bluuebunny/crossref_metadata_2025 huggingface dataset:
Table S1 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
Authors: Larson Sarah M. , Walthers Christopher M. , Ji Brenda , Ghafouri Sanaz N. , Naparstek Jacob , Trent Jacqueline , Chen Jia Ming , Roshandell Mobina , Harris Caitlin , Khericha Mobina , Schweppe Thomas , Berent-Maoz Beata , Gosliner Stanley B. , Almaktari Amr , Ceja Melanie Ayala , Allen-Auerbach Martin S. , Said Jonathan , Nawaly Karla , Mead Monica , de Vos Sven , Young Patricia A. , Oliai Caspian , Schiller Gary J. , Timmerman John M. , Ribas Antoni , Chen Yvonne Y.
Published: April 2023

Comparison of CART19/20 cell therapy results with reported data from trials evaluating other CD19/CD20 bispecific CAR-T cell therapies and commercially available CD19 CAR-T cell therapies.
Figure S6 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
Authors: Larson Sarah M. , Walthers Christopher M. , Ji Brenda , Ghafouri Sanaz N. , Naparstek Jacob , Trent Jacqueline , Chen Jia Ming , Roshandell Mobina , Harris Caitlin , Khericha Mobina , Schweppe Thomas , Berent-Maoz Beata , Gosliner Stanley B. , Almaktari Amr , Ceja Melanie Ayala , Allen-Auerbach Martin S. , Said Jonathan , Nawaly Karla , Mead Monica , de Vos Sven , Young Patricia A. , Oliai Caspian , Schiller Gary J. , Timmerman John M. , Ribas Antoni , Chen Yvonne Y.
Published: April 2023

T cell populations become CD8-dominant post CART19/20 cell infusion. % CD8+ among (A) CAR-expressing T cells and (B) all CD3+ T cells was quantified by flow cytometry. Data are shown for CAR-T cells only up to day 90 post infusion as values post day 90 become unreliable due to low CAR+ cell count detected by flow. FP: final product (i.e., cryopreserved CART19/20 cells).
Supplementary Tables S1-S2 from Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology
Authors: Pourmaleki Maryam , Socci Nicholas D. , Hollmann Travis J. , Mellinghoff Ingo K.
Published: April 2023

Supplementary Table S1: Overview of multiplexed antibody-based imaging technologies.Supplementary Table S2: Application of multiplexed antibody-based imaging in cancer research.
Figure S6 from LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma
Authors: Stein Benjamin D. , Ferrarone John R. , Gardner Eric E. , Chang Jae Won , Wu David , Hollstein Pablo E. , Liang Roger J. , Yuan Min , Chen Qiuying , Coukos John S. , Sindelar Miriam , Ngo Bryan , Gross Steven S. , Shaw Reuben J. , Zhang Chen , Asara John M. , Moellering Raymond E. , Varmus Harold , Cantley Lewis C.
Published: April 2023

Figure S6. TPI1 allelic variants effects central carbon metabolic flux.
Supplementary Tables S1-S11 from Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
Authors: Dharanipragada Prashanthi , Zhang Xiao , Liu Sixue , Lomeli Shirley H. , Hong Aayoung , Wang Yan , Yang Zhentao , Lo Kara Z. , Vega-Crespo Agustin , Ribas Antoni , Moschos Stergios J. , Moriceau Gatien , Lo Roger S.
Published: April 2023

Table S1: Clinical characteristics of patients who donated MAPKi-sensitive/-naive and acquired MAPKi-resistant melanoma. Table S2: Genomic alterations, chromothripsis, and ecDNA-/CGR-amplicons detected in MAPKi-sensitive/-naive and acquired MAPKi-resistant melanoma genomes. Table S3: Genes amplified by ecDNAs, CGRs, and linear amplicons along with copy numbers in MAPKi-sensitive/-naïve and acquired MAPKi-resistant melanoma genomes. Table S4: Co-occurrence of resistance-associated genetic alterations (identified in prior studies) with resistance-driver ecDNA and CGR amplicons (identified in the current study). Table S5: Normalized RNA-seq-based transcript expression in MAPKi-sensitive/-naïve and acquired-resistant tumors. Table S6: MAPK-reactivation amplicons in acquired resistance, copy numbers, and amplicon sub-types. Table S7: MAPKi-resistant genes amplified by ecDNAs and CGRs utilized for pathway enrichment analysis. Table S8: Enhancers associated with ecDNAs and CGRs in MAPKi-sensitive/-naive and acquired MAPKi-resistant melanoma genomes. Table S9: Frequencies of enriched SBS signatures reflecting defective DNA repair mechanisms within chromothripsis and non-chromothriptic regions in MAPKi-sensitive (n = 16) and acquired-resistant (n = 31) tumors. Table S10: ecDNAs, CGRs, copy numbers, and associated genes in human melanoma cell lines (M229, M249) on vehicle treatment and early on treatment. Table S11: ecDNAs, CGRs, copy numbers, associated genes in vehicle-treated and early on-treatment PDX tumors.
Table S6 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Enhancer-enhancer interaction results of MYC and MYCL ecDNAs in the DMS-273 cell line.
Table S1 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Expression and copy-number status of recurrently highly amplified genes in patient and cell line samples. The tables summarize copy-number signal and AmpliconArchitect curation, expression of key genes and results of the multivariate analysis.
Figure S1-S19 from Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer
Authors: Weng Weining , Meng Tao , Zhao Qianqian , Shen Yi , Fu Guoxiang , Shi Jing , Zhang Yue , Wang Zhaohui , Wang Mingqiao , Pan Rong , Ma Linjie , Chen Caiwei , Wang Lijun , Zhou Biao , Zhang Hui , Pu Junyi , Zhang Jianjian , Hu Yi Peter , Hua Guoqiang , Qian Yu , Liu Shu-Hui , Hu Wenhao , Meng Xun
Published: April 2023

Supplementary Figure S1 shows Exatecan cytotoxicity and sensitivity to multidrug resistant genes. Supplementary Figure S2 shows Exatecan and DXd/SN-38 sensitivity to multidrug resistant genes. Supplementary Figure S3 shows Exatecan toxicity in rat. Supplementary Figure S4 shows the design and optimization of T moiety. Supplementary Figure S5 shows physicochemical and functional equivalence of Tras-GGFG-DXd and DS-8201a. Supplementary Figure S6 show physicochemical profile of antibody-exatecan conjugates enabled by T moiety. Supplementary Figure S7 shows additional T moiety-exatecan and belotecan conjugates. Supplementary Figure S8 shows in vitro and in vivo stability of MTX-1000. Supplementary Figure S9 shows cellular dynamics and mechanism of MTX-1000. Supplementary Figure S10 shows colon cancer organoid response to ADCs. Supplementary Figure S11 shows bystander killing effect of MTX-1000, T-DM1 and Tras-GGFG-DXd in coculture conditions in vitro. Supplementary Figure S12 shows hematology and serum chemistry of MTX-1000 in monkey. Supplementary Figure S13 shows T moiety-exatecan ADCs show potent antitumor efficacy and improved therapeutic index. Supplementary Figure S14 shows T moiety-exatecan ADCs show higher antitumor potency in PDX models and better intratumor pharmacodynamic response. Supplementary Figure S15 shows T moiety-exatecan ADCs overcome treatment-resistance due to improved therapeutic index and intratumor pharmacodynamic response. Supplementary Figure S16 shows overcoming MDR resistance by T moiety exatecan ADCs or a combination of MDR inhibitor with DXd/SN-38 ADCs. Supplementary Figure S17 shows Exatecan/MTX-1000 and PARP/ATR inhibitor synergize in colon cancer cells. Supplementary Figure S18 shows a patient-derived xenograft (PDX) model with EGFR triple mutation. Supplementary Figure S19 shows MTX-1000 induces immunological cell death and enhances antitumor immunity of anti-PD-1.
Supplementary Table S5 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.
Supplementary Table S1 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Baseline characteristics of the patients treated.
Supplementary Figure S3 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Further descriptions of tumor immune infiltrates.
Supplemental Figure S2 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Supplemental Figure S2 describes that oxidative stress in microglia promotes the immunosuppressive functions of microglia.
Data from Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation
Authors: Heckler Max , Ali Lestat R. , Clancy-Thompson Eleanor , Qiang Li , Ventre Katherine S. , Lenehan Patrick , Roehle Kevin , Luoma Adrienne , Boelaars Kelly , Peters Vera , McCreary Julia , Boschert Tamara , Wang Eric S. , Suo Shengbao , Marangoni Francesco , Mempel Thorsten R. , Long Henry W. , Wucherpfennig Kai W. , Dougan Michael , Gray Nathanael S. , Yuan Guo-Cheng , Goel Shom , Tolaney Sara M. , Dougan Stephanie K.
Published: April 2023

Abstract
CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity.
Significance:
CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.

This article is highlighted in the In This Issue feature, p. 2355
Data from SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia
Authors: Wei Yiliang , Huang Yu-Han , Skopelitis Damianos S. , Iyer Shruti V. , Costa Ana S.H. , Yang Zhaolin , Kramer Melissa , Adelman Emmalee R. , Klingbeil Olaf , Demerdash Osama E. , Polyanskaya Sofya A. , Chang Kenneth , Goodwin Sara , Hodges Emily , McCombie W. Richard , Figueroa Maria E. , Vakoc Christopher R.
Published: April 2023

Abstract
An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate-limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme.
Significance:
We show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML.

This article is highlighted in the In This Issue feature, p. 275
Data from Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial
Authors: Riely Gregory J. , Neal Joel W. , Camidge D. Ross , Spira Alexander I. , Piotrowska Zofia , Costa Daniel B. , Tsao Anne S. , Patel Jyoti D. , Gadgeel Shirish M. , Bazhenova Lyudmila , Zhu Viola W. , West Howard L. , Mekhail Tarek , Gentzler Ryan D. , Nguyen Danny , Vincent Sylvie , Zhang Steven , Lin Jianchang , Bunn Veronica , Jin Shu , Li Shuanglian , Jänne Pasi A.
Published: April 2023

Abstract
Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.
Significance:
No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.

See related commentary by Pacheco, p. 1617.

This article is highlighted in the In This Issue feature, p. 1601
Data from Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial
Authors: Riely Gregory J. , Neal Joel W. , Camidge D. Ross , Spira Alexander I. , Piotrowska Zofia , Costa Daniel B. , Tsao Anne S. , Patel Jyoti D. , Gadgeel Shirish M. , Bazhenova Lyudmila , Zhu Viola W. , West Howard L. , Mekhail Tarek , Gentzler Ryan D. , Nguyen Danny , Vincent Sylvie , Zhang Steven , Lin Jianchang , Bunn Veronica , Jin Shu , Li Shuanglian , Jänne Pasi A.
Published: April 2023

Abstract
Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.
Significance:
No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.

See related commentary by Pacheco, p. 1617.

This article is highlighted in the In This Issue feature, p. 1601
Data from Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy
Authors: Herrera Fernanda G. , Ronet Catherine , Ochoa de Olza Maria , Barras David , Crespo Isaac , Andreatta Massimo , Corria-Osorio Jesus , Spill Aodrenn , Benedetti Fabrizio , Genolet Raphael , Orcurto Angela , Imbimbo Martina , Ghisoni Eleonora , Navarro Rodrigo Blanca , Berthold Dominik R. , Sarivalasis Apostolos , Zaman Khalil , Duran Rafael , Dromain Clarisse , Prior John , Schaefer Niklaus , Bourhis Jean , Dimopoulou Georgia , Tsourti Zoi , Messemaker Marius , Smith Thomas , Warren Sarah E. , Foukas Periklis , Rusakiewicz Sylvie , Pittet Mikaël J. , Zimmermann Stefan , Sempoux Christine , Dafni Urania , Harari Alexandre , Kandalaft Lana E. , Carmona Santiago J. , Dangaj Laniti Denarda , Irving Melita , Coukos George
Published: April 2023

Abstract
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell–infiltrated tumors.
Significance:
Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.

This article is highlighted in the In This Issue feature, p. 1
Data from Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer
Authors: Ciampricotti Metamia , Karakousi Triantafyllia , Richards Allison L. , Quintanal-Villalonga Àlvaro , Karatza Angeliki , Caeser Rebecca , Costa Emily A. , Allaj Viola , Manoj Parvathy , Spainhower Kyle B. , Kombak Faruk E. , Sanchez-Rivera Francisco J. , Jaspers Janneke E. , Zavitsanou Anastasia-Maria , Maddalo Danilo , Ventura Andrea , Rideout William M. , Akama-Garren Elliot H. , Jacks Tyler , Donoghue Mark T.A. , Sen Triparna , Oliver Trudy G. , Poirier John T. , Papagiannakopoulos Thales , Rudin Charles M.
Published: April 2023

Abstract
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf–Mycl-driven mouse model of SCLC. RLF–MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF–MYCL genetically engineered mouse model displayed gene expression similarities with human RLF–MYCL SCLC. Together, our studies support RLF–MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.
Significance:
The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF–MYCL gene fusion by developing a Rlf–Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis.

This article is highlighted in the In This Issue feature, p. 2945
Data from Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
Authors: Foggetti Giorgia , Li Chuan , Cai Hongchen , Hellyer Jessica A. , Lin Wen-Yang , Ayeni Deborah , Hastings Katherine , Choi Jungmin , Wurtz Anna , Andrejka Laura , Maghini Dylan G. , Rashleigh Nicholas , Levy Stellar , Homer Robert , Gettinger Scott N. , Diehn Maximilian , Wakelee Heather A. , Petrov Dmitri A. , Winslow Monte M. , Politi Katerina
Published: April 2023

Abstract
In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2—the strongest drivers of growth in a KRAS-driven model—reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment.
Significance:
By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.

This article is highlighted in the In This Issue feature, p. 1601
Data from Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer
Authors: Vernieri Claudio , Fucà Giovanni , Ligorio Francesca , Huber Veronica , Vingiani Andrea , Iannelli Fabio , Raimondi Alessandra , Rinchai Darawan , Frigè Gianmaria , Belfiore Antonino , Lalli Luca , Chiodoni Claudia , Cancila Valeria , Zanardi Federica , Ajazi Arta , Cortellino Salvatore , Vallacchi Viviana , Squarcina Paola , Cova Agata , Pesce Samantha , Frati Paola , Mall Raghvendra , Corsetto Paola Antonia , Rizzo Angela Maria , Ferraris Cristina , Folli Secondo , Garassino Marina Chiara , Capri Giuseppe , Bianchi Giulia , Colombo Mario Paolo , Minucci Saverio , Foiani Marco , Longo Valter Daniel , Apolone Giovanni , Torri Valter , Pruneri Giancarlo , Bedognetti Davide , Rivoltini Licia , de Braud Filippo
Published: April 2023

Abstract
In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments.
Significance:
Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs. Phase II/III clinical trials are needed to investigate FMD antitumor activity/efficacy.

This article is highlighted in the In This Issue feature, p. 1
Data from TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin
Authors: Torres-Ayuso Pedro , An Elvira , Nyswaner Katherine M. , Bensen Ryan C. , Ritt Daniel A. , Specht Suzanne I. , Das Sudipto , Andresson Thorkell , Cachau Raul E. , Liang Roger J. , Ries Amy L. , Robinson Christina M. , Difilippantonio Simone , Gouker Brad , Bassel Laura , Karim Baktiar O. , Miller Chad J. , Turk Benjamin E. , Morrison Deborah K. , Brognard John
Published: April 2023

Abstract
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacologic inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC.
Significance:
Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC.

This article is highlighted in the In This Issue feature, p. 1307
Data from PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry
Authors: Patel Amish J. , Warda Sarah , Maag Jesper L.V. , Misra Rohan , Miranda-Román Miguel A. , Pachai Mohini R. , Lee Cindy J. , Li Dan , Wang Naitao , Bayshtok Gabriella , Fishinevich Eve , Meng Yinuo , Wong Elissa W.P. , Yan Juan , Giff Emily , Pappalardi Melissa B. , McCabe Michael T. , Fletcher Jonathan A. , Rudin Charles M. , Chandarlapaty Sarat , Scandura Joseph M. , Koche Richard P. , Glass Jacob L. , Antonescu Cristina R. , Zheng Deyou , Chen Yu , Chi Ping
Published: April 2023

Abstract
Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor–mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)–dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy.
Significance:
PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context–specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity.

See related commentary by Guil and Esteller, p. 2020.

This article is highlighted in the In This Issue feature, p. 2007
Data from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Authors: Savas Peter , Lo Louisa L. , Luen Stephen J. , Blackley Elizabeth F. , Callahan Jason , Moodie Kate , van Geelen Courtney T. , Ko Yi-An , Weng Chen-Fang , Wein Lironne , Silva Maria João , Bujak Andjelija Zivanovic , Yeung Miriam M. , Ftouni Sarah , Hicks Rodney J. , Francis Prudence A. , Lee Chee Khoon , Dawson Sarah-Jane , Loi Sherene
Published: April 2023

Abstract
There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER+) HER2− and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2− and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083–0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, P = 0.003).
Significance:
Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting.

This article is highlighted in the In This Issue feature, p. 2007
Data from Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements
Authors: Schram Alison M. , Odintsov Igor , Espinosa-Cotton Madelyn , Khodos Inna , Sisso Whitney J. , Mattar Marissa S. , Lui Allan J.W. , Vojnic Morana , Shameem Sara H. , Chauhan Thrusha , Torrisi Jean , Ford Jim , O'Connor Marie N. , Geuijen Cecile A.W. , Schackmann Ron C.J. , Lammerts van Bueren Jeroen J. , Wasserman Ernesto , de Stanchina Elisa , O'Reilly Eileen M. , Ladanyi Marc , Drilon Alexander , Somwar Romel
Published: April 2023

Abstract
NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity–enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion–positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion–positive metastatic cancer were treated with Zeno. Two patients with ATP1B1–NRG1–positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74–NRG1-positive non–small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion–positive cancers.
Significance:
NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion–positive cancers and is thus an effective therapeutic strategy.

This article is highlighted in the In This Issue feature, p. 1171
Data from KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs
Authors: Yan Fangxue , Li Jinyang , Milosevic Jelena , Petroni Ricardo , Liu Suying , Shi Zhennan , Yuan Salina , Reynaga Janice M. , Qi Yuwei , Rico Joshua , Yu Sixiang , Liu Yiman , Rokudai Susumu , Palmisiano Neil , Meyer Sara E. , Sung Pamela J. , Wan Liling , Lan Fei , Garcia Benjamin A. , Stanger Ben Z. , Sykes David B. , Blanco M. Andrés
Published: April 2023

Abstract
Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML.
Significance:
AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML.

This article is highlighted in the In This Issue feature, p. 587
Data from Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer
Authors: Ravichandran Mirunalini , Hu Jingjie , Cai Charles , Ward Nathan P. , Venida Anthony , Foakes Callum , Kuljanin Miljan , Yang Annan , Hennessey Connor J. , Yang Yang , Desousa Brandon R. , Rademaker Gilles , Staes Annelot A.L. , Cakir Zeynep , Jain Isha H. , Aguirre Andrew J. , Mancias Joseph D. , Shen Yin , DeNicola Gina M. , Perera Rushika M.
Published: April 2023

Abstract
The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS–MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron–sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS–MAPK inhibition.
Significance:
Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy–lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS–MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency.

See related commentary by Jain and Amaravadi, p. 2023.

See related article by Santana-Codina et al., p. 2180.

This article is highlighted in the In This Issue feature, p. 2007
Data from Human Colon Cancer–Derived Clostridioides difficile Strains Drive Colonic Tumorigenesis in Mice
Authors: Drewes Julia L. , Chen Jie , Markham Nicholas O. , Knippel Reece J. , Domingue Jada C. , Tam Ada J. , Chan June L. , Kim Lana , McMann Madison , Stevens Courtney , Dejea Christine M. , Tomkovich Sarah , Michel John , White James R. , Mohammad Fuad , Campodónico Victoria L. , Heiser Cody N. , Wu Xinqun , Wu Shaoguang , Ding Hua , Simner Patricia , Carroll Karen , Shrubsole Martha J. , Anders Robert A. , Walk Seth T. , Jobin Christian , Wan Fengyi , Coffey Robert J. , Housseau Franck , Lau Ken S. , Sears Cynthia L.
Published: April 2023

Abstract
Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of colorectal cancer patient–derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and protumorigenic mucosal immune responses marked by the infiltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of colorectal cancer in patients.
Significance:
Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric pathogen C. difficile is a previously unrecognized contributor to colonic tumorigenesis.

See related commentary by Jain and Dudeja, p. 1838.

This article is highlighted in the In This Issue feature, p. 1825
Data from Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma
Authors: Jackson Zachary , Hong Changjin , Schauner Robert , Dropulic Boro , Caimi Paolo F. , de Lima Marcos , Giraudo Maria Florencia , Gupta Kalpana , Reese Jane S. , Hwang Tae Hyun , Wald David N.
Published: April 2023

Abstract
Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL.
Significance:
This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone.

This article is highlighted in the In This Issue feature, p. 1825
Data from Cancer-Causative Mutations Occurring in Early Embryogenesis
Authors: Pareja Fresia , Ptashkin Ryan N. , Brown David N. , Derakhshan Fatemeh , Selenica Pier , da Silva Edaise M. , Gazzo Andrea M. , Da Cruz Paula Arnaud , Breen Kelsey , Shen Ronglai , Marra Antonio , Zehir Ahmet , Benayed Ryma , Berger Michael F. , Ceyhan-Birsoy Ozge , Jairam Sowmya , Sheehan Margaret , Patel Utsav , Kemel Yelena , Casanova-Murphy Jacklyn , Schwartz Christopher J. , Vahdatinia Mahsa , Comen Elizabeth , Borsu Laetitia , Pei Xin , Riaz Nadeem , Abramson David H. , Weigelt Britta , Walsh Michael F. , Hadjantonakis Anna-Katerina , Ladanyi Marc , Offit Kenneth , Stadler Zsofia K. , Robson Mark E. , Reis-Filho Jorge S. , Mandelker Diana
Published: April 2023

Abstract
Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers.
Significance:
Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring.

See related commentary by Liggett and Sankaran, p. 889.

This article is highlighted in the In This Issue feature, p. 873