title: Novel ALK fusion partners in lung cancer.
abstract: Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. To improve the performance of PCR-based tests, we utilized the combination of 2 assays, i.e. the variant-specific PCR for the 5 most common ALK rearrangements and the test for unbalanced 5'/3'-end ALK expression. Overall, convincing evidence for the presence of ALK translocation was obtained for 34/400 (8.5%) cases, including 14 EML4ex13/ALKex20, 12 EML4ex6/ALKex20, 3 EML4ex18/ALKex20, 2 EML4ex20/ALKex20 variants and 3 tumors with novel translocation partners. 386 (96.5%) out of 400 EGFR mutation-negative NSCLCs were concordant for both tests, being either positive (n = 26) or negative (n = 360) for ALK translocation; 49 of these samples (6 ALK+, 43 ALK-) were further evaluated by FISH, and there were no instances of disagreement. Among the 14 (3.5%) "discordant" tumors, 5 demonstrated ALK translocation by the first but not by the second PCR assay, and 9 had unbalanced ALK expression in the absence of known ALK fusion variants. 5 samples from the latter group were subjected to FISH, and the presence of translocation was confirmed in 2 cases. Next generation sequencing analysis of these 2 samples identified novel translocation partners, DCTN1 and SQSTM1; furthermore, the DCTN1/ALK fusion was also found in another NSCLC sample with unbalanced 5'/3'-end ALK expression, indicating a recurrent nature of this translocation. We conclude that the combination of 2 different PCR tests is a viable approach for the diagnostics of ALK rearrangements. Systematic typing of ALK fusions is likely to reveal new NSCLC-specific ALK partners.
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors: Aglaya G
authors: AG
authors: Iyevleva
authors: Department of Morphology, Russian Research Centre for Radiology and Surgical Technologies, St.-Petersburg 197758, Russia.
authors: Grigory A
authors: GA
authors: Raskin
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Vladislav I
authors: VI
authors: Tiurin
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors: Anna P
authors: AP
authors: Sokolenko
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Natalia V
authors: NV
authors: Mitiushkina
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Svetlana N
authors: SN
authors: Aleksakhina
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Aigul R
authors: AR
authors: Garifullina
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Tatiana N
authors: TN
authors: Strelkova
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Valery O
authors: VO
authors: Merkulov
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Alexandr O
authors: AO
authors: Ivantsov
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Ekatherina Sh
authors: ESh
authors: Kuligina
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors: Kazimir M
authors: KM
authors: Pozharisski
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors: Alexandr V
authors: AV
authors: Togo
authors: Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg 191015, Russia. Electronic address: evgeny@imyanitov.spb.ru.
authors: Evgeny N
authors: EN
authors: Imyanitov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D000072159:Dynactin Complex; D005260:Female; D015870:Gene Expression; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Fusion partner; Lung cancer; PCR; Rearrangement; Translocation