Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population

PLoS One. 2015 Dec 17;10(12):e0144731. doi: 10.1371/journal.pone.0144731. eCollection 2015.

Abstract

Background: Anaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.

Patients and methods: Tissue microarray (TMA) was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC) cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC) assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (qRT-PCR), target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.

Results: Among the tested cases, 2 (0.44%) CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1). One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.

Conclusions: The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anaplastic Lymphoma Kinase
  • Asian People / genetics
  • China
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • DNA, Neoplasm / genetics
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / genetics*
  • Female
  • Gene Rearrangement*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Neoplasms, Squamous Cell / enzymology
  • Neoplasms, Squamous Cell / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / genetics*
  • Targeted Gene Repair* / methods
  • Tissue Array Analysis
  • Young Adult

Substances

  • DNA, Neoplasm
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases

Grants and funding

This study was supported by grants from the Natural Basic Research Program of China (973 program 2014CB542002) and the National Natural Science Foundation of China (31470073), National Natural Science Foundation of China (81201967), the Beijing Natural Science Foundation (7144238) and Beijing Nova Program (No. 2009A69). MyGenostics Inc., provided support in the form of salaries for author Jian Wu, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author is articulated in the ‘author contributions’ section.