Molecular characterization of cancers with ALK gene fusions in nonlung tumors.

Abstract

3121 Background: ALK gene rearrangement is known as “diamond mutation”. Targeted tyrosine kinase inhibitors have perfect therapeutic effects on ALK fusion lung cancer patients (pts), but the molecular characteristics of ALK fusions in other cancers have not been systematically elucidated. Methods: We retrospectively analyzed the NGS data of ALK fusion-positive Chinese tumor pts (n = 1068) to characterize ALK fusions in pan-cancer (excluding lung cancer) pts. Results: A total of 66 ALK fusion-positive pts with 13 types of cancer (excluding lung cancer) were screened, including 0.4% (24/5800) of brain tumor pts, 0.1% (11/7725) of gastrointestinal cancer pts, 0.4% (7/1741) of thyroid cancer pts, 0.5% (8/1732) of sarcoma pts, 0.2% (4/2031) of liver cancer pts, 0.6% (3/540) of melanoma pts, 9% (2/22) of inflammatory myofibroblastic tumor pts, 2.5% (2/79) of embryonal tumor pts, 0.4% (1/282) of lymphoma pts, 3.2% (1/31) of parotid carcinoma pts, 0.1% (1/985) of breast cancer pts, 0.4% (1/241) of prostatic cancer pts and 0.3% (1/320) of ovarian cancer pts. Herein, we reported 28 ALK fusion patterns, of which the most common partners were EML4 (n = 24) and STRN (n = 8), and mainly occurred in brain tumors (14/24, 58.8%) and thyroid cancers (6/8, 75%), respectively. In addition, there were 8 ALK fusion modes that were never reported before. Of the ALK fusion patterns described above, 92.4% (61/66) of fusions were located at the most canonical site of ALK (exon20), preserving the intact kinase domain. Meanwhile, rare fusion positions in the ALK gene were also found, such as PPP1CB-ALK(ex2:ex4), NUP107-ALK(ex20:ex3), COL14A1-ALK(ex8:ex4), BRAF-ALK(ex9:ex4), which preserve the extracellular and transmembrane domains, as well as RASD2-ALK(ex2:ex24), of which the breakpoint in ALK gene may disrupt the formation of kinase domain. Conclusions: We demonstrated the rarity of ALK gene fusions in nonlung cancers. Analyzing the ALK fusion characteristics of these cancer may help to clarify their pathogenesis and provide ideas for new drug treatment.[Table: see text]