title: ALK alteration is a frequent event in aggressive breast cancers.
abstract: BACKGROUND
  Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population.
  
  
  METHODS
  ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.
  
  
  RESULTS
  Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001).
  
  
  CONCLUSIONS
  Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. asiraj@kfshrc.edu.sa.
authors.forename: Abdul K
authors.initials: AK
authors.lastname: Siraj
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. bshaham@kfshrc.edu.sa.
authors.forename: Shaham
authors.initials: S
authors.lastname: Beg
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. zjehan@kfshrc.edu.sa.
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Jehan
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. sprabakaran@kfshrc.edu.sa.
authors.forename: Sarita
authors.initials: S
authors.lastname: Prabhakaran
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. amaqbool@kfshrc.edu.sa.
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. arajabali@kfshrc.edu.sa.
authors.forename: Azhar
authors.initials: A
authors.lastname: R Hussain
authors.affiliation: Department of Pathology, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. dayelf@kfshrc.edu.sa.
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.affiliation: Department of Pathology, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. tulbah@kfshrc.edu.sa.
authors.forename: Asma
authors.initials: A
authors.lastname: Tulbah
authors.affiliation: Oncology Center, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. ajarim@kfshrc.edu.sa.
authors.forename: Dahish
authors.initials: D
authors.lastname: Ajarim
authors.affiliation: Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia. kkuraya@kfshrc.edu.sa.|Department of Pathology, Al-Faisal University, Al Zahrawi Street, Riyadh, 11533, Saudi Arabia. kkuraya@kfshrc.edu.sa.
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D019394:Ki-67 Antigen / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases