Intratumoral Heterogeneity of ALK Fusions and ALK/EGFR Co-alterations in Lung Adenocarcinomas


Key Points

  • Intratumoral heterogeneity of ALK fusions was identified in some patients with lung adenocarcinomas.
  • In two patients with ALK/EGFR co-alterations, heterogeneity was found across and within growth patterns in the same tumor.

In a study reported in the Journal of Clinical Oncology, Cai et al found intratumoral genetic heterogeneity of ALK rearrangement and coexisting ALK rearrangement and EGFR mutation in lung adenocarcinomas.

Study Details

The study involved evaluation for ALK fusions and EGFR mutations in 629 patients using laser-capture microdissection to isolate spatially separated tumor cell subpopulations in various adenocarcinoma subtypes. ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutant, and ALK/EGFR co-altered tumors were assessed to compare the oncogenic driver status between different tumor cell subpopulations in individual tumors.

Alterations and Heterogeneity

Overall, 30 patients (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and 2 had ALK fusions coexisting with EGFR mutations. Intratumoral genetic heterogeneity of ALK fusions was found in nine patients using reverse transcriptase–polymerase chain reaction. In the two patients with ALK/EGFR co-alteration, intratumoral genetic heterogeneity was observed both across different growth patterns and within the same growth pattern, and the relative abundance of ALK and EGFR alterations differed within the same captured areas.

In an expanded statistical analysis of 900 adenocarcinoma components, ALK fusions were significantly more common in adenocarcinomas with mucin production (P < .001). ALK fusions were not significantly associated with an acinar pattern but were positively associated with a micropapillary pattern (P = .002) and negatively associated with a lepidic pattern (P = .008).

The investigators concluded: “Intratumoral genetic heterogeneity was demonstrated to coexist with histologic heterogeneity in both single-driver and ALK/EGFR coaltered [lung adenocarcinomas]. Altered oncogenic drivers in spatially separated subclones of the same tumor may be different.”

The study was supported by Pfizer Investment, National Natural Science Foundation of China, and Science and Technology Commission of Shanghai Municipality.

Caicun Zhou, MD, PhD, of Tongji University School of Medicine, Shanghai, is the corresponding author of the Journal of Clinical Oncology article.

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