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1. SPOT/Dx Pilot Reanalysis and College of American Pathologists Proficiency Testing for KRAS and NRAS Demonstrate Excellent Laboratory Performance

Author

Zehir, Ahmet, Nardi, Valentina, Konnick, Eric Q., Lockwood, Christina M., Long, Thomas A., Sidiropoulos, Nikoletta, Souers, Rhona J., Vasalos, Patricia, Lindeman, Neal I., and Moncur, Joel T.

Subjects
United States. Food and Drug Administration, Therapeutics, Physiological, Physical therapy, Medical care -- Quality management, Panitumumab, Health
Abstract

* Context.--The Sustainable Predictive Oncology Therapeutics and Diagnostics quality assurance pilot study (SPOT/ Dx pilot) on molecular oncology next-generation sequencing (NGS) reportedly demonstrated performance limitations of NGS laboratory-developed tests, including discrepancies with a US Food and Drug Administration-approved companion diagnostic. The SPOT/Dx pilot methods differ from those used in proficiency testing (PT) programs. Objective.--To reanalyze SPOT/Dx pilot data using PT program methods and compare to PT program data. Design.--The College of American Pathologists (CAP) Molecular Oncology Committee reanalyzed SPOT/Dx pilot data applying PT program methods, adjusting for confounding conditions, and compared them to CAP NGS PT program performance (2019-2022). Results.--Overall detection rates of KRAS and NRAS single-nucleotide variants (SNVs) and multinucleotide variants (MNVs) by SPOT/Dx pilot laboratories were 96.8% (716 of 740) and 81.1% (129 of 159), respectively. In CAP PT programs, the overall detection rates for the same SNVs and MNVs were 97.2% (2671 of 2748) and 91.8% (1853 of 2019), respectively. In 2022, the overall detection rate for 5 KRAS and NRAS MNVs in CAP PT programs was 97.3% (1161 of 1193). Conclusions.--CAP PT program data demonstrate that laboratories consistently have high detection rates for KRAS and NRAS variants. The SPOT/Dx pilot has multiple design and analytic differences with established PT programs. Reanalyzed pilot data that adjust for confounding conditions demonstrate that laboratories proficiently detect SNVs and less successfully detect rare to never-observed MNVs. The SPOT/Dx pilot results are not generalizable to all molecular oncology testing and should not be used to market products or change policy affecting all molecular oncology testing. (Arch Pathol Lab Med. 2024;148:139-148; doi: 10.5858/arpa.2023-0322-CP, Proficiency testing (PT) constitutes a critical component of clinical diagnostics, ensuring laboratories can identify the biomarkers that their validated assays are designed to detect. It is also an essential part [...]

Published
2024
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2. Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities

Author

Wang, Tao, Askan, Gokce, Ozcan, Kerem, Rana, Satshil, Zehir, Ahmet, Bhanot, Umeshkumar K., Yantiss, Rhonda K., Rao, Deepthi S., Wahl, Samuel J., Bagci, Pelin, Balci, Serdar, Balachandran, Vinod, Jarnagin, William R., Adsay, N. Volkan, Klimstra, David S., and Basturk, Olca

Subjects
Gene mutations, Tumors, Tumor proteins, Dysplasia, Health, World Health Organization
Abstract

* Context.--Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. Objective.--To investigate their morphologic, immunohistochemical, and molecular features. Design.--Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. Results.--The mean age at diagnosis was 69 years (4281 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinaltype IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Conclusions.--Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous. (Arch Pathol Lab Med. 2023;147:1390-1401; doi: 10.5858/arpa.2022-0343-OA), Tumoral (grossly visible) intraductal neoplasms of the bile ducts are rare tumors, which exhibit variable histomorphology and behavior. The nomenclature for these biliary neoplasms has been inconsistent, and they have [...]

Published
2023
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3. Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations of Potential Biologic and Therapeutic Relevance

Author

Ogura, Koichi, Elkrief, Arielle, Bowman, Anita S, Koche, Richard P, de Stanchina, Elisa, Benayed, Ryma, Mauguen, Audrey, Mattar, Marissa S, Khodos, Inna, Meyers, Paul A, Healey, John H, Tap, William D, Hameed, Meera, Zehir, Ahmet, Shukla, Neerav, Sawyers, Charles, Bose, Rohit, Slotkin, Emily, and Ladanyi, Marc

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Pediatric Cancer, Genetics, Human Genome, Pediatric, Clinical Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adult, Biological Products, Genomics, Humans, Mutation, Neuroectodermal Tumors, Primitive, Peripheral, Prospective Studies, Receptor, Fibroblast Growth Factor, Type 1, Repressor Proteins, Sarcoma, Ewing, United States, Oncology and carcinogenesis
Abstract

PurposeEwing sarcoma (ES) is a primitive sarcoma defined by EWSR1-ETS fusions as the primary driver alteration. To better define the landscape of cooperating secondary genetic alterations in ES, we analyzed clinical genomic profiling data of 113 patients with ES, a cohort including more adult patients (> 18 years) and more patients with advanced stage at presentation than previous genomic cohorts.MethodsThe data set consisted of patients with ES prospectively tested with the US Food and Drug Administration-cleared Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets large panel, hybrid capture-based next-generation sequencing assay. To assess the functional significance of ERF loss, we generated ES cell lines with increased expression of ERF and lines with knockdown of ERF. We assessed cell viability, clonogenic growth, and motility in these ES lines and performed transcriptomic and epigenetic analyses. Finally, we validated our findings in vivo using cell line xenografts.ResultsNovel subsets were defined by recurrent secondary alterations in ERF, which encodes an ETS domain transcriptional repressor, in 7% of patients (five truncating mutations, one deep deletion, and two missense mutations) and in FGFR1 in another 2.7% (one amplification and two known activating mutations). ERF alterations were nonoverlapping with STAG2 alterations. In vitro, increased expression of ERF decreased tumor cell growth, colony formation, and motility in two ES cell lines, whereas ERF loss induced cellular proliferation and clonogenic growth. Transcriptomic analysis of cell lines with ERF loss revealed an increased expression of genes and pathways associated with aggressive tumor biology, and epigenetic, chromatin-based studies revealed that ERF competes with EWSR1-FLI1 at ETS-binding sites.ConclusionOur findings open avenues to new insights into ES pathobiology and to novel therapeutic approaches in a subset of patients with ES.

Published
2022

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

Author

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

Published
2023
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6. Microsatellite Instability and Mismatch Repair Deficiency Define a Distinct Subset of Lung Cancers Characterized by Smoking Exposure, High Tumor Mutational Burden, and Recurrent Somatic MLH1 Inactivation

Author

Yang, Soo-Ryum, Gedvilaite, Erika, Ptashkin, Ryan, Chang, Jason, Ziegler, John, Mata, Douglas A., Villafania, Liliana B., Nafa, Khedoudja, Hechtman, Jaclyn F., Benayed, Ryma, Zehir, Ahmet, Benhamida, Jamal, Arcila, Maria E., Mandelker, Diana, Rudin, Charles M., Paik, Paul K., Drilon, Alexander, Schoenfeld, Adam J., and Ladanyi, Marc

Published
2024
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7. The context-specific role of germline pathogenicity in tumorigenesis

Author

Srinivasan, Preethi, Bandlamudi, Chaitanya, Jonsson, Philip, Kemel, Yelena, Chavan, Shweta S, Richards, Allison L, Penson, Alexander V, Bielski, Craig M, Fong, Christopher, Syed, Aijazuddin, Jayakumaran, Gowtham, Prasad, Meera, Hwee, Jason, Sumer, Selcuk Onur, de Bruijn, Ino, Li, Xiang, Gao, JianJiong, Schultz, Nikolaus, Cambria, Roy, Galle, Jesse, Mukherjee, Semanti, Vijai, Joseph, Cadoo, Karen A, Carlo, Maria I, Walsh, Michael F, Mandelker, Diana, Ceyhan-Birsoy, Ozge, Shia, Jinru, Zehir, Ahmet, Ladanyi, Marc, Hyman, David M, Zhang, Liying, Offit, Kenneth, Robson, Mark E, Solit, David B, Stadler, Zsofia K, Berger, Michael F, and Taylor, Barry S

Subjects
Biological Sciences, Genetics, Human Genome, Rare Diseases, Cancer, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Carcinogenesis, DNA Copy Number Variations, DNA Mismatch Repair, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Humans, Neoplasms, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.

Published
2021

8. Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors

Author

Fiala, Elise M, Jayakumaran, Gowtham, Mauguen, Audrey, Kennedy, Jennifer A, Bouvier, Nancy, Kemel, Yelena, Fleischut, Megan Harlan, Maio, Anna, Salo-Mullen, Erin E, Sheehan, Margaret, Arnold, Angela G, Latham, Alicia, Carlo, Maria I, Cadoo, Karen, Murkherjee, Semanti, Slotkin, Emily K, Trippett, Tanya, Glade Bender, Julia, Meyers, Paul A, Wexler, Leonard, Dela Cruz, Filemon S, Cheung, Nai-Kong, Basu, Ellen, Kentsis, Alex, Ortiz, Michael, Francis, Jasmine H, Dunkel, Ira J, Khakoo, Yasmin, Gilheeney, Stephen, Farouk Sait, Sameer, Forlenza, Christopher J, Sulis, Maria, Karajannis, Matthias, Modak, Shakeel, Gerstle, Justin T, Heaton, Todd E, Roberts, Stephen, Yang, Ciyu, Jairam, Sowmya, Vijai, Joseph, Topka, Sabine, Friedman, Danielle N, Stadler, Zsofia K, Robson, Mark, Berger, Michael F, Schultz, Nikolaus, Ladanyi, Marc, O’Reilly, Richard J, Abramson, David H, Ceyhan-Birsoy, Ozge, Zhang, Liying, Mandelker, Diana, Shukla, Neerav N, Kung, Andrew L, Offit, Kenneth, Zehir, Ahmet, and Walsh, Michael F

Subjects
Rare Diseases, Genetic Testing, Genetics, Pediatric, Human Genome, Clinical Research, Pediatric Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Child, Genetic Predisposition to Disease, Germ Cells, Germ-Line Mutation, Humans, Neoplasms, Prospective Studies
Abstract

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

Published
2021

9. Single-cell mutation analysis of clonal evolution in myeloid malignancies

Author

Miles, Linde A, Bowman, Robert L, Merlinsky, Tiffany R, Csete, Isabelle S, Ooi, Aik T, Durruthy-Durruthy, Robert, Bowman, Michael, Famulare, Christopher, Patel, Minal A, Mendez, Pedro, Ainali, Chrysanthi, Demaree, Benjamin, Delley, Cyrille L, Abate, Adam R, Manivannan, Manimozhi, Sahu, Sombeet, Goldberg, Aaron D, Bolton, Kelly L, Zehir, Ahmet, Rampal, Raajit, Carroll, Martin P, Meyer, Sara E, Viny, Aaron D, and Levine, Ross L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Biotechnology, Rare Diseases, Genetics, Clinical Research, Hematology, Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Cell Separation, Clone Cells, DNA Mutational Analysis, Humans, Immunophenotyping, Mutation, Myeloproliferative Disorders, Single-Cell Analysis, General Science & Technology
Abstract

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1-3. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.

Published
2020

10. Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Author

Bolton, Kelly, Ptashkin, Ryan, Gao, Teng, Braunstein, Lior, Devlin, Sean, Kelly, Daniel, Patel, Minal, Berthon, Antonin, Syed, Aijazuddin, Yabe, Mariko, Coombs, Catherine, Caltabellotta, Nicole, Walsh, Mike, Offit, Kenneth, Stadler, Zsofia, Mandelker, Diana, Schulman, Jessica, Patel, Akshar, Philip, John, Bernard, Elsa, Gundem, Gunes, Ossa, Juan, Levine, Max, Martinez, Juan, Farnoud, Noushin, Glodzik, Dominik, Li, Sonya, Robson, Mark, Lee, Choonsik, Pharoah, Paul, Stopsack, Konrad, Spitzer, Barbara, Mantha, Simon, Fagin, James, Boucai, Laura, Gibson, Christopher, Ebert, Benjamin, Young, Andrew, Druley, Todd, Takahashi, Koichi, Gillis, Nancy, Ball, Markus, Padron, Eric, Hyman, David, Baselga, Jose, Norton, Larry, Gardos, Stuart, Klimek, Virginia, Scher, Howard, Bajorin, Dean, Paraiso, Eder, Benayed, Ryma, Arcila, Maria, Ladanyi, Marc, Solit, David, Berger, Michael, Tallman, Martin, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Diaz, Luis, Levine, Ross, Morton, Lindsay, Zehir, Ahmet, and Papaemmanuil, Elli

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Cell Transformation, Neoplastic, Child, Child, Preschool, Clonal Evolution, Clonal Hematopoiesis, Cohort Studies, Female, Genetic Fitness, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Male, Middle Aged, Models, Biological, Mutation, Neoplasms, Neoplasms, Second Primary, Selection, Genetic, Young Adult
Abstract

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Published
2020

11. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer

Author

Jee, Justin, Lebow, Emily S., Yeh, Randy, Das, Jeeban P., Namakydoust, Azadeh, Paik, Paul K., Chaft, Jamie E., Jayakumaran, Gowtham, Rose Brannon, A., Benayed, Ryma, Zehir, Ahmet, Donoghue, Mark, Schultz, Nikolaus, Chakravarty, Debyani, Kundra, Ritika, Madupuri, Ramyasree, Murciano-Goroff, Yonina R., Tu, Hai-Yan, Xu, Chong-Rui, Martinez, Andrés, Wilhelm, Clare, Galle, Jesse, Daly, Bobby, Yu, Helena A., Offin, Michael, Hellmann, Matthew D., Lito, Piro, Arbour, Kathryn C., Zauderer, Marjorie G., Kris, Mark G., Ng, Kenneth K., Eng, Juliana, Preeshagul, Isabel, Victoria Lai, W., Fiore, John J., Iqbal, Afsheen, Molena, Daniela, Rocco, Gaetano, Park, Bernard J., Lim, Lee P., Li, Mark, Tong-Li, Candace, De Silva, Madhawa, Chan, David L., Diakos, Connie I., Itchins, Malinda, Clarke, Stephen, Pavlakis, Nick, Lee, Adrian, Rekhtman, Natasha, Chang, Jason, Travis, William D., Riely, Gregory J., Solit, David B., Gonen, Mithat, Rusch, Valerie W., Rimner, Andreas, Gomez, Daniel, Drilon, Alexander, Scher, Howard I., Shah, Sohrab P., Berger, Michael F., Arcila, Maria E., Ladanyi, Marc, Levine, Ross L., Shen, Ronglai, Razavi, Pedram, Reis-Filho, Jorge S., Jones, David R., Rudin, Charles M., Isbell, James M., and Li, Bob T.

Published
2022
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12. Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

Author

Ma, Xiaoxiao, Riaz, Nadeem, Samstein, Robert M., Lee, Mark, Makarov, Vladimir, Valero, Cristina, Chowell, Diego, Kuo, Fengshen, Hoen, Douglas, Fitzgerald, Conall W. R., Jiang, Hui, Alektiar, Jonathan, Alban, Tyler J., Juric, Ivan, Parthasarathy, Prerana Bangalore, Zhao, Yu, Sabio, Erich Y., Verma, Richa, Srivastava, Raghvendra M., Vuong, Lynda, Yang, Wei, Zhang, Xiao, Wang, Jingming, Chu, Lawrence K., Wang, Stephen L., Kelly, Daniel W., Pei, Xin, Chen, Jiapeng, Yaeger, Rona, Zamarin, Dmitriy, Zehir, Ahmet, Gönen, Mithat, Morris, Luc G. T., and Chan, Timothy A.

Published
2022
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13. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma

Author

Ho, Allen S, Ochoa, Angelica, Jayakumaran, Gowtham, Zehir, Ahmet, Mayor, Cristina Valero, Tepe, Justin, Makarov, Vladimir, Dalin, Martin G, He, Jie, Bailey, Mark, Montesion, Meagan, Ross, Jeffrey S, Miller, Vincent A, Chan, Lindsay, Ganly, Ian, Dogan, Snjezana, Katabi, Nora, Tsipouras, Petros, Ha, Patrick, Agrawal, Nishant, Solit, David B, Futreal, P Andrew, Naggar, Adel K El, Reis-Filho, Jorge S, Weigelt, Britta, Ho, Alan L, Schultz, Nikolaus, Chan, Timothy A, and Morris, Luc GT

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Clinical Research, Digestive Diseases, Good Health and Well Being, Adult, Carcinoma, Adenoid Cystic, Chromatin Assembly and Disassembly, Female, Genes, myb, Genomics, Humans, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Receptors, Notch, Salivary Gland Neoplasms, Telomerase, Head and neck cancer, Oncology, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).

Published
2019

14. Identification of Clonal Hematopoiesis Mutations in Solid Tumor Patients Undergoing Unpaired Next-Generation Sequencing Assays.

Author

Coombs, Catherine, Gillis, Nancy, Tan, Xianming, Berg, Jonathan, Ball, Markus, Balasis, Maria, Montgomery, Nathan, Bolton, Kelly, Parker, Joel, Mesa, Tania, Yoder, Sean, Hayward, Michele, Patel, Nirali, Richards, Kristy, Walko, Christine, Knepper, Todd, Soper, John, Weiss, Jared, Grilley-Olson, Juneko, Kim, William, Earp, H, Levine, Ross, Papaemmanuil, Elli, Zehir, Ahmet, Hayes, D, and Padron, Eric

Subjects
Adult, Aged, Biomarkers, Clonal Evolution, Computational Biology, Female, Genome-Wide Association Study, Hematopoiesis, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Neoplasms
Abstract

PURPOSE: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays. EXPERIMENTAL DESIGN: This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing. RESULTS: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. CONCLUSIONS: Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patients care.See related commentary by Pollyea, p. 5790.

Published
2018

15. Improved prediction of immune checkpoint blockade efficacy across multiple cancer types

Author

Chowell, Diego, Yoo, Seong-Keun, Valero, Cristina, Pastore, Alessandro, Krishna, Chirag, Lee, Mark, Hoen, Douglas, Shi, Hongyu, Kelly, Daniel W., Patel, Neal, Makarov, Vladimir, Ma, Xiaoxiao, Vuong, Lynda, Sabio, Erich Y., Weiss, Kate, Kuo, Fengshen, Lenz, Tobias L., Samstein, Robert M., Riaz, Nadeem, Adusumilli, Prasad S., Balachandran, Vinod P., Plitas, George, Ari Hakimi, A., Abdel-Wahab, Omar, Shoushtari, Alexander N., Postow, Michael A., Motzer, Robert J., Ladanyi, Marc, Zehir, Ahmet, Berger, Michael F., Gönen, Mithat, Morris, Luc G. T., Weinhold, Nils, and Chan, Timothy A.

Published
2022
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16. Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

Author

Ceyhan-Birsoy, Ozge, Jayakumaran, Gowtham, Kemel, Yelena, Misyura, Maksym, Aypar, Umut, Jairam, Sowmya, Yang, Ciyu, Li, Yirong, Mehta, Nikita, Maio, Anna, Arnold, Angela, Salo-Mullen, Erin, Sheehan, Margaret, Syed, Aijazuddin, Walsh, Michael, Carlo, Maria, Robson, Mark, Offit, Kenneth, Ladanyi, Marc, Reis-Filho, Jorge S., Stadler, Zsofia K., Zhang, Liying, Latham, Alicia, Zehir, Ahmet, and Mandelker, Diana

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

Author

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

Published
2022
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18. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing

Author

Cheng, Donavan T, Prasad, Meera, Chekaluk, Yvonne, Benayed, Ryma, Sadowska, Justyna, Zehir, Ahmet, Syed, Aijazuddin, Wang, Yan Elsa, Somar, Joshua, Li, Yirong, Yelskaya, Zarina, Wong, Donna, Robson, Mark E, Offit, Kenneth, Berger, Michael F, Nafa, Khedoudja, Ladanyi, Marc, and Zhang, Liying

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Cancer, Biotechnology, Prevention, Clinical Research, Genetic Testing, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Adenomatous Polyposis Coli Protein, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, BRCA2 Protein, Biomarkers, Tumor, Checkpoint Kinase 2, DNA Copy Number Variations, DNA Mutational Analysis, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Neoplasm Proteins, Neoplasms, Polymorphism, Single Nucleotide, Reproducibility of Results, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Medical Biochemistry and Metabolomics, Genetics & Heredity, Medical biochemistry and metabolomics
Abstract

BackgroundThe growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families.MethodsHere, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes. Output from hybridization-based capture was sequenced on an Illumina HiSeq 2500. A custom analysis pipeline was used to detect single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants (CNVs).ResultsMSK-IMPACT detected all germline variants in a set of 233 unique patient DNA samples, previously confirmed by previous single gene testing. Reproducibility of variant calls was demonstrated using inter- and intra- run replicates. Moreover, in 16 samples, we identified additional pathogenic mutations other than those previously identified through a traditional gene-by-gene approach, including founder mutations in BRCA1, BRCA2, CHEK2 and APC, and truncating mutations in TP53, TSC2, ATM and VHL.ConclusionsThis study highlights the importance of the NGS-based gene panel testing approach in comprehensively identifying germline variants contributing to cancer predisposition and simultaneous detection of somatic and germline alterations.

Published
2017

19. Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors

Author

Franch-Expósito, Sebastià, Mehine, Miika, Ptashkin, Ryan N., Bolton, Kelly L., Bandlamudi, Chaitanya, Srinivasan, Preethi, Zhang, Linda, Goodell, Margaret A., Gedvilaite, Erika, Menghrajani, Kamal, Sánchez-Vela, Pablo, Mandelker, Diana, Comen, Elizabeth, Norton, Larry, Benayed, Ryma, Gao, Teng, Papaemmanuil, Elli, Taylor, Barry, Levine, Ross, Offit, Kenneth, Stadler, Zsofia, Berger, Michael F., and Zehir, Ahmet

Published
2023
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20. Clinical Targeted Next-Generation Panel Sequencing Reveals MYC Amplification Is a Poor Prognostic Factor in Osteosarcoma

Author

Marinoff, Amanda E., Spurr, Liam F., Fong, Christina, Li, Yvonne Y., Forrest, Suzanne J., Ward, Abigail, Doan, Duong, Corson, Laura, Mauguen, Audrey, Pinto, Navin, Maese, Luke, Colace, Susan, Macy, Margaret E., Kim, AeRang, Sabnis, Amit J., Applebaum, Mark A., Laetsch, Theodore W., Glade-Bender, Julia, Weiser, Daniel A., Anderson, Megan, Crompton, Brian D., Meyers, Paul, Zehir, Ahmet, MacConaill, Laura, Lindeman, Neal, Nowak, Jonathan A., Ladanyi, Marc, Church, Alanna J., Cherniack, Andrew D., Shukla, Neerav, and Janeway, Katherine A.

Published
2023
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21. Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases

Author

da Silva, Edaise M., Fix, Daniel J., Sebastiao, Ana Paula Martins, Selenica, Pier, Ferrando, Lorenzo, Kim, Sarah H., Stylianou, Anthe, Da Cruz Paula, Arnaud, Pareja, Fresia, Smith, Evan S., Zehir, Ahmet, Konner, Jason A., Cadoo, Karen, Reis-Filho, Jorge S., Abu-Rustum, Nadeem R., Mueller, Jennifer J., Weigelt, Britta, and Park, Kay J.

Published
2021
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22. Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer

Author

Da Cruz Paula, Arnaud, DeLair, Deborah F., Ferrando, Lorenzo, Fix, Daniel J., Soslow, Robert A., Park, Kay J., Chiang, Sarah, Reis-Filho, Jorge S., Zehir, Ahmet, Donoghue, Mark T.A., Wu, Michelle, Brown, David N., Murali, Rajmohan, Friedman, Claire F., Zamarin, Dmitriy, Makker, Vicky, Mueller, Jennifer J., Leitao, Mario M., Jr, Abu-Rustum, Nadeem R., Aghajanian, Carol, and Weigelt, Britta

Published
2021
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23. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes.

Author

Coombs, Catherine, Zehir, Ahmet, Devlin, Sean, Kishtagari, Ashwin, Syed, Aijazuddin, Jonsson, Philip, Hyman, David, Solit, David, Robson, Mark, Baselga, José, Arcila, Maria, Ladanyi, Marc, Tallman, Martin, Levine, Ross, and Berger, Michael

Subjects
biological sciences, cancer, cancer genomics, diseases, genetics, health sciences, hematological cancer, hematological diseases, mutation, Aged, Clone Cells, Cohort Studies, Female, Genetic Association Studies, Hematologic Neoplasms, Hematopoiesis, Humans, Male, Middle Aged, Mutation, Risk Factors, Survival Analysis, Treatment Outcome
Abstract

Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

Published
2017

24. The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee

Author

Sholl, Lynette M., Hirsch, Fred R., Hwang, David, Botling, Johan, Lopez-Rios, Fernando, Bubendorf, Lukas, Mino-Kenudson, Mari, Roden, Anja C., Beasley, Mary Beth, Borczuk, Alain, Brambilla, Elisabeth, Chen, Gang, Chou, Teh-Ying, Chung, Jin-Haeng, Cooper, Wendy A., Dacic, Sanja, Lantuejoul, Sylvie, Jain, Deepali, Lin, Dongmei, Minami, Yuko, Moreira, Andre, Nicholson, Andrew G., Noguchi, Masayuki, Papotti, Mauro, Pelosi, Giuseppe, Poleri, Claudia, Rekhtman, Natasha, Tsao, Ming-Sound, Thunnissen, Erik, Travis, William, Yatabe, Yasushi, Yoshida, Akihiko, Daigneault, Jillian B., Zehir, Ahmet, Peters, Solange, Wistuba, Ignacio I., Kerr, Keith M., and Longshore, John W.

Published
2020
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27. Matched Molecular Profiling of Cell-Free DNA and Tumor Tissue in Patients With Advanced Clear Cell Renal Cell Carcinoma

Author

Kotecha, Ritesh R., Gedvilaite, Erika, Ptashkin, Ryan, Knezevic, Andrea, Murray, Samuel, Johnson, Ian, Shapnik, Natalie, Feldman, Darren R., Carlo, Maria I., Shah, Neil J., Dunigan, Marisa, Huberman, Kety, Benayed, Ryma, Zehir, Ahmet, Berger, Michael F., Ladanyi, Marc, Tsui, Dana W. Y., Motzer, Robert J., Lee, Chung-Han, and Voss, Martin H.

Published
2022
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28. Figure S1 from Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer

Author

Suehnholz, Sarah P., primary, Nissan, Moriah H., primary, Zhang, Hongxin, primary, Kundra, Ritika, primary, Nandakumar, Subhiksha, primary, Lu, Calvin, primary, Carrero, Stephanie, primary, Dhaneshwar, Amanda, primary, Fernandez, Nicole, primary, Xu, Benjamin W., primary, Arcila, Maria E., primary, Zehir, Ahmet, primary, Syed, Aijazuddin, primary, Brannon, A. Rose, primary, Rudolph, Julia E., primary, Paraiso, Eder, primary, Sabbatini, Paul J., primary, Levine, Ross L., primary, Dogan, Ahmet, primary, Gao, Jianjiong, primary, Ladanyi, Marc, primary, Drilon, Alexander, primary, Berger, Michael F., primary, Solit, David B., primary, Schultz, Nikolaus, primary, and Chakravarty, Debyani, primary

Published
2024
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29. Table S3 from Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer

Author

Suehnholz, Sarah P., primary, Nissan, Moriah H., primary, Zhang, Hongxin, primary, Kundra, Ritika, primary, Nandakumar, Subhiksha, primary, Lu, Calvin, primary, Carrero, Stephanie, primary, Dhaneshwar, Amanda, primary, Fernandez, Nicole, primary, Xu, Benjamin W., primary, Arcila, Maria E., primary, Zehir, Ahmet, primary, Syed, Aijazuddin, primary, Brannon, A. Rose, primary, Rudolph, Julia E., primary, Paraiso, Eder, primary, Sabbatini, Paul J., primary, Levine, Ross L., primary, Dogan, Ahmet, primary, Gao, Jianjiong, primary, Ladanyi, Marc, primary, Drilon, Alexander, primary, Berger, Michael F., primary, Solit, David B., primary, Schultz, Nikolaus, primary, and Chakravarty, Debyani, primary

Published
2024
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30. The association between tumor mutational burden and prognosis is dependent on treatment context

Author

Valero, Cristina, Lee, Mark, Hoen, Douglas, Wang, Jingming, Nadeem, Zaineb, Patel, Neal, Postow, Michael A., Shoushtari, Alexander N., Plitas, George, Balachandran, Vinod P., Smith, J. Joshua, Crago, Aimee M., Long Roche, Kara C., Kelly, Daniel W., Samstein, Robert M., Rana, Satshil, Ganly, Ian, Wong, Richard J., Hakimi, A. Ari, Berger, Michael F., Zehir, Ahmet, Solit, David B., Ladanyi, Marc, Riaz, Nadeem, Chan, Timothy A., Seshan, Venkatraman E., and Morris, Luc G. T.

Published
2021
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31. Clonal hematopoiesis is associated with risk of severe Covid-19

Author

Bolton, Kelly L., Koh, Youngil, Foote, Michael B., Im, Hogune, Jee, Justin, Sun, Choong Hyun, Safonov, Anton, Ptashkin, Ryan, Moon, Joon Ho, Lee, Ji Yeon, Jung, Jongtak, Kang, Chang Kyung, Song, Kyoung-Ho, Choe, Pyoeng Gyun, Park, Wan Beom, Kim, Hong Bin, Oh, Myoung-don, Song, Han, Kim, Sugyeong, Patel, Minal, Derkach, Andriy, Gedvilaite, Erika, Tkachuk, Kaitlyn A., Wiley, Brian J., Chan, Ireaneus C., Braunstein, Lior Z., Gao, Teng, Papaemmanuil, Elli, Esther Babady, N., Pessin, Melissa S., Kamboj, Mini, Diaz, Jr, Luis A., Ladanyi, Marc, Rauh, Michael J., Natarajan, Pradeep, Machiela, Mitchell J., Awadalla, Philip, Joseph, Vijai, Offit, Kenneth, Norton, Larry, Berger, Michael F., Levine, Ross L., Kim, Eu Suk, Kim, Nam Joong, and Zehir, Ahmet

Published
2021
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32. Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

Author

Rose Brannon, A., Jayakumaran, Gowtham, Diosdado, Monica, Patel, Juber, Razumova, Anna, Hu, Yu, Meng, Fanli, Haque, Mohammad, Sadowska, Justyna, Murphy, Brian J., Baldi, Tessara, Johnson, Ian, Ptashkin, Ryan, Hasan, Maysun, Srinivasan, Preethi, Rema, Anoop Balakrishnan, Rijo, Ivelise, Agarunov, Aaron, Won, Helen, Perera, Dilmi, Brown, David N., Samoila, Aliaksandra, Jing, Xiaohong, Gedvilaite, Erika, Yang, Julie L., Stephens, Dennis P., Dix, Jenna-Marie, DeGroat, Nicole, Nafa, Khedoudja, Syed, Aijazuddin, Li, Alan, Lebow, Emily S., Bowman, Anita S., Ferguson, Donna C., Liu, Ying, Mata, Douglas A., Sharma, Rohit, Yang, Soo-Ryum, Bale, Tejus, Benhamida, Jamal K., Chang, Jason C., Dogan, Snjezana, Hameed, Meera R., Hechtman, Jaclyn F., Moung, Christine, Ross, Dara S., Vakiani, Efsevia, Vanderbilt, Chad M., Yao, JinJuan, Razavi, Pedram, Smyth, Lillian M., Chandarlapaty, Sarat, Iyer, Gopa, Abida, Wassim, Harding, James J., Krantz, Benjamin, O’Reilly, Eileen, Yu, Helena A., Li, Bob T., Rudin, Charles M., Diaz, Luis, Solit, David B., Arcila, Maria E., Ladanyi, Marc, Loomis, Brian, Tsui, Dana, Berger, Michael F., Zehir, Ahmet, and Benayed, Ryma

Published
2021
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33. Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients

Author

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

Published
2021
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34. Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting

Author

Du, Zhenfang, Brown, Benjamin P., Kim, Soyeon, Ferguson, Donna, Pavlick, Dean C., Jayakumaran, Gowtham, Benayed, Ryma, Gallant, Jean-Nicolas, Zhang, Yun-Kai, Yan, Yingjun, Red-Brewer, Monica, Ali, Siraj M., Schrock, Alexa B., Zehir, Ahmet, Ladanyi, Marc, Smith, Adam W., Meiler, Jens, and Lovly, Christine M.

Published
2021
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35. Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors

Author

Valero, Cristina, Lee, Mark, Hoen, Douglas, Weiss, Kate, Kelly, Daniel W., Adusumilli, Prasad S., Paik, Paul K., Plitas, George, Ladanyi, Marc, Postow, Michael A., Ariyan, Charlotte E., Shoushtari, Alexander N., Balachandran, Vinod P., Hakimi, A. Ari, Crago, Aimee M., Long Roche, Kara C., Smith, J. Joshua, Ganly, Ian, Wong, Richard J., Patel, Snehal G., Shah, Jatin P., Lee, Nancy Y., Riaz, Nadeem, Wang, Jingming, Zehir, Ahmet, Berger, Michael F., Chan, Timothy A., Seshan, Venkatraman E., and Morris, Luc G. T.

Published
2021
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36. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis

Author

Gao, Teng, Ptashkin, Ryan, Bolton, Kelly L., Sirenko, Maria, Fong, Christopher, Spitzer, Barbara, Menghrajani, Kamal, Ossa, Juan E. Arango, Zhou, Yangyu, Bernard, Elsa, Levine, Max, Martinez, Juan S. Medina, Zhang, Yanming, Franch-Expósito, Sebastià, Patel, Minal, Braunstein, Lior Z., Kelly, Daniel, Yabe, Mariko, Benayed, Ryma, Caltabellotta, Nicole M., Philip, John, Paraiso, Ederlinda, Mantha, Simon, Solit, David B., Diaz, Jr, Luis A., Berger, Michael F., Klimek, Virginia, Levine, Ross L., Zehir, Ahmet, Devlin, Sean M., and Papaemmanuil, Elli

Published
2021
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37. Same-Cell Co-Occurrence of RAS Hotspot and BRAF V600E Mutations in Treatment-Naive Colorectal Cancer

Author

Gularte-Mérida, Rodrigo, Smith, Shaleigh, Bowman, Anita S., da Cruz Paula, Arnaud, Chatila, Walid, Bielski, Craig M., Vyas, Monika, Borsu, Laetitia, Zehir, Ahmet, Martelotto, Luciano G., Shia, Jinru, Yaeger, Rona, Fang, Fang, Gardner, Rui, Luo, Ruibang, Schatz, Michael C., Shen, Ronglai, Weigelt, Britta, Sánchez-Vega, Francisco, Reis-Filho, Jorge S., and Hechtman, Jaclyn F.

Published
2022
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39. Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer

Author

Suehnholz, Sarah P., primary, Nissan, Moriah H., additional, Zhang, Hongxin, additional, Kundra, Ritika, additional, Nandakumar, Subhiksha, additional, Lu, Calvin, additional, Carrero, Stephanie, additional, Dhaneshwar, Amanda, additional, Fernandez, Nicole, additional, Xu, Benjamin W., additional, Arcila, Maria E., additional, ZEHIR, Ahmet, additional, Syed, Aijazuddin, additional, Brannon, A. Rose, additional, Rudolph, Julia E., additional, Paraiso, Eder, additional, Sabbatini, Paul J., additional, Levine, Ross L., additional, Dogan, Ahmet, additional, Gao, Jianjiong, additional, Ladanyi, Marc, additional, Drilon, Alexander, additional, Berger, Michael F., additional, Solit, David B., additional, Schultz, Nikolaus, additional, and Chakravarty, Debyani, additional

Published
2023
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40. Microsatellite instability and mismatch repair deficiency define a distinct subset of lung cancers characterized by smoking exposure, high tumor mutational burden and recurrent somatic MLH1 inactivation.

Author

Yang, Soo-Ryum, primary, Gedvilaite, Erika, additional, Ptashkin, Ryan, additional, Chang, Jason, additional, Ziegler, John, additional, Mata, Douglas A., additional, Villafania, Liliana B., additional, Nafa, Khedoudja, additional, Hechtman, Jaclyn F., additional, Benayed, Ryma, additional, Zehir, Ahmet, additional, Benhamida, Jamal, additional, Arcila, Maria E., additional, Mandelker, Diana, additional, Rudin, Charles M., additional, Paik, Paul K., additional, Drilon, Alexander, additional, Schoenfeld, Adam J., additional, and Ladanyi, Marc, additional

Published
2023
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41. SPOT/Dx Pilot Reanalysis and College of American Pathologists Proficiency Testing for KRAS and NRAS Demonstrate Excellent Laboratory Performance

Author

Zehir, Ahmet, primary, Nardi, Valentina, additional, Konnick, Eric Q., additional, Lockwood, Christina M., additional, Long, Thomas A., additional, Sidiropoulos, Nikoletta, additional, Souers, Rhona J., additional, Vasalos, Patricia, additional, Lindeman, Neal I., additional, and Moncur, Joel T., additional

Published
2023
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42. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

Author

Chowell, Diego, Morris, Luc G. T., Grigg, Claud M., Weber, Jeffrey K., Samstein, Robert M., Makarov, Vladimir, Kuo, Fengshen, Kendall, Sviatoslav M., Requena, David, Riaz, Nadeem, Greenbaum, Benjamin, Carroll, James, Garon, Edward, Hyman, David M., Zehir, Ahmet, Solit, David, Berger, Michael, Zhou, Ruhong, Rizvi, Naiyer A., and Chan, Timothy A.

Published
2018

45. Tumour lineage shapes BRCA-mediated phenotypes

Author

Jonsson, Philip, Bandlamudi, Chaitanya, Cheng, Michael L., Srinivasan, Preethi, Chavan, Shweta S., Friedman, Noah D., Rosen, Ezra Y., Richards, Allison L., Bouvier, Nancy, Selcuklu, S. Duygu, Bielski, Craig M., Abida, Wassim, Mandelker, Diana, Birsoy, Ozge, Zhang, Liying, Zehir, Ahmet, Donoghue, Mark T. A., Baselga, José, Offit, Kenneth, Scher, Howard I., O’Reilly, Eileen M., Stadler, Zsofia K., Schultz, Nikolaus, Socci, Nicholas D., Viale, Agnes, Ladanyi, Marc, Robson, Mark E., Hyman, David M., Berger, Michael F., Solit, David B., and Taylor, Barry S.

Published
2019
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46. Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Author

Samstein, Robert M., Lee, Chung-Han, Shoushtari, Alexander N., Hellmann, Matthew D., Shen, Ronglai, Janjigian, Yelena Y., Barron, David A., Zehir, Ahmet, Jordan, Emmet J., Omuro, Antonio, Kaley, Thomas J., Kendall, Sviatoslav M., Motzer, Robert J., Hakimi, A. Ari, Voss, Martin H., Russo, Paul, Rosenberg, Jonathan, Iyer, Gopa, Bochner, Bernard H., Bajorin, Dean F., Al-Ahmadie, Hikmat A., Chaft, Jamie E., Rudin, Charles M., Riely, Gregory J., Baxi, Shrujal, Ho, Alan L., Wong, Richard J., Pfister, David G., Wolchok, Jedd D., Barker, Christopher A., Gutin, Philip H., Brennan, Cameron W., Tabar, Viviane, Mellinghoff, Ingo K., DeAngelis, Lisa M., Ariyan, Charlotte E., Lee, Nancy, Tap, William D., Gounder, Mrinal M., D’Angelo, Sandra P., Saltz, Leonard, Stadler, Zsofia K., Scher, Howard I., Baselga, Jose, Razavi, Pedram, Klebanoff, Christopher A., Yaeger, Rona, Segal, Neil H., Ku, Geoffrey Y., DeMatteo, Ronald P., Ladanyi, Marc, Rizvi, Naiyer A., Berger, Michael F., Riaz, Nadeem, Solit, David B., Chan, Timothy A., and Morris, Luc G. T.

Published
2019
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47. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma

Author

Basturk, Olca, Berger, Michael F, Yamaguchi, Hiroshi, Adsay, Volkan, Askan, Gokce, Bhanot, Umesh K, Zehir, Ahmet, Carneiro, Fatima, Hong, Seung-Mo, Zamboni, Giuseppe, Dikoglu, Esra, Jobanputra, Vaidehi, Wrzeszczynski, Kazimierz O, Balci, Serdar, Allen, Peter, Ikari, Naoki, Takeuchi, Shoko, Akagawa, Hiroyuki, Kanno, Atsushi, Shimosegawa, Tooru, Morikawa, Takanori, Motoi, Fuyuhiko, Unno, Michiaki, Higuchi, Ryota, Yamamoto, Masakazu, Shimizu, Kyoko, Furukawa, Toru, and Klimstra, David S

Published
2017
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49. OncoTree: A Cancer Classification System for Precision Oncology

Author

Kundra, Ritika, Zhang, Hongxin, Sheridan, Robert, Sirintrapun, Sahussapont Joseph, Wang, Avery, Ochoa, Angelica, Wilson, Manda, Gross, Benjamin, Sun, Yichao, Madupuri, Ramyasree, Satravada, Baby A., Reales, Dalicia, Vakiani, Efsevia, Al-Ahmadie, Hikmat A., Dogan, Ahmet, Arcila, Maria, Zehir, Ahmet, Maron, Steven, Berger, Michael F., Viaplana, Cristina, Janeway, Katherine, Ducar, Matthew, Sholl, Lynette, Dogan, Snjezana, Bedard, Philippe, Surrey, Lea F., Sanchez, Iker Huerga, Syed, Aijaz, Rema, Anoop Balakrishnan, Chakravarty, Debyani, Suehnholz, Sarah, Nissan, Moriah, Iyer, Gopakumar V., Murali, Rajmohan, Bouvier, Nancy, Soslow, Robert A., Hyman, David, Younes, Anas, Intlekofer, Andrew, Harding, James J., Carvajal, Richard D., Sabbatini, Paul J., Abou-Alfa, Ghassan K., Morris, Luc, Janjigian, Yelena Y., Gallagher, Meighan M., Soumerai, Tara A., Mellinghoff, Ingo K., Hakimi, Abraham A., Fury, Matthew, Huse, Jason T., Bagrodia, Aditya, Hameed, Meera, Thomas, Stacy, Gardos, Stuart, Cerami, Ethan, Mazor, Tali, Kumari, Priti, Raman, Pichai, Shivdasani, Priyanka, MacFarland, Suzanne, Newman, Scott, Waanders, Angela, Gao, Jianjiong, Solit, David, and Schultz, Nikolaus

Published
2021
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