Table 3.

Selected examples of tumors with ALK alterations and their clinical implications.

Examples of diseases	ALK alterations and their frequency	Comments	References
All cancers	~3.1% of cancers have ALK alterations.a ~0.2% of all cancer types have ALK fusions/rearrangements	Alterations other than fusions may include mutations, amplifications and ALK positivity by immunohistochemistry. ALK mutations are found in about ~3% of various cancer types	1,2
Solid tumors
Breast carcinoma (including inflammatory breast cancers)	ALK gene amplifications are found in ~13% of all breast cancers, more frequently triple negative breast cancers or inflammatory breast cancer70 75–80% of inflammatory breast cancers can have ALK copy number gains and amplifications77 EML4-ALK fusions are found in ~2.4% of breast cancers52b ALK mutations were observed in ~1.8% of cases of breast carcinomas in AACR Genie database.	ALK protein positivity may not be present in many inflammatory breast cancers despite ALK high copy number gains and amplifications88 Data on responsiveness to ALK inhibitors in ALK-amplified breast cancer is not well described in the literature.	1,52,70,77,88
GBM	ALK amplifications are present in around 0.2% of all of glioblastoma cases. ALK Mutations were observed in ~2.7% cases of GBM in the AACR Genie database. PPP1CB-ALK fusions were observed in ~43% (7/16) and ALK amplification was observed in 31% (5/16) of ALK-expressing pediatric glioblastoma cases89	ALK overexpression by IHC may be present in over 40% of cases, but fusions are uncommon.	1,76,89
IMTs	ALK fusions are found in ~50% of IMT patients. The majority of ALK alterations seen in IMT are fusions. Multiple fusion partners to ALK occur some of them are included in (Table 2)	ALK expression in these tumors can be associated with better prognosis. When RANBP2 is the fusion partner to ALK, it is often associated with epithelioid inflammatory myofibroblastic sarcoma, an aggressive subtype of IMT66 The FDA approved crizotinib for unresectable, recurrent, or refractory ALK-aberrant inflammatory myofibroblastic tumors.	1,36,66,79–81
Melanoma	Spitz nevi and spitzoid melanomas are associated with ALK fusions in around 8–15% cases. ALK Mutations were observed in ~7.5% of cases of melanoma in AACR Genie database.		1,2,75,78
NSCLC	ALK fusions, ~3–7% of NSCLC ALK amplification were observed in~ 0.02% and ALK Mutations seen ~3.6% NSCLC cases of AACR genie data base.	EML4-ALK is the most common ALK fusion. Multiple ALK inhibitors approved (see Table 1)	1,20–22
Neuroblastomas	8–16% of newly diagnosed neuroblastoma have somatic ALK alterations. ALK mutations were observed in ~12.4% of cases of neuroblastoma in AACR Genie database. Around ~1–2% of neuroblastoma cases are inherited (autosomal dominant) and almost 50% of them have germline gain of function ALK mutation. ~1–3% of neuroblastoma have ALK amplification.	ALK-mutant versus wild-type neuroblastoma have inferior survival, aggressive disease. Mutations in three positions in kinase domain—R1275, F1174, and F1245—account for around~85% of ALK mutations in neuroblastomas; R1275Q is the most common mutation, present in 45% of familial cases and a third of sporadic cases, whereas F1174 and F1245 mutants are exclusively found in sporadic disease at frequencies of around 30% and 12%, respectively. ALK can be co-amplified or co-mutated with MYCN, consistent with the proximity of these genes at 2p23-24 which is associated with aggressive prognosis.	1,82–84
Prostate	ALK gene truncations were found in 6.4% of cases in some studies. ALK protein overexpression through IHC found in 9% cases of prostate cancer	Rare SLC45A3-ALK fusion and ALK F1174C mutation has been observed	1,85–87
Hematologic malignancies
ALCL	~80% of pediatric and ~50% of adult ALCL harbor NPM1-ALK ALK mutations were observed in ~2.8% cases of ALCL in the AACR Genie database.	The FDA approved crizotinib for pediatric patients (one year of age and older) and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-aberrant.	1,34,71,72
Histiocytosis	In a study of 39 ALK positive histiocytosis, 37 had ALK rearrangements, 27 with KIF5B-ALK fusion	ALK-fusion histiocytosis is a rare subtype of histiocytic neoplasm. KIF5B is the most common ALK fusion partner. Others observed DCTN1, TPM3, EML4 and TFG fusions with ALK	74
Leukemia		RANBP2-ALK fusion has been reported in an AML case63 ALK mutations in 2/185 (<1%) cases of leukemias)	63,90
Multiple myeloma	TFG-ALK fusion has been reported in non-secretory multiple myeloma	TFG-ALK fusion has been reported in non-secretory multiple myeloma	73

Abbreviations: ALCL anaplastic large cell lymphoma, ALL acute lymphoblastic leukemia, AML acute myelogenous leukemia, EML4 echinoderm microtubule-associated protein like-4, GBM glioblastoma multiforme, IHC immunohistochemistry, IMT inflammatory myofibroblastic tumor, KIF5B kinesin family member 5B, NPM1 nucleophosmin1, NSCLC non-small cell lung cancer, PPP1CB protein phosphatase 1 catalytic subunit beta, RANBP2 RAN binding protein 2, TFG TRK-fused gene, TPM3 tropomyosin 3.

^aALK alterations in AACR genie database included rearrangements, mutations and amplification.

^bThe incidence rate of EML4-ALK fusion in this study was reported by using relatively older technology (exon array profiling) and no further studies have supported this finding.