Genomic basis for RNA alterations in cancer

Area of Science:

• Genomics
• Cancer Biology
• Transcriptomics

Background:

• Transcript alterations are common in cancer genomes but linking them to specific genomic changes is challenging due to data heterogeneity.
• Previous studies analyzed limited cohorts with both transcriptome and whole-genome sequencing, hindering comprehensive analysis of RNA alterations in cancer.

Purpose of the Study:

• To create the most comprehensive catalog of cancer-associated gene alterations to date.
• To associate RNA alterations with germline and somatic DNA alterations and identify underlying genetic mechanisms.
• To provide a resource for understanding genes and mechanisms functionally implicated in cancer.

Main Methods:

• Characterized tumor transcriptomes from 1,188 donors within the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium.
• Utilized matched whole-genome sequencing data to link RNA alterations with DNA alterations.
• Identified associations between somatic copy-number alterations, single-nucleotide variants, splicing alterations, and gene fusions with gene expression.

Main Results:

• Somatic copy-number alterations were identified as major drivers of gene expression variability.
• Discovered 649 associations between somatic single-nucleotide variants and gene expression in cis, with many linked to non-coding regions.
• Found 1,900 splicing alterations linked to somatic mutations, including novel exon formation near Alu elements.
• Observed that 82% of gene fusions were associated with structural variants, including a new class termed 'bridged' fusions.

Conclusions:

• This comprehensive compendium links RNA alterations to genomic context, offering insights into cancer mechanisms.
• The study highlights somatic copy-number alterations and specific mutation types as key drivers of transcriptomic changes in cancer.
• Identified novel splicing alterations and gene fusion mechanisms, expanding the understanding of cancer genomics.