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1. CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Author

Alvaro Quintanal-Villalonga, Kenta Kawasaki, Esther Redin, Fathema Uddin, Swanand Rakhade, Vidushi Durani, Amin Sabet, Moniquetta Shafer, Wouter R. Karthaus, Samir Zaidi, Yingqian A. Zhan, Parvathy Manoj, Harsha Sridhar, Dennis Kinyua, Hong Zhong, Barbara P. Mello, Metamia Ciampricotti, Umesh K. Bhanot, Irina Linkov, Juan Qiu, Radhika A. Patel, Colm Morrissey, Sanjoy Mehta, Jesse Barnes, Michael C. Haffner, Nicholas D. Socci, Richard P. Koche, Elisa de Stanchina, Sonia Molina-Pinelo, Sohrab Salehi, Helena A. Yu, Joseph M. Chan, and Charles M. Rudin

Subjects
Medicine, Biology (General), QH301-705.5
Abstract

Abstract Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

Published
2024
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2. Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

Author

Benjamin A. Nacev, Yakshi Dabas, Matthew R. Paul, Christian Pacheco, Michelle Mitchener, Yekaterina Perez, Yan Fang, Alexey A. Soshnev, Douglas Barrows, Thomas Carroll, Nicholas D. Socci, Samantha C. St. Jean, Sagarika Tiwari, Michael J. Gruss, Sebastien Monette, William D. Tap, Benjamin A. Garcia, Tom Muir, and C. David Allis

Subjects
Science
Abstract

Abstract Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

Published
2024
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3. FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

Author

Joshua I. Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M. Craig, Lan L. Gellert, Mauro A. A. Castro, A. Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N. Clinton, Andrew T. Lenis, Timothy A. Chan, Zhiyu Chen, Manisha Rao, Travis J. Hollman, Yanyun Li, Nicholas D. Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H. Bochner, Eugene J. Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin, Matthew Kaag, Suzanne B. Merrill, Monika Joshi, Rosalyn Adam, John A. Taylor, Peter E. Clark, Jay D. Raman, Victor E. Reuter, Yu Chen, Samuel A. Funt, David B. Solit, David J. DeGraff, and Hikmat A. Al-Ahmadie

Subjects
Science
Abstract

Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.

Published
2022
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4. Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets

Author

Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh A. Smith, Cristina R. Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas D. Socci, Satshil Rana, Rodrigo Gularte-Mérida, Ahmet Zehir, Mrinal M. Gounder, Timothy G. Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan A. Strong, Jake Stoller, Jason E. Chan, Ping Chi, Sandra P. D’Angelo, Mark A. Dickson, Ciara M. Kelly, Mary Louise Keohan, Sujana Movva, Katherine Thornton, Paul A. Meyers, Leonard H. Wexler, Emily K. Slotkin, Julia L. Glade Bender, Neerav N. Shukla, Martee L. Hensley, John H. Healey, Michael P. La Quaglia, Kaled M. Alektiar, Aimee M. Crago, Sam S. Yoon, Brian R. Untch, Sarah Chiang, Narasimhan P. Agaram, Meera R. Hameed, Michael F. Berger, David B. Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, and William D. Tap

Subjects
Science
Abstract

Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.

Published
2022
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5. Genomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts

Author

Rebecca Caeser, Jacklynn V. Egger, Shweta Chavan, Nicholas D. Socci, Caitlin Byrne Jones, Faruk Erdem Kombak, Marina Asher, Michael H. Roehrl, Nisargbhai S. Shah, Viola Allaj, Parvathy Manoj, Sam E. Tischfield, Amanda Kulick, Maximiliano Meneses, Christine A. Iacobuzio-Donahue, W. Victoria Lai, Umeshkumar Bhanot, Marina K. Baine, Natasha Rekhtman, Travis J. Hollmann, Elisa de Stanchina, John T. Poirier, Charles M. Rudin, and Triparna Sen

Subjects
Science
Abstract

Creating accurate models of small cell lung cancer is essential to ensure the clinical relevance of results. Here, the authors create patient derived xenograft models from 33 patients and show, through multi-omics sequencing, that these models retain the primary features of the original.

Published
2022
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6. Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors

Author

Ivan J. Cohen, Fresia Pareja, Nicholas D. Socci, Ronglai Shen, Ashley S. Doane, Jazmin Schwartz, Raya Khanin, Elizabeth A. Morris, Elizabeth J. Sutton, and Ronald G. Blasberg

Subjects
tumor metabolism, immunotherapy, tumor microenvironment, solid tumors, glycolysis, immune infiltration, Immunologic diseases. Allergy, RC581-607
Abstract

Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pleiotropic immune suppressive effects using in-vitro and in-vivo models of disease. To determine whether the immune suppressive effect of tumor glycolysis is observed across human solid tumors, we analyzed glycolytic and immune gene expression patterns in multiple solid malignancies. We found that increased expression of a glycolytic signature was associated with decreased immune infiltration and a more aggressive disease across multiple tumor types. Radiologic and pathologic analysis of untreated estrogen receptor (ER)-negative breast cancers corroborated these observations, and demonstrated that protein expression of glycolytic enzymes correlates positively with glucose uptake and negatively with infiltration of CD3+ and CD8+ lymphocytes. This study reveals an inverse relationship between tumor glycolysis and immune infiltration in a large cohort of multiple solid tumor types.

Published
2022
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7. Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients

Author

Dana W. Y. Tsui, Michael L. Cheng, Maha Shady, Julie L. Yang, Dennis Stephens, Helen Won, Preethi Srinivasan, Kety Huberman, Fanli Meng, Xiaohong Jing, Juber Patel, Maysun Hasan, Ian Johnson, Erika Gedvilaite, Brian Houck-Loomis, Nicholas D. Socci, S. Duygu Selcuklu, Venkatraman E. Seshan, Hongxin Zhang, Debyani Chakravarty, Ahmet Zehir, Ryma Benayed, Maria Arcila, Marc Ladanyi, Samuel A. Funt, Darren R. Feldman, Bob T. Li, Pedram Razavi, Jonathan Rosenberg, Dean Bajorin, Gopa Iyer, Wassim Abida, Howard I. Scher, Dana Rathkopf, Agnes Viale, Michael F. Berger, and David B. Solit

Subjects
Liquid biopsy, Plasma DNA, Molecular diagnostic, Cancer, Sequencing, Noninvasive, Medicine, Genetics, QH426-470
Abstract

Abstract Background Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Methods Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES). Results cfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction (z-score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction (z-score

Published
2021
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8. Author Correction: FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

Author

Joshua I. Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M. Craig, Lan L. Gellert, Mauro A. A. Castro, A. Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N. Clinton, Andrew T. Lenis, Timothy A. Chan, Ziyu Chen, Manisha Rao, Travis J. Hollman, Yanyun Li, Nicholas D. Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H. Bochner, Eugene J. Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin, Matthew Kaag, Suzanne B. Merrill, Monika Joshi, Rosalyn Adam, John A. Taylor, Peter E. Clark, Jay D. Raman, Victor E. Reuter, Yu Chen, Samuel A. Funt, David B. Solit, David J. DeGraff, and Hikmat A. Al-Ahmadie

Subjects
Science
Published
2022
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9. PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Author

Eneda Toska, Pau Castel, Sagar Chhangawala, Amaia Arruabarrena-Aristorena, Carmen Chan, Vasilis C. Hristidis, Emiliano Cocco, Mirna Sallaku, Guotai Xu, Jane Park, Gerard Minuesa, Sophie G. Shifman, Nicholas D. Socci, Richard Koche, Christina S. Leslie, Maurizio Scaltriti, and José Baselga

Subjects
Biology (General), QH301-705.5
Abstract

Summary: The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output. : Toska, Castel, et al. show that the PI3K pathway propagates its effects to control chromatin and estrogen receptor (ER) function through SGK1, a PI3K effector. PI3K inhibitors, via a negative-feedback loop, activate SGK1, which phosphorylates the histone lysine methyltransferase KMT2D to attenuate its activity and regulate ER response. Keywords: SGK1, KMT2D, PI3K pathway, estrogen receptor, breast cancer, chromatin regulation, AKT, PI3K inhibitors

Published
2019
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10. Genome-wide mapping of the distribution of CarD, RNAP σA, and RNAP β on the Mycobacterium smegmatis chromosome using chromatin immunoprecipitation sequencing

Author

Robert Landick, Azra Krek, Michael S. Glickman, Nicholas D. Socci, and Christina L. Stallings

Subjects
Mycobacteria, RNA polymerase, Transcription, Tuberculosis, CarD, Genetics, QH426-470
Abstract

CarD is an essential mycobacterial protein that binds the RNA polymerase (RNAP) and affects the transcriptional profile of Mycobacterium smegmatis and Mycobacterium tuberculosis [6]. We predicted that CarD was directly regulating RNAP function but our prior experiments had not determined at what stage of transcription CarD was functioning and at which genes CarD interacted with the RNAP. To begin to address these open questions, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to survey the distribution of CarD throughout the M. smegmatis chromosome. The distribution of RNAP subunits β and σA were also profiled. We expected that RNAP β would be present throughout transcribed regions and RNAP σA would be predominantly enriched at promoters based on work in Escherichia coli [3], however this had yet to be determined in mycobacteria. The ChIP-seq analyses revealed that CarD was never present on the genome in the absence of RNAP, was primarily associated with promoter regions, and was highly correlated with the distribution of RNAP σA. The colocalization of σA and CarD led us to propose that in vivo, CarD associates with RNAP initiation complexes at most promoters and is therefore a global regulator of transcription initiation. Here we describe in detail the data from the ChIP-seq experiments associated with the study published by Srivastava and colleagues in the Proceedings of the National Academy of Science in 2013 [5] as well as discuss the findings from this dataset in relation to both CarD and mycobacterial transcription as a whole. The ChIP-seq data have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE48164).

Published
2014
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11. Indirect measurements of differential gene expression with cDNA microarrays

Author

Thomas J. Belbin, John Gaspar, Missak Haigentz, Roman Perez-Soler, Steven M. Keller, Michael B. Prystowsky, Geoffrey Childs, and Nicholas D. Socci

Subjects
Biology (General), QH301-705.5
Abstract

The use of universal RNA reference sets is an increasingly common approach to molecular classification studies with cDNA microarrays. Here we evaluated the reliability of indirect measurements of fluorescence ratios with a common RNA reference as a means of identifying differentially expressed genes. Comparisons of direct and indirect measures of differential gene expression showed a strong overall correlation in fluorescence ratio measurements but also a high degree of false positives in our indirect measurements. These results indicated that the application of more stringent ratio filters may be required when assessing differential gene expression utilizing a common RNA reference in classification studies.

Published
2004
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12. Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology

Author

Maryam Pourmaleki, Nicholas D. Socci, Travis J. Hollmann, and Ingo K. Mellinghoff

Subjects
Oncology
Abstract

Summary: The shift in cancer therapy from broadly cytotoxic agents toward “personalized” treatments that target specific alterations in each patient's tumor requires diagnostic pathology approaches that are quantitative and biospecimen-friendly. Novel multiplexed antibody-based imaging technologies can measure single-cell expression of over 60 proteins in intact tumor sections and hold promise for clinical oncology.

Published
2023

13. Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach

Author

Seyram A. Doe-Tetteh, Sabrina Y. Camp, Dalicia Reales, Jett Crowdis, Anne Marie Noronha, Bernadette Wolff, Tina Alano, Jesse Galle, S. Duygu Selcuklu, Agnes Viale, Nicholas D. Socci, Ying L. Liu, William P. Tew, Carol Aghajanian, Marc Ladanyi, Meng Xiao He, Saud H. AlDubayan, Roei David Mazor, Ofer Shpilberg, Oshrat Hershkovitz-Rokah, Jose A. Riancho, Jose L. Hernandez, M. Carmen Gonzalez-Vela, Justin J. Buthorn, Manda Wilson, Amy E. Webber, Mariko Yabe, Kseniya Petrova-Drus, Marc Rosenblum, Benjamin H. Durham, Omar Abdel-Wahab, Michael F. Berger, Mark T.A. Donoghue, Andrew L. Kung, Julia Glade Bender, Neerav N. Shukla, Samuel A. Funt, Ahmet Dogan, Robert A. Soslow, Hikmat Al-Ahmadie, Darren R. Feldman, Eliezer M. Van Allen, Eli L. Diamond, and David B. Solit

Subjects
Cancer Research, Oncology
Abstract

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental Design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

Published
2023

15. Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer

Author

Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J. Nanjangud, Michael F. Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D. Socci, Jinru Shia, Gregory J. Riely, Yonina R. Murciano-Goroff, Bob T. Li, James G. Christensen, Jorge S. Reis-Filho, David B. Solit, Elisa de Stanchina, Scott W. Lowe, Neal Rosen, and Sandra Misale

Subjects
Oncology
Abstract

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. Significance: Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches.

Published
2022

16. Ordered and deterministic cancer genome evolution after p53 loss

Author

Timour Baslan, John P. Morris, Zhen Zhao, Jose Reyes, Yu-Jui Ho, Kaloyan M. Tsanov, Jonathan Bermeo, Sha Tian, Sean Zhang, Gokce Askan, Aslihan Yavas, Nicolas Lecomte, Amanda Erakky, Anna M. Varghese, Amy Zhang, Jude Kendall, Elena Ghiban, Lubomir Chorbadjiev, Jie Wu, Nevenka Dimitrova, Kalyani Chadalavada, Gouri J. Nanjangud, Chaitanya Bandlamudi, Yixiao Gong, Mark T. A. Donoghue, Nicholas D. Socci, Alex Krasnitz, Faiyaz Notta, Steve D. Leach, Christine A. Iacobuzio-Donahue, and Scott W. Lowe

Subjects
Genome, Multidisciplinary, Models, Genetic, Carcinogenesis, Loss of Heterozygosity, Adenocarcinoma, Genes, p53, Evolution, Molecular, Pancreatic Neoplasms, Mice, Disease Progression, Animals, Tumor Suppressor Protein p53, Gene Deletion, Carcinoma, Pancreatic Ductal
Abstract

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

Published
2022

17. A transposase-derived gene required for human brain development

Author

Luz Jubierre Zapater, Elias Rodriguez-Fos, Merce Planas-Felix, Sara Lewis, Daniel Cameron, Phillip Demarest, Anika Nabila, Junfei Zhao, Paul Bergin, Casie Reed, Makiko Yamada, Alex Pagnozzi, Caroline Nava, Emilie Bourel-Ponchel, Derek E. Neilson, Ali Dursun, R. Köksal Özgül, Halil Tuna Akar, Nicholas D. Socci, Matthew Hayes, Raul Rabadan, David Torrents, Michael C. Kruer, Miklos Toth, and Alex Kentsis

Subjects
Article
Abstract

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements in neurons. Together, these studies nominate PGBD5 as the long-hypothesized neuronal DNA nuclease required for brain function in mammals.One-Sentence SummaryPiggyBac Transposable Element Derived 5 (PGBD5) is required for brain development in humans and mice by promoting somatic neuronal genome rearrangements.

Published
2023

18. Data from Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma

Author

Travis J. Hollmann, Ingo K. Mellinghoff, Nicholas D. Socci, Andrea Schietinger, Margaret K. Callahan, Fiona Ginty, Elizabeth McDonough, Alex D. Corwin, Stephanie L. Goff, Billel Gasmi, John M. Kirkwood, Jennifer A. Wargo, Raymond Traweek, Michael G. White, Janis M. Taube, Julie E. Stein, Kara M. Schenk, Evan J. Lipson, Thomas Brenn, Claire F. Temple-Oberle, David S. Klimstra, Saad Nadeem, Carl Campos, Subhiksha Nandakumar, Mianlei Zhang, Yanyun Li, Daniel A. Navarrete, Mono Pirun, Zheng Zeng, Charlotte E. Ariyan, Caitlin J. Jones, and Maryam Pourmaleki

Abstract

Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8+ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1−LAG-3−TIM-3−). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as “extreme responders”) were characterized by proliferating CD8+ T cells with an exhausted phenotype (PD-1+LAG-3+TIM-3+), stromal B-cell aggregates, and expression of IFNγ and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.

Published
2023

19. Supplementary Figure 6 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

C106 resistant cells drug withdrawal and Patient #12 MSK-Impact data

Published
2023

20. Supplementary Table 2 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Progression Cell Free DNA data

Published
2023

21. Supplementary Table 1 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Characteristics

Published
2023

22. Supplementary Data from Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma

Author

Travis J. Hollmann, Ingo K. Mellinghoff, Nicholas D. Socci, Andrea Schietinger, Margaret K. Callahan, Fiona Ginty, Elizabeth McDonough, Alex D. Corwin, Stephanie L. Goff, Billel Gasmi, John M. Kirkwood, Jennifer A. Wargo, Raymond Traweek, Michael G. White, Janis M. Taube, Julie E. Stein, Kara M. Schenk, Evan J. Lipson, Thomas Brenn, Claire F. Temple-Oberle, David S. Klimstra, Saad Nadeem, Carl Campos, Subhiksha Nandakumar, Mianlei Zhang, Yanyun Li, Daniel A. Navarrete, Mono Pirun, Zheng Zeng, Charlotte E. Ariyan, Caitlin J. Jones, and Maryam Pourmaleki

Abstract

Supplementary Data from Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma

Published
2023

23. Supplementary Figure 2 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

C106 cell lines single cell sequencing analysis

Published
2023

24. Supplementary Figure 3 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

RW7213 cell lines sequencing analysis

Published
2023

26. Data from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.Significance:Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches.This article is highlighted in the In This Issue feature, p. 1

Published
2023

27. Supplementary Figure 4 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Generation of acquired resistance PDX model

Published
2023

28. Supplementary Figure 1 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Characterization of acquired resistance in vitro models

Published
2023

29. Supplementary Figure 5 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Oncoprint of baseline alterations in CRC patients who developed resistance to KRAS G12C and EGFR inhibitors

Published
2023

30. Supplementary Table 3 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Longitudinal Cell Free DNA data

Published
2023

31. Data from Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology

Author

Ingo K. Mellinghoff, Travis J. Hollmann, Nicholas D. Socci, and Maryam Pourmaleki

Abstract

Summary:The shift in cancer therapy from broadly cytotoxic agents toward “personalized” treatments that target specific alterations in each patient's tumor requires diagnostic pathology approaches that are quantitative and biospecimen-friendly. Novel multiplexed antibody-based imaging technologies can measure single-cell expression of over 60 proteins in intact tumor sections and hold promise for clinical oncology.

Published
2023

32. Figure S1-7 from Accelerating Discovery of Functional Mutant Alleles in Cancer

Author

Barry S. Taylor, David M. Hyman, David B. Solit, Neal Rosen, Michael F. Berger, José Baselga, Nikolaus Schultz, Marc Ladanyi, Sarat Chandarlapaty, Maria E. Arcila, Ryma Benayed, Ahmet Zehir, Gowtham Jayakumaran, Nicholas D. Socci, Dalicia N. Reales, Bob T. Li, Pedram Razavi, Ritika Kundra, Selcuk Onur Sumer, JianJiong Gao, Christopher Harris, Swati Patel, Tambudzai Shamu, Alexander Gorelick, Alexander Penson, Cyriac Kandoth, Sarah Phillips, Debyani Chakravarty, Philip Jonsson, Mark T.A. Donoghue, Craig M. Bielski, Alison M. Schram, Tripti Shrestha Bhattarai, and Matthew T. Chang

Abstract

Supplementary Figures 1-7

Published
2023

33. Supplementary Tables S1 - S7 from Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma

Author

Samuel Singer, Chris Sander, Fumi Shima, Aimee M. Crago, Nicholas D. Socci, Evan Molinelli, Phaedra Agius, Martin L. Miller, Amanda Craig, Miguel A. López-Lago, Rachael O'Connor, Yawei Shen, Takahiro Mimae, Narasimhan Agaram, Li-Xuan Qin, Ann Y. Lee, and Tomoyo Okada

Abstract

Supplementary Table S1, patient characteristics. Supplementary Table S2, genes in the signature distinguishing Cluster 1 and Cluster 2. Supplementary Table S3, genes associated with disease-specific survival. Supplementary Table S4, pathway modules identified by NetBox. Supplementary Table S5, functional annotation enrichment analysis. Supplementary Table S6, antibodies used. Supplementary Table S7, samples analyzed for ITGA10 mRNA in the comparison of primary and metastatic tissue.

Published
2023

35. Supplementary Figures 1 - 10 from Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy

Author

Barry S. Taylor, David B. Solit, John H.J. Petrini, Michael F. Berger, Dean F. Bajorin, Jonathan E. Rosenberg, Bernard H. Bochner, Victor Reuter, Gary K. Schwartz, Agnes Viale, Nicholas D. Socci, Philip Kim, Irina Ostrovnaya, Mono Pirun, Gregory C. McDermott, A. Rose Brannon, Sasinya N. Scott, Aphrothiti J. Hanrahan, Nikolaus Schultz, Akiko Inagaki, Saurabh Asthana, Marcel Hohl, Gopa Iyer, and Hikmat Al-Ahmadie

Abstract

PDF file - 470KB, All supplementary figures including tumor histology, RAD50 immunohistochemistry, candidate mutations and their clonality, and supporting yeast and MEF experimental data.

Published
2023

36. Table S1-4 from Accelerating Discovery of Functional Mutant Alleles in Cancer

Author

Barry S. Taylor, David M. Hyman, David B. Solit, Neal Rosen, Michael F. Berger, José Baselga, Nikolaus Schultz, Marc Ladanyi, Sarat Chandarlapaty, Maria E. Arcila, Ryma Benayed, Ahmet Zehir, Gowtham Jayakumaran, Nicholas D. Socci, Dalicia N. Reales, Bob T. Li, Pedram Razavi, Ritika Kundra, Selcuk Onur Sumer, JianJiong Gao, Christopher Harris, Swati Patel, Tambudzai Shamu, Alexander Gorelick, Alexander Penson, Cyriac Kandoth, Sarah Phillips, Debyani Chakravarty, Philip Jonsson, Mark T.A. Donoghue, Craig M. Bielski, Alison M. Schram, Tripti Shrestha Bhattarai, and Matthew T. Chang

Abstract

Supplementary Tables 1-4

Published
2023

37. Supplementary Tables 1 - 6 from Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy

Author

Barry S. Taylor, David B. Solit, John H.J. Petrini, Michael F. Berger, Dean F. Bajorin, Jonathan E. Rosenberg, Bernard H. Bochner, Victor Reuter, Gary K. Schwartz, Agnes Viale, Nicholas D. Socci, Philip Kim, Irina Ostrovnaya, Mono Pirun, Gregory C. McDermott, A. Rose Brannon, Sasinya N. Scott, Aphrothiti J. Hanrahan, Nikolaus Schultz, Akiko Inagaki, Saurabh Asthana, Marcel Hohl, Gopa Iyer, and Hikmat Al-Ahmadie

Abstract

PDF file - 2461KB, A complete listing of somatic mutations and rearrangements detected as well as targeted genes, sequences, MRN complex mutation frequency, and strains utilized.

Published
2023

39. Supplementary Data from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Christine A. Iacobuzio-Donahue, Barry S. Taylor, Nicholas D. Socci, Martin A. Nowak, Ralph H. Hruban, Laura D. Wood, Eileen M. O'Reilly, Debyani Chakravarty, Mithat Gönen, Alexander V. Penson, Craig M. Bielski, Alexander Heyde, Johannes G. Reiter, Jerry P. Melchor, Lance Zhang, Rajya Kappagantula, Jungeui Hong, Akimasa Hayashi, Alvin P. Makohon-Moore, Jeffrey M. Gerold, Marc A. Attiyeh, and Hitomi Sakamoto

Abstract

Figures S1-S3

Published
2023

41. Supplementary Materials from Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy

Author

Barry S. Taylor, David B. Solit, John H.J. Petrini, Michael F. Berger, Dean F. Bajorin, Jonathan E. Rosenberg, Bernard H. Bochner, Victor Reuter, Gary K. Schwartz, Agnes Viale, Nicholas D. Socci, Philip Kim, Irina Ostrovnaya, Mono Pirun, Gregory C. McDermott, A. Rose Brannon, Sasinya N. Scott, Aphrothiti J. Hanrahan, Nikolaus Schultz, Akiko Inagaki, Saurabh Asthana, Marcel Hohl, Gopa Iyer, and Hikmat Al-Ahmadie

Abstract

PDF file - 321KB, A detailed description of additional methods utilized (and associated references) for sequencing and analysis as well as an explanatory note regarding the TM pathway in yeast.

Published
2023

42. Supplementary Figures S1 - S8 from Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma

Author

Samuel Singer, Chris Sander, Fumi Shima, Aimee M. Crago, Nicholas D. Socci, Evan Molinelli, Phaedra Agius, Martin L. Miller, Amanda Craig, Miguel A. López-Lago, Rachael O'Connor, Yawei Shen, Takahiro Mimae, Narasimhan Agaram, Li-Xuan Qin, Ann Y. Lee, and Tomoyo Okada

Abstract

Supplementary Figure S1, showing clustering of myxofibrosarcomas compared to normal tissue and showing the validation of the association of 5 genes with survival. Supplementary Figure S2, showing the effects of ITGA10 knockdown and overexpression. Supplementary Figure S3, showing the cell biology of integrin-alpha10 in myxofibrosarcoma cells. Supplementary Figure S4, showing the associations of TRIO and RICTOR amplification and overexpression with clinical outcomes. Supplementary Figure S5, showing that TRIO and RAC1 knockdown induce apoptosis in myxofibrosarcoma cells, but not in ASCs. Supplementary Figure S6, showing that RAPTOR knockdown does not induce apoptosis in myxofibrosarcoma cells. Supplementary Figure S7, showing the effects of RAC/PAK and mTOR inhibitors in myxofibrosarcoma cells and normal cells. Supplementary Figure S8, showing that mice treated with INK128 and/or EHop-016 maintain their weight.

Published
2023

43. Tables S1-S8 from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Christine A. Iacobuzio-Donahue, Barry S. Taylor, Nicholas D. Socci, Martin A. Nowak, Ralph H. Hruban, Laura D. Wood, Eileen M. O'Reilly, Debyani Chakravarty, Mithat Gönen, Alexander V. Penson, Craig M. Bielski, Alexander Heyde, Johannes G. Reiter, Jerry P. Melchor, Lance Zhang, Rajya Kappagantula, Jungeui Hong, Akimasa Hayashi, Alvin P. Makohon-Moore, Jeffrey M. Gerold, Marc A. Attiyeh, and Hitomi Sakamoto

Abstract

Supplemental Tables

Published
2023

44. Data from Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach

Author

David B. Solit, Eli L. Diamond, Eliezer M. Van Allen, Darren R. Feldman, Hikmat Al-Ahmadie, Robert A. Soslow, Ahmet Dogan, Samuel A. Funt, Neerav N. Shukla, Julia Glade Bender, Andrew L. Kung, Mark T.A. Donoghue, Michael F. Berger, Omar Abdel-Wahab, Benjamin H. Durham, Marc Rosenblum, Kseniya Petrova-Drus, Mariko Yabe, Amy E. Webber, Manda Wilson, Justin J. Buthorn, M. Carmen Gonzalez-Vela, Jose L. Hernandez, Jose A. Riancho, Oshrat Hershkovitz-Rokah, Ofer Shpilberg, Roei David Mazor, Saud H. AlDubayan, Meng Xiao He, Marc Ladanyi, Carol Aghajanian, William P. Tew, Ying L. Liu, Nicholas D. Socci, Agnes Viale, S. Duygu Selcuklu, Jesse Galle, Tina Alano, Bernadette Wolff, Anne Marie Noronha, Jett Crowdis, Dalicia Reales, Sabrina Y. Camp, and Seyram A. Doe-Tetteh

Abstract

Purpose:To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes.Experimental Design:Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype.Results:A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab.Conclusions:Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

Published
2023

45. Supplementary Table S1 from Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach

Author

David B. Solit, Eli L. Diamond, Eliezer M. Van Allen, Darren R. Feldman, Hikmat Al-Ahmadie, Robert A. Soslow, Ahmet Dogan, Samuel A. Funt, Neerav N. Shukla, Julia Glade Bender, Andrew L. Kung, Mark T.A. Donoghue, Michael F. Berger, Omar Abdel-Wahab, Benjamin H. Durham, Marc Rosenblum, Kseniya Petrova-Drus, Mariko Yabe, Amy E. Webber, Manda Wilson, Justin J. Buthorn, M. Carmen Gonzalez-Vela, Jose L. Hernandez, Jose A. Riancho, Oshrat Hershkovitz-Rokah, Ofer Shpilberg, Roei David Mazor, Saud H. AlDubayan, Meng Xiao He, Marc Ladanyi, Carol Aghajanian, William P. Tew, Ying L. Liu, Nicholas D. Socci, Agnes Viale, S. Duygu Selcuklu, Jesse Galle, Tina Alano, Bernadette Wolff, Anne Marie Noronha, Jett Crowdis, Dalicia Reales, Sabrina Y. Camp, and Seyram A. Doe-Tetteh

Abstract

Genomically matched targeted therapies guided by MSK-IMPACT testing (n=22).

Published
2023

46. Supplementary Figure S1 from Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach

Author

David B. Solit, Eli L. Diamond, Eliezer M. Van Allen, Darren R. Feldman, Hikmat Al-Ahmadie, Robert A. Soslow, Ahmet Dogan, Samuel A. Funt, Neerav N. Shukla, Julia Glade Bender, Andrew L. Kung, Mark T.A. Donoghue, Michael F. Berger, Omar Abdel-Wahab, Benjamin H. Durham, Marc Rosenblum, Kseniya Petrova-Drus, Mariko Yabe, Amy E. Webber, Manda Wilson, Justin J. Buthorn, M. Carmen Gonzalez-Vela, Jose L. Hernandez, Jose A. Riancho, Oshrat Hershkovitz-Rokah, Ofer Shpilberg, Roei David Mazor, Saud H. AlDubayan, Meng Xiao He, Marc Ladanyi, Carol Aghajanian, William P. Tew, Ying L. Liu, Nicholas D. Socci, Agnes Viale, S. Duygu Selcuklu, Jesse Galle, Tina Alano, Bernadette Wolff, Anne Marie Noronha, Jett Crowdis, Dalicia Reales, Sabrina Y. Camp, and Seyram A. Doe-Tetteh

Abstract

Clonality assessment of known oncogenic mutations in the female GCT cohort.

Published
2023

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