Oncogenic Fusions Involving Exon 19 of ALK

Penzel et al.¹ recently described a lung adenocarcinoma patient with an EML4-ALK fusion between exon 6 of echinoderm microtubule associated protein like 4 (EML4) and exon 19 of anaplastic lymphoma kinase (ALK) (E6;A19) as a novel molecular variant. It should be noted that this EML4-ALK (E6;A19) fusion has been previously reported by our group in a 62-year-old woman also with lung adenocarcinoma.² The second finding of this atypical EML4-ALK breakpoint (the majority of ALK gene fusions occur at exon 20 of ALK) suggests that it may not be an isolated event, and highlights the great diversity of fusion events involving this gene. Furthermore, an FN1-ALK gene fusion was previously identified in a malignant stromal sarcoma patient, in which the fusion also occurs at exon 19 of ALK.³ The significance of these ALK exon 19 fusion variants is currently unknown, but is interesting as it expresses the ALK transmembrane domain. The subcellular localization of these exon 19-containing variants should be further investigated to better understand the implications of this finding; prior evidence suggests EML4-ALK (E13;A20) is localized within the cytoplasm.⁴ Oncogenic fusions involving ROS1 and RET in lung cancer have been shown previously to also include the transmembrane domain in some instances.⁵ The patient described by our group demonstrated a partial response to crizotinib and experienced a progression free survival of approximately 6.5-months, supporting the argument that these patients be considered for ALK inhibitor therapy like other patients who are positive for ALK rearrangements.²