FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastr…

Abstract

About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations. We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions. Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.

Keywords

ETV6–NTRK3 FGFR1 GIST Gene sequencing Mutation

MeSH 主题词

Adult Demography Female Gastrointestinal Stromal Tumors/genetics,metabolism Genome, Human Humans Male Mutation/genetics Oncogene Proteins, Fusion/metabolism Receptor, Fibroblast Growth Factor, Type 1/metabolism Receptor, trkC/metabolism

化学物质

Oncogene Proteins, Fusion FGFR1 protein, human Receptor, Fibroblast Growth Factor, Type 1 Receptor, trkC

作者与单位

共 23 位作者，点击展开单位 / ORCID

Shi Eileen

School of Medicine, University of California San Diego, La Jolla, CA, USA.

Chmielecki Juliann

Foundation Medicine, Inc., Cambridge, MA, USA.

Tang Chih-Min

Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 2313, Mail Code 0987, La Jolla, CA, 92093-0987, USA.

Wang Kai

Foundation Medicine, Inc., Cambridge, MA, USA.

Heinrich Michael C

Portland VA Health Care System, Portland, OR, USA. | Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.

Kang Guhyun

Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA. | Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea.

Corless Christopher L

Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.

Hong David

Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Fero Katherine E

School of Medicine, University of California San Diego, La Jolla, CA, USA. | UCSD Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Murphy James D

School of Medicine, University of California San Diego, La Jolla, CA, USA. | UCSD Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Fanta Paul T

School of Medicine, University of California San Diego, La Jolla, CA, USA. | Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Ali Siraj M

Foundation Medicine, Inc., Cambridge, MA, USA.

De Siena Martina

Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 2313, Mail Code 0987, La Jolla, CA, 92093-0987, USA.

Burgoyne Adam M

School of Medicine, University of California San Diego, La Jolla, CA, USA. | Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Movva Sujana

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Madlensky Lisa

School of Medicine, University of California San Diego, La Jolla, CA, USA. | UCSD Department of Family and Preventive Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Heestand Gregory M

School of Medicine, University of California San Diego, La Jolla, CA, USA. | Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Trent Jonathan C

Sarcoma Medical Oncology Program, University of Miami Sylvester Cancer Center, Miami, FL, USA.

Kurzrock Razelle

School of Medicine, University of California San Diego, La Jolla, CA, USA. | Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.

Morosini Deborah

Foundation Medicine, Inc., Cambridge, MA, USA.

Ross Jeffrey S

Foundation Medicine, Inc., Cambridge, MA, USA.

Harismendy Olivier

School of Medicine, University of California San Diego, La Jolla, CA, USA. oharismendy@ucsd.edu. | Oncogenomics Laboratory, Division of Biomedical Informatics, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 4335, Mail Code 0820, La Jolla, CA, 92093-0820, USA. oharismendy@ucsd.edu.

Sicklick Jason K

School of Medicine, University of California San Diego, La Jolla, CA, USA. jsicklick@ucsd.edu. | Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 2313, Mail Code 0987, La Jolla, CA, 92093-0987, USA. jsicklick@ucsd.edu.

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.

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