Loss-of-function uORF mutations in human malignancies

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• Upstream open reading frames (uORFs) regulate gene expression, often repressively.
• Loss-of-function mutations in uORFs can activate proto-oncogenes, but systematic cancer-associated uORF mutation analysis is lacking.

Purpose of the Study:

• To systematically screen for cancer-associated genetic alterations in uORFs of human tyrosine kinases and proto-oncogenes.
• To investigate the functional impact of identified uORF mutations on gene translation and their potential role in carcinogenesis.

Main Methods:

• Utilized a PCR-based, multiplex identifier-tagged deep sequencing approach to screen uORF translation initiation sites.
• Analyzed whole exome sequencing datasets to identify somatic mutations affecting uORF initiation and termination codons.

Main Results:

• Identified loss-of-function uORF mutations in EPHB1 (breast and colon cancer) and MAP2K6 (colon adenocarcinoma), associated with enhanced translation.
• Discovered 53 additional non-recurrent somatic mutations affecting uORF initiation and termination codons in colon adenocarcinomas.
• Provided evidence for somatic mutations impacting uORF initiation and termination codons in human cancer.

Conclusions:

• Loss-of-uORF mutations can lead to translational induction of downstream coding sequences, potentially contributing to cancer development.
• Somatic mutations affecting uORFs are present in human cancers, highlighting their role in oncogenesis.
• Future genome-wide analyses are needed to fully define the contribution of uORF deregulation in cancer.