title: Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target.
abstract: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.
  
  
  
  Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.
  
  
  
  Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.
  
  
  
  Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. ©2016 AACR.
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island. eyakirevich@lifespan.org.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Yakirevich
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Murray B
authors.initials: MB
authors.lastname: Resnick
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Shamlal
authors.initials: S
authors.lastname: Mangray
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Michael
authors.initials: M
authors.lastname: Wheeler
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Jackson
authors.affiliation: Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Kara A
authors.initials: KA
authors.lastname: Lombardo
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards and University of Sydney, Sydney NSW, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Sun
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts. Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Oncology Division, Department of Internal Medicine, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor; D001706:Biopsy; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases