Distinct ALK Expression Patterns Are Associated with Canonical and Noncanonical STRN::ALK Transcript Architectures in...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Oncocytic thyroid carcinomas present unique chromosomal features and resistance to radioactive iodine therapy.
• The role of ALK rearrangements, specifically STRN::ALK fusions, in oncocytic thyroid neoplasms requires further investigation due to unclear biological and clinical significance.

Purpose of the Study:

• To investigate the frequency and characteristics of STRN exon 3-ALK exon 20-derived transcripts in oncocytic thyroid neoplasms.
• To evaluate the biological and clinical implications of different STRN::ALK transcript architectures, including ALK protein expression and potential therapeutic relevance.

Main Methods:

• RT-PCR was used to detect STRN::ALK transcripts in 56 oncocytic thyroid neoplasms.
• Positive cases underwent cloning, Sanger sequencing, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and in silico structural modeling.

Main Results:

• STRN::ALK transcripts were found in 9 of 56 tumors, with 2 (3.6%) canonical in-frame fusions and 7 (12.5%) noncanonical out-of-frame variants.
• ALK rearrangement by FISH was confirmed in all transcript-positive cases, but detectable ALK protein by IHC was only seen in canonical fusions.
• Structural modeling suggested preserved kinase-domain function in canonical fusions and disruption in noncanonical variants.

Conclusions:

• STRN::ALK transcripts in oncocytic thyroid neoplasms display significant architectural heterogeneity.
• ALK FISH-positive/IHC-negative cases require cautious interpretation due to potential lack of biological equivalence and uncertain therapeutic relevance.
• Integrated molecular and protein-level analysis is crucial for accurate interpretation of ALK alterations in these neoplasms.