Larissa V Furtado, Marija Kacar, Roya Mostafavi, Zonggao Shi, Robert Ruiz, Selene C Koo, Teresa Santiago, Blair Segers, Matthew J Krasin, Zachary R Abramson, Barry Shulkin, Lindsay J Talbot, Alberto Pappo, Jessica Gartrell
{"title":"伴有多种获得性突变的进展性转移性婴儿纤维肉瘤。","authors":"Larissa V Furtado, Marija Kacar, Roya Mostafavi, Zonggao Shi, Robert Ruiz, Selene C Koo, Teresa Santiago, Blair Segers, Matthew J Krasin, Zachary R Abramson, Barry Shulkin, Lindsay J Talbot, Alberto Pappo, Jessica Gartrell","doi":"10.1101/mcs.a006277","DOIUrl":null,"url":null,"abstract":"<p><p>Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by <i>NTRK</i> fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The <i>NTRK</i> fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation <i>TRK</i> inhibitors. Although <i>NTRK</i> gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and <i>TRK</i> inhibition that developed metastatic, progressive disease with multiple acquired mutations, including <i>TP53</i>, <i>SUFU</i>, and an <i>NTRK</i> F617L gatekeeper mutation. Alterations in pathways of <i>SUFU</i> and <i>TP53</i> have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to <i>TRK</i> inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with <i>ETV6::NTRK3</i> and acquired <i>SUFU</i>, <i>TP53</i>, and <i>NTRK</i> F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/0e/MCS006277Fur.PMC10240842.pdf","citationCount":"1","resultStr":"{\"title\":\"Progressive metastatic infantile fibrosarcoma with multiple acquired mutations.\",\"authors\":\"Larissa V Furtado, Marija Kacar, Roya Mostafavi, Zonggao Shi, Robert Ruiz, Selene C Koo, Teresa Santiago, Blair Segers, Matthew J Krasin, Zachary R Abramson, Barry Shulkin, Lindsay J Talbot, Alberto Pappo, Jessica Gartrell\",\"doi\":\"10.1101/mcs.a006277\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by <i>NTRK</i> fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The <i>NTRK</i> fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation <i>TRK</i> inhibitors. Although <i>NTRK</i> gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and <i>TRK</i> inhibition that developed metastatic, progressive disease with multiple acquired mutations, including <i>TP53</i>, <i>SUFU</i>, and an <i>NTRK</i> F617L gatekeeper mutation. Alterations in pathways of <i>SUFU</i> and <i>TP53</i> have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to <i>TRK</i> inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with <i>ETV6::NTRK3</i> and acquired <i>SUFU</i>, <i>TP53</i>, and <i>NTRK</i> F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.</p>\",\"PeriodicalId\":10360,\"journal\":{\"name\":\"Cold Spring Harbor Molecular Case Studies\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2023-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/0e/MCS006277Fur.PMC10240842.pdf\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cold Spring Harbor Molecular Case Studies\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/mcs.a006277\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cold Spring Harbor Molecular Case Studies","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/mcs.a006277","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Progressive metastatic infantile fibrosarcoma with multiple acquired mutations.
Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.
期刊介绍:
Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.