Tumour mutations in long noncoding RNAs enhance cell fitness

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Long noncoding RNAs (lncRNAs) are implicated in cancer, primarily through altered expression levels.
• The role of function-altering somatic mutations in lncRNAs impacting tumor cell fitness remains largely unexplored.

Purpose of the Study:

• To identify long noncoding RNAs (lncRNAs) that harbor cancer-promoting somatic mutations.
• To investigate the functional impact of these mutations on tumor cell fitness and cancer progression.

Main Methods:

• Genome-wide analysis of single nucleotide variants (SNVs) in 2583 primary and 3527 metastatic tumors to identify fitness-altering SNVs in lncRNAs.
• In vitro overexpression studies of candidate lncRNAs to assess their impact on tumor cell proliferation.
• In cellulo mutagenesis and mouse models to evaluate the functional significance of NEAT1 SNVs.
• Mechanistic studies to elucidate how NEAT1 SNVs affect its ribonucleoprotein structure and paraspeckle formation.

Main Results:

• Identified 54 positively selected and mutated lncRNAs, enriched for known cancer genes and clinical features.
• Demonstrated that overexpression of several identified lncRNAs promotes tumor cell proliferation in vitro.
• Confirmed a hotspot of SNVs in the NEAT1 oncogene, with tumor-like mutations significantly increasing cell fitness in vitro and in vivo.
• Revealed that NEAT1 SNVs remodel its ribonucleoprotein complex, leading to boosted paraspeckle formation.

Conclusions:

• Driver mutation analysis is a valuable approach for discovering cancer-promoting lncRNAs.
• Somatic mutations in lncRNAs, such as NEAT1, can directly enhance pathological cancer cell fitness by altering their structure and function.