, Zon R, Zhang Z, Miller PG, Belizaire R, Sperling AS, Fischer ES, Irizarry R, Armstrong SA, Ebert BL
Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
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Nature Genetics
Landscape of mSWI/SNF Chromatin Remodeling Complex Perturbations in Neurodevelopmental Disorders
Valencia AM, Sankar A, Satterstrom FK, Fu J, Talkowski ME, Kadoch C
DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
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Nature Medicine
Machine Learning for Genetics-Based Classification and Treatment Response Prediction in Cancer of Unknown Primary
Moon I, LoPiccolo J, Baca SC, Sholl LM, Kehl KL, Hassett MJ, Liu D, Gusev A
Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3-5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions ([Formula: see text]) on held-out tumor samples, which made up 65.2% of all the held-out samples. When applied to 971 CUP tumors collected at the Dana-Farber Cancer Institute, OncoNPC predicted primary cancer types with high confidence in 41.2% of the tumors. OncoNPC also identified CUP subgroups with significantly higher polygenic germline risk for the predicted cancer types and with significantly different survival outcomes. Notably, patients with CUP who received first palliative intent treatments concordant with their OncoNPC-predicted cancers had significantly better outcomes (hazard ratio (HR) = 0.348; 95% confidence interval (CI) = 0.210-0.570; P = [Formula: see text]). Furthermore, OncoNPC enabled a 2.2-fold increase in patients with CUP who could have received genomically guided therapies. OncoNPC thus provides evidence of distinct CUP subgroups and offers the potential for clinical decision support for managing patients with CUP.
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New England Journal of Medicine
Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Reply
Choueiri TK
The COSMIC-313 trial by Choueiri et al. (May 11 issue) may potentially have a practice-changing effect in oncology. In this phase 3 trial, the investigators found that adding cabozantinib to nivolumab and ipilimumab has a promising effect on progression-free survival as compared with placebo plus nivolumab and ipilimumab. The median progression-free survival was not reached in the experimental group and was 11.3 months in the control group (hazard ratio for disease progression or death, 0.73; P=0.01).
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Blood Advances
Cytokine Release Syndrome in Haploidentical Stem Cell Transplant May Impact T-Cell Recovery and Relapse
Shapiro RM, Kim HT, Ansuinelli M, Guleria I, Cutler CS, Koreth J, Gooptu M, Antin JH, Kelkar A, Ritz J, Wu CJ, Soiffer RJ, Ho VT, Nikiforow S, Romee R
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Blood Advances
More Intensive Therapy as More Effective Treatment for Frail Patients with Multiple Myeloma
DuMontier C, La J, Bihn J, Corrigan J, Dharne M, Abel GA, Gaziano JMM, Kim DH, Munshi NC, Fillmore NR, Driver JA
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Blood Advances
Posttransplant Cyclophosphamide vs Tacrolimus-Based GVHD Prophylaxis: Lower Incidence of Relapse and Chronic GVHD
Maurer K, Ho VT, Inyang E, Cutler C, Koreth J, Shapiro RM, Gooptu M, Romee R, Nikiforow S, Antin JH, Wu CJ, Ritz J, Soiffer RJ, Kim HT
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Cancer Epidemiology, Biomarkers, and Prevention
Sex-Specific Associations Between Adiponectin and Leptin Signaling and Pancreatic Cancer Survival
Babic A, Wang QL, Lee AA, Yuan C, Rifai N, Kim J, Kraft P, Sesso HD, Buring JE, Giovannucci EL, Manson JE, Stampfer MJ, Ng K, Wolpin BM
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Cancer Immunology Research
Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma
Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Denize T, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, Braun DA
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Clinical and Translational Immunology
Inverse Relationship Between Fusobacterium Nucleatum Amount and Tumor CD274 (PD-L1) Expression in Colorectal Carcinoma
Ugai T, Shimizu T, Kawamura H, Ugai S, Takashima Y, Usui G, Väyrynen JP, Okadome K, Haruki K, Akimoto N, Masugi Y, da Zhang X, Chan AT, Wang M, Garrett WS, Freeman GJ, Meyerhardt JA, Nowak JA, Song M, Giannakis M, Ogino S
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Contemporary Clinical Trials
Feasibility of a Positive Psychology Intervention (PATH) in Allogeneic Hematopoietic Stem Cell Transplantation Survivors: Randomized Pilot Trial Design and Methods
Amonoo HL, Daskalakis E, Deary EC, Celano CM, Ghanime PM, Healy BC, Cutler C, Pirl WF, Park ER, El-Jawahri A, Huffman JC
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Journal of the American College of Surgeons
Impact of Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab on Breast Tumor Downsizing for Patients with HER2+ Breast Cancer: Single-Arm Prospective Clinical Trial
Weiss A, Li T, Desai NV, Tung NM, Poorvu PD, Partridge AH, Nakhlis F, Dominici L, Sinclair N, Spring LM, Faggen M, Constantine M, Krop IE, DeMeo M, Wrabel E, Alberti J, Chikarmane S, Tayob N, King TA, Tolaney SM, Winer EP, Mittendorf EA, Waks AG
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JAMA Network Open
Development and Validation of an Automated Image-Based Deep Learning Platform for Sarcopenia Assessment in Head and Neck Cancer
Ye Z, Saraf A, Ravipati Y, Hoebers F, Catalano PJ, Zha Y, Zapaishchykova A, Likitlersuang J, Guthier C, Tishler RB, Schoenfeld JD, Margalit DN, Haddad RI, Mak RH, Aerts HJWL, Kann BH
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JCO Oncology Practice
Identifying Patterns and Barriers in OncotypeDX Recurrence Score Testing in Older Patients With Early-Stage, Estrogen Receptor-Positive Breast Cancer: Implications for Guidance and Reimbursement
Trapani D, Jin Q, Block CC, Freedman RA, Lin NU, Tarantino P, Mittendorf EA, King TA, Lester SC, Brock JE, Tayob N, Bunnell CA, Tolaney SM, Burstein HJ
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JCO Oncology Practice
Identifying Patterns and Barriers in OncotypeDX Recurrence Score Testing in Older Patients With Early-Stage, Estrogen Receptor-Positive Breast Cancer: Implications for Guidance and Reimbursement
Trapani D, Jin Q, Block CC, Freedman RA, Lin NU, Tarantino P, Mittendorf EA, King TA, Lester SC, Brock JE, Tayob N, Bunnell CA, Tolaney SM, Burstein HJ
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Laboratory Investigation
Profiling of Natural Killer Interactions With Cancer Cells Using Mass Cytometry
Hallisey M, Dennis J, Gabriel EP, Masciarelli A, Chen J, Abrecht C, Brainard M, Marcotte WM, Dong H, Hathaway E, Tarannum M, Vergara JA, Schork AN, Tyan K, Tarantino G, Liu D, Romee R, Rahma OE, Severgnini M, Hodi FS, Baginska J
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Nature Protocols
Tutorial: Integrative Computational Analysis of Bulk RNA-Sequencing Data to Characterize Tumor Immunity Using RIMA
Yang L, Wang J, Altreuter J, Jhaveri A, Wong CJ, Song L, Fu J, Taing L, Bodapati S, Sahu A, Tokheim C, Zhang Y, Zeng Z, Bai G, Tang M, Qiu X, Long HW, Michor F, Liu Y, Liu XS
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Pain
Daily Pain and Opioid Administration in Hospitalized Patients with Cancer: The Importance of Psychological Factors, Recent Surgery, and Current Opioid Use
Azizoddin DR, Wilson JM, Flowers KM, Beck M, Chai P, Enzinger AC, Edwards R, Tulsky JA, Schreiber KL
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