title: ALK fusion and its association with other driver gene mutations in Finnish non-small cell lung cancer patients.
abstract: Screening of anaplastic lymphoma tyrosine kinase (ALK) gene fusions in non-small cell lung cancer (NSCLC) patients enables the identification of the patients likely to benefit from ALK-targeted therapy. Our aim was to assess the prevalence of ALK fusion in Finnish NSCLC patients, which has not been reported earlier, and to study the presence of ALK fusion in relation to clinicopathological characteristics and other driver gene mutations. A total of 469 formalin-fixed paraffin-embedded tumor tissue specimens from Finnish NSCLC patients were screened for ALK fusion by immunohistochemistry (IHC). For confirmation of IHC results, fluorescence in situ hybridization (FISH) was conducted for 171 specimens. Next-generation sequencing was performed for all ALK-positive specimens to characterize the association of ALK fusion with mutations in targeted regions of 22 driver genes. Of the 469 tumors screened, 11 (2.3%) harbored an ALK fusion, including nine adenocarcinomas and two large cell carcinomas. The IHC results for all 11 ALK-positive and 160 random ALK-negative specimens were confirmed by FISH. ALK fusion was significantly associated with never/ex-light smoking history (P<0.001) and younger age (P=0.004). Seven ALK-positive tumors showed additional mutations; three in MET, one in MET and CTNNB1, two in TP53, and one in PIK3CA. Our results show that ALK fusion is an infrequent alteration in Finnish NSCLC patients. Although the majority of ALK-positive cases were adenocarcinomas, the fusion was also seen in large cell carcinomas. Further studies are needed to elucidate the clinical significance of the coexistence of ALK fusion with MET, TP53, CTNNB1, and PIK3CA mutations.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Katja
authors.initials: K
authors.lastname: Tuononen
authors.forename: Mia
authors.initials: M
authors.lastname: Kero
authors.forename: Satu
authors.initials: S
authors.lastname: Mäki-Nevala
authors.forename: Virinder Kaur
authors.initials: VK
authors.lastname: Sarhadi
authors.forename: Milja
authors.initials: M
authors.lastname: Tikkanen
authors.forename: Tiina
authors.initials: T
authors.lastname: Wirtanen
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.forename: Aija
authors.initials: A
authors.lastname: Knuuttila
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D005260:Female; D005387:Finland; D050939:Gene Fusion; D056726:Genetic Association Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases