伴有多种获得性突变的进展性转移性婴儿纤维肉瘤。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2023-04-01 DOI:10.1101/mcs.a006277
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
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引用次数: 1

摘要

婴儿纤维肉瘤是1岁以下儿童最常见的软组织肉瘤,由NTRK融合蛋白在分子上定义。已知该肿瘤具有局部侵袭性;然而,虽然罕见,但也可能发生转移。NTRK融合作为肿瘤形成的驱动因素,可以被第一代和第二代TRK抑制剂靶向。尽管NTRK看门人突变已被很好地描述为对这些药物的耐药机制,但替代途径突变很少。在这里,我们报告了一例接受化疗和TRK抑制治疗的婴儿纤维肉瘤患者,该患者发展为转移性进展性疾病,并伴有多种获得性突变,包括TP53, SUFU和NTRK F617L守门人突变。SUFU和TP53通路的改变已经在其他肿瘤的文献中被广泛描述;然而,在婴儿纤维肉瘤中尚未发现。虽然大多数患者对TRK抑制剂有持续的反应,但一小部分患者将继续发展耐药机制,这对临床管理有影响,例如我们的患者。我们假设这一系列突变导致了患者的侵袭性临床病程。综上所述,我们报告了首例伴有ETV6::NTRK3和获得性SUFU、TP53和NTRK F617L守门人突变的婴儿纤维肉瘤,并详细介绍了临床病程和治疗方法。我们的报告强调了在复发性婴儿纤维肉瘤中进行基因组分析的重要性,以揭示可操作的突变,如守门人突变,可以改善患者的预后。
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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.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
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.
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