Colonic Adenocarcinomas Harboring NTRK Fusion Genes

Supplemental Digital Content is available in the text. This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair–deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

[1]  P. A. Futreal,et al.  Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS , 2019, Modern Pathology.

[2]  J. Swensen,et al.  Molecular characterization of cancers with NTRK gene fusions , 2018, Modern Pathology.

[3]  Chien‐Hung Yeh,et al.  FBXW7: a critical tumor suppressor of human cancers , 2018, Molecular Cancer.

[4]  Jessica L. Davis,et al.  Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors , 2018, The American journal of surgical pathology.

[5]  D. Park,et al.  Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer , 2018, British Journal of Cancer.

[6]  Tao Liu,et al.  Prognostic Value of MUC2 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis , 2018, Gastroenterology research and practice.

[7]  M. Ladanyi,et al.  NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma , 2018, The American journal of surgical pathology.

[8]  D. Park,et al.  Cytoplasmic TrkA Expression as a Screen for Detecting NTRK1 Fusions in Colorectal Cancer12 , 2018, Translational oncology.

[9]  Peter W. Laird,et al.  Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer , 2018, Cell.

[10]  M. Harris,et al.  Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy , 2018, Modern Pathology.

[11]  R. Jorissen,et al.  Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes , 2018, Gut.

[12]  James X. Sun,et al.  ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer , 2017, Journal of the National Cancer Institute.

[13]  Jeffrey S. Morris,et al.  Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes , 2017, Clinical Cancer Research.

[14]  M. Ladanyi,et al.  Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions , 2017, The American journal of surgical pathology.

[15]  R. Bosotti,et al.  Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient , 2017, Oncotarget.

[16]  J. Foekens,et al.  A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer. , 2017, Cancer research.

[17]  M. Ladanyi,et al.  Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms. , 2017, The Journal of molecular diagnostics : JMD.

[18]  J. Guinney,et al.  Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer , 2017, Nature Reviews Cancer.

[19]  Narasimhan P. Agaram,et al.  Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors , 2016, The American journal of surgical pathology.

[20]  D. Goldstein,et al.  The Impact of Mismatch Repair Status in Colorectal Cancer on the Decision to Treat With Adjuvant Chemotherapy: An Australian Population-Based Multicenter Study. , 2016, The oncologist.

[21]  S. Wiemann,et al.  Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern , 2016, The Journal of pathology.

[22]  R. Shoemaker,et al.  Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing , 2016, Applied immunohistochemistry & molecular morphology : AIMM.

[23]  J. Lee,et al.  NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer , 2015, Oncotarget.

[24]  A. Chinnaiyan,et al.  Landscape of gene fusions in epithelial cancers: seq and ye shall find , 2015, Genome Medicine.

[25]  L. Borsu,et al.  Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF , 2015, Molecular Cancer Research.

[26]  R. Shoemaker,et al.  Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer , 2015, British Journal of Cancer.

[27]  R. Bosotti,et al.  Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer , 2015, Journal of the National Cancer Institute.

[28]  Su Jin Lee,et al.  NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line , 2015, Oncotarget.

[29]  Dara L Aisner,et al.  An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. , 2015, Cancer discovery.

[30]  Stuart J. Andrews,et al.  Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma , 2015, Cold Spring Harbor molecular case studies.

[31]  L. Créancier,et al.  Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma. , 2015, Cancer letters.

[32]  Marco Beccuti,et al.  The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets , 2015, Nature Communications.

[33]  D. Bernardo,et al.  Is right-sided colon cancer different to left-sided colorectal cancer? - a systematic review. , 2015, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[34]  Andrea Lombardi Borgia,et al.  The TPM3‐NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition , 2014, Molecular oncology.

[35]  Nicolas Stransky,et al.  The landscape of kinase fusions in cancer , 2014, Nature Communications.

[36]  Amar Gajjar,et al.  The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma , 2014, Nature Genetics.

[37]  Jinkuk Kim,et al.  NTRK1 Fusion in Glioblastoma Multiforme , 2014, PloS one.

[38]  M. Nikiforova,et al.  ETV6‐NTRK3 is a common chromosomal rearrangement in radiation‐associated thyroid cancer , 2014, Cancer.

[39]  David M. Jones,et al.  New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. , 2014, The oncologist.

[40]  Iwei Yeh,et al.  Kinase fusions are frequent in Spitz tumours and spitzoid melanomas , 2014, Nature Communications.

[41]  Y. Ueda,et al.  Aberrant cytokeratin expression as a possible prognostic predictor in poorly differentiated colorectal carcinoma , 2013, Journal of gastroenterology and hepatology.

[42]  N. Cho,et al.  Loss of CDX2/CK20 Expression Is Associated With Poorly Differentiated Carcinoma, the CpG Island Methylator Phenotype, and Adverse Prognosis in Microsatellite-unstable Colorectal Cancer , 2013, The American journal of surgical pathology.

[43]  Melanie A. Huntley,et al.  Recurrent R-spondin fusions in colon cancer , 2012, Nature.

[44]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[45]  M. Miettinen A Simple Method for Generating Multitissue Blocks Without Special Equipment , 2012, Applied immunohistochemistry & molecular morphology : AIMM.

[46]  G. Webersinke,et al.  Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia , 2011, Diagnostic pathology.

[47]  E. Fearon Molecular genetics of colorectal cancer. , 2011, Annual review of pathology.

[48]  B. Perez-Ordonez,et al.  Mammary Analogue Secretory Carcinoma of Salivary Glands, Containing the ETV6-NTRK3 Fusion Gene: A Hitherto Undescribed Salivary Gland Tumor Entity , 2010, The American journal of surgical pathology.

[49]  S. Gruber,et al.  Pathologic Predictors of Microsatellite Instability in Colorectal Cancer , 2009, The American journal of surgical pathology.

[50]  S. Leung,et al.  Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer , 2006, Nature Genetics.

[51]  D. R. Lewis,et al.  A population‐based study of colorectal cancer histology in the United States, 1998–2001 , 2006, Cancer.

[52]  P. Sorensen,et al.  Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. , 2002, Cancer cell.

[53]  B. Leggett,et al.  Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. , 2001, The American journal of pathology.

[54]  A. Nakagawara,et al.  Trk receptor tyrosine kinases: a bridge between cancer and neural development. , 2001, Cancer letters.

[55]  J. Fletcher,et al.  Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. , 1998, The American journal of pathology.

[56]  M. Pierotti,et al.  Chromosome I rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid‐specific TRK oncogenes , 1997, Genes, chromosomes & cancer.

[57]  C. Dukes,et al.  The classification of cancer of the rectum , 1980 .

[58]  F. Bosman,et al.  WHO Classification of Tumours of the Digestive System , 2010 .

[59]  M. Barbacid,et al.  A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences , 1986, Nature.