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. 2023 Oct 28;14(1):6895.
doi: 10.1038/s41467-023-42585-9.

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing

Ryan N Ptashkin #  1   2 , Mark D Ewalt #  3 , Gowtham Jayakumaran  1   4 , Iwona Kiecka  1 , Anita S Bowman  1 , JinJuan Yao  1 , Jacklyn Casanova  1 , Yun-Te David Lin  1 , Kseniya Petrova-Drus  1 , Abhinita S Mohanty  1 , Ruben Bacares  1 , Jamal Benhamida  1 , Satshil Rana  1 , Anna Razumova  1 , Chad Vanderbilt  1 , Anoop Balakrishnan Rema  1 , Ivelise Rijo  1 , Julie Son-Garcia  1 , Ino de Bruijn  5 , Menglei Zhu  1 , Sean Lachhander  1 , Wei Wang  1 , Mohammad S Haque  1 , Venkatraman E Seshan  6 , Jiajing Wang  1 , Ying Liu  1 , Khedoudja Nafa  1 , Laetitia Borsu  1 , Yanming Zhang  1 , Umut Aypar  1 , Sarah P Suehnholz  5 , Debyani Chakravarty  1 , Jae H Park  7 , Omar Abdel-Wahab  5   7 , Anthony R Mato  7 , Wenbin Xiao  1 , Mikhail Roshal  1 , Mariko Yabe  1 , Connie Lee Batlevi  7 , Sergio Giralt  7 , Gilles Salles  7 , Raajit Rampal  1 , Martin Tallman  7   8 , Eytan M Stein  7 , Anas Younes  7   9 , Ross L Levine  5   7 , Miguel-Angel Perales  7   10 , Marcel R M van den Brink  5   7 , Ahmet Dogan  1 , Marc Ladanyi  1 , Michael F Berger  1   5 , A Rose Brannon  1 , Ryma Benayed  1   9 , Ahmet Zehir #  11   12 , Maria E Arcila #  13
Affiliations

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing

Ryan N Ptashkin et al. Nat Commun. .

Abstract

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.

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Conflict of interest statement

The authors declare the following competing interests: Ryan N. Ptashkin is an employee of C2i Genomics. Gowtham Jayakumaran is an employee of Guardant Health. Chad Vanderbilt reports intellectual property rights and equity interest in Paige.AI, Inc. Menglei Zhu has received advisory or consulting fees from Leica Biosystems. Jae Park has received advisory or consulting fees from Allogene, Amgen, Artiva, Autolus, BMS, Curocel, Incyte, InnatePharma, Kite Pharma, Kura Oncology, Minerva, Novartis, Pfizer, PrecisionBio, Servier, and served on a data monitoring committee for Affyimmune, BrightPharma and Intellia. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen; is on the Scientific Advisory Board of Pfizer Boulder, Envisagenics Inc., and AIChemy; and has received prior research funding from H3B Biomedicine, Loxo/Lilly, and Nurix Therapeutics. Anthony Mato has received research funding from TG Therapeutics, Pharmacyclics, AbbVie, Johnson and Johnson, Astra Zeneca, DTRM BioPharma, BeiGene, Genentech, Genmab Janssen, LOXO, Nurix, Octopharma, Pfizer and has received honoraria from TG Therapeutics, Pharmacyclics LLC, AbbVie, Adaptive Biotechnologies, Johnson and Johnson AcertaDTRM BioPharma, Nurix, AstraZeneca BeiGene Genentech Janssen LOXO, Curio, Dava, Octopharma, Genmab, BMS, Medscape, PER, PerView. Mikhail Roshal has received research funding from Roche, NGM, and Beat AML and has served on an advisory board and holds stock/stock options in Auron Therapeutics. Mariko Yabe has served as a consultant for Janssen R&D. Connie Batlevi has received advisory or consulting fees from ADC Therapeutics, AbbVie, Bristol-Myers Squibb, Dava Oncology, Defined Health, Epizyme, Gerson Lehrman Group, Juno Therapeutics, Karyopharm, Kite Pharmaceuticals, LifeSci Capital, LLC, Medscape, MorphoSys AG, NeuroAxis LLC, Seattle Genetics, Skipta LLC, TG Therapeutics, Inc, Touch Independent Medical Education Ltd, and Treeline Biosciences, Inc., and reports ownership/equity interest in Bristol-Myers Squibb, Moderna, Inc., Novavax, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., and Viatris Inc. Sergio Giralt has received advisory or consulting fees from Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen Research & Development, LLC, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Inc., Physicians’ Education Resource, Sanofi US Services Inc., TRM Oncology, and Xcenda. Gilles Salles has received advisory or consulting fees from Abbvie, Beigene, Bayer, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Ipsen, Janssen, Kite/Gilead, Loxo, Milteniy, Molecular Partners, Morphosys, Nordic Nanovector, Novartis, Rapt, Regeneron, and Takeda, and reports equity interest in Owkin. Raajit Rampal has received advisory or consulting fees from Constellation, Incyte, Celgene/BMS, Novartis, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, Galecto, PharmaEssentia, AbbVie, Sierra Oncology,Servier, and Disc Medicines; and research funding from Incyte, Constellation, and Stemline. Eytan Stein has received advisory or consulting fees from AbbVie, Agios Pharmaceuticals, Bristol-Myers Squibb, CTI BioPharma Corp., Calithera, Celgene, Epizyme, Genentech, Genesis Therapeutics, Gilead Pharmaceutical, Janssen Pharmaceuticals, Inc., Jazz Pharmaceuticals, Kronos Bio, Inc, Kura Oncology, Neoleukin Therapeutics, Inc., Novartis Pharmaceuticals Corporation, PinotBio, Inc., Servier, Syndax, and Takeda Millennium, and reports ownership/equity interests in Auron Therapeutics, Inc. Anas Younes is an employee of AstraZeneca. Ross Levine is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Syndax. Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics and Isoplexis for which he receives equity support; receives research support from Ajax and Abbvie; has consulted for Incyte, Janssen, Morphosys and Novartis; and has received honoraria from Astra Zeneca and Kura for invited lectures. Miguel Perales reports honoraria from Abbvie, Allovir, Astellas, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, OrcaBio, Takeda, and VectivBio AG, Vor Biopharma; serves on DSMBs for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier, and the scientific advisory board of NexImmune; has ownership interests in NexImmune and Omeros; and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. Marcel van den Brink has received advisory or consulting fees from Ceramedix, DKMS, Da Volterra, Garuda Therapeutics, GlaxoSmithKline, LyGenesis, Inc., Vor Biopharma, Pluto Immunotherapeutics, Rheos Medicines, Inc, Seres Therapeutics, Frazier Healthcare Partners, and Notch Therapeutics and has ownership/equity interests in Pluto Immunotherapeutics, Seres Therapeutics, ThymoFox, Inc., and Notch Therapeutics and is in a fiduciary role/position for DKMS, holds intellectual property rights with Juno Therapeutics and Seres Therapeutics, and has received royalties from Wolters Kluwer. Ahmet Dogan has received advisory or consulting fees from Incyte, Loxo Oncology, and Physicians’ Education Resource and has received research funding from Roche and Takeda. Marc Ladanyi has received advisory or consulting fees from Takeda Oncology, Janssen Pharmaceuticals, AstraZeneca, ADC Therapeutics, Paige.AI, Merck, Bayer, and Lilly Oncology and has received research funding from Loxo Oncology, Helsinn Therapeutics, Merus NV, Elevation Oncology, and Rain Therapeutics. Michael Berger has received advisory or consulting fees from AstraZeneca, Eli Lilly and Company, and PetDx, Inc. A. Rose Brannon has ownership/equity interests in Johnson and Johnson. Ryma Benayed is an employee of AstraZeneca. Ahmet Zehir is an employee of AstraZeneca. Maria Arcila has received advisory or consulting fees from Axis Medical Education, Clinical Education Alliance, LLC, Merck Sharp & Dohme, PeerView Institute for Medical Education (PVI), Physicians’ Education Resource, RMEI Medical Education, LLC, and Roche. The following Authors declare no competing interests: Mark D. Ewalt, Iwona Kiecka, Anita S. Bowman, JinJuan Yao, Jacklyn Casanova, Yun-Te David Lin, Kseniya Petrova-Drus, Abhinita S. Mohanty, Ruben Bacares, Jamal Benhamida, Satshil Rana, Anna Razumova, Anoop Balakrishnan Rema, Ivelise Rijo, Julie Son-Garcia, Ino de Bruijn, Sean Lachhander, Wei Wang, Mohammad S. Haque, Venkatraman E. Seshan, Jiajing Wang, Ying Liu, Khedoudja Nafa, Laetitia Borsu, Yanming Zhang, Umut Aypar, Sarah P. Suehnholz, Debyani Chakravarty, Wenbin Xiao, and Martin Tallman.

Figures

Fig. 1
Fig. 1. MSK-IMPACT Heme workflow, sample distribution, and somatic mutation distribution in normal tissues.
a Overview of the MSK-IMPACT Heme clinical workflow. Distribution of (b) tumor types profiled by MSK-IMPACT Heme including (c) patient sex by tumor type, and (d) patient-matched normal sample type used for analysis. (e) Variant allele frequency (VAF) of somatic mutations in tumor and matched normal tissues. f Heatmap showing the percentage of patients with tumor somatic mutations observed in matched nail or saliva tissues. The first number in each cell indicates the number of patients where a tumor mutation is observed in the normal comparator, and the second number indicates the total number of patients profiled with the corresponding normal. g Heatmap showing the distribution of genes, where a somatic mutation is found in the tumor and the rate of observing the same variant in the matched normal, indicated with the color-scale. Gray cells indicate that for a given tumor type, either a somatic alteration was not detected in the tumor in that gene or the matched normal sample type (nail or saliva, shown above the heatmap) was not sequenced. Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Example patient case highlighting ability of IMPACT-HEME and donor/host matching to detect complex mutations and allele-specific copy number in a post-transplant chimeric patient.
a The distribution of VAF of somatic mutations, host SNPs, and donor SNPs. b Detection of CN-LOH of chromosome 13q, including FLT3. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Example case of utility for flow-sorted genomic analysis in a patient with AITL and an atypical plasma cell population.
a Somatic mutational profiles of T cells, plasma cells and unsorted bone marrow highlighting distinct mutation patterns in different populations. b ARID5B structural rearrangement (inversion) detected only in the T cell population. c The unique somatic copy number alteration profiles of sorted T cells and plasma cells compared to unsorted bone marrow further support that these populations are clonally distinct. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Somatic genomic landscape of hematologic malignancies profiled by MSK-IMPACT HEME.
a Recurrent somatic alterations across common tumor types and pathways in lymphoid and myeloid neoplasms. b Bars indicate the percentage of cases harboring different classes of genomic alterations, with integration of mutation and allele specific copy number status. c Genome-wide somatic copy number (SCNA) profiles in main tumor types. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Mutation signature analysis in MSK-IMPACT Heme cohort.
a Prevalence of somatic mutations across main tumor types and the mutational spectra. The median TMB for each tumor type is indicated by a red line. b Mutational signatures, sorted by dominant signature for the 261 tumors with elevated mutation burden (>12.9 Mut/Mb). Source data are provided as a Source Data file.
Fig. 6
Fig. 6. Clinical actionability of MSK-IMPACT Heme results.
a Percentage of samples across all tumor types that harbor a mutation considered clinically actionable according to the OncoKB therapeutic levels of evidence. b Distribution of IPSS-M algorithm calculated scores and risk categories identified in the 101 cases in the MSK-IMPACT Heme cohort. In the box plots, the central line represents the median; the box corresponds to 25–75% quartiles; the upper whisker extends to the largest value no farther than 1.5× IQR; and the lower whisker extends from the 25% quartile to the smallest value no farther than 1.5× IQR. c The number of patients in the MSK-IMPACT Heme MDS cohort with the given genomic alteration and their stratification into IPSS-M risk categories. Source data are provided as a Source Data file.
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