Dataset Information

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

ABSTRACT:

Purpose

Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer.

Experimental design

We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results.

Results

We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E-mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy.

Conclusions

RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.

SUBMITTER: Singh H

PROVIDER: S-EPMC9063924 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Singh Harshabad H Li Yvonne Y YY Spurr Liam F LF Shinagare Atul B AB Abhyankar Ritika R Reilly Emma E Brais Lauren K LK Nag Anwesha A Ducar Matthew D MD Thorner Aaron R AR Shapiro Geoffrey I GI Keller Rachel B RB Siletti Cheta C Clark Jeffrey W JW Farago Anna F AF Lin Jessica J JJ Demetri George D GD Gujrathi Rahul R Kulke Matthew H MH MacConaill Laura E LE Ligon Azra H AH Sicinska Ewa E Meyerson Matthew L ML Meyerhardt Jeffrey A JA Cherniack Andrew D AD Wolpin Brian M BM Ng Kimmie K Giannakis Marios M Hornick Jason L JL Cleary James M JM

Clinical cancer research : an official journal of the American Association for Cancer Research 20210107 6

<h4>Purpose</h4>Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer.<h4>Experimental design</h4>We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from t ...[more]

PMID: 33414136

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Project description:BackgroundReceptor tyrosine kinases (RTKs) are a class of tyrosine kinases that regulate cell-to-cell communication and control a variety of complex biological functions. Dysregulation of RTK signaling partly due to chromosomal rearrangements leads to novel tyrosine kinase fusion oncoproteins that are possibly driver alterations to cancers. Targeting some RTK fusions with specific tyrosine kinases inhibitors (TKIs) is an effective therapeutic strategy across a spectrum of RTK fusion-related cancers. However, there is still a paucity of extensive RTK fusion investigations in breast cancer. This study aims to characterize RTK fusions in Chinese breast cancer patients.MethodsAn in-house DNA sequencing database of 1440 Chinese breast cancer patients with a capture-based panel (520 gene or 108 gene-panel) was thoroughly reviewed. A total of 2,229 samples including 1,045 tissues and 1,184 plasmas were analyzed. RTK fusion was defined as an in-frame fusion with the tyrosine kinase domain of the RTK completely retained. Concomitant mutations were also analyzed and tumor mutational burden (TMB) was calculated. Patients' clinical characteristics were retrieved from case records.ResultsA total of 30 RTK fusion events were identified from 27 breast cancer patients with a prevalence of 1.875%%. FGFR2 fusions were seen the most commonly (n=7), followed by RET (n=5), ROS1 (n=3), NTRK3 (n=3), BRAF (n=2), and NTRK1 (n=2). Other RTK fusions including ALK, EGFR, FGFR1, FGFR3, MET, and NTRK2 were identified in one patient each. A total of 27 unique resultant fusion proteins (22 with a novel partner) were discovered including 19 intrachromosomal rearrangements and 8 interchromosomal ones. Twenty-one fusions had the tyrosine kinase domain in-frame fused with a partner gene and six were juxtaposed with an intergenic space. Among the 27 fusions, FGFR2-WDR11 (E17: intergenic) (n=3) and ETV6-NTRK3 (E5:E15) (n=2) occurred recurrently. Of note, the normalized abundance of RTK fusion (fusion AF/max AF) correlated negatively with TMB (r=-0.48, P=0.017). Patients with TMB < 8 (Mutations/Mb) displayed a higher fusion abundance than those with TMB ≥ 8 (Mutations/Mb) (P=0.025). Moreover, CREBBP mutation only co-occurred with FGFR2 fusion (P=0.012), while NTRK3 fusion and TP53 mutation were mutually exclusive (P=0.019).ConclusionThis is the first study comprehensively delineating the prevalence and spectrum of RTK fusions in Chinese breast cancers. Further study is ongoing to identify the enriched subpopulation who may benefit from RTK fusion inhibitors.

Project description:We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

Dataset Information

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Purpose

Experimental design

Results

Conclusions

Publications

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Similar Datasets

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