Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

It is increasingly appreciated that alternative splicing
plays a key role in generating functional specificity
and diversity in cancer. However, the mechanisms
by which cancer mutations perturb splicing remain
unknown. Here, we developed a network-based strategy,
DrAS-Net, to investigate more than 2.5 million
variants across cancer types and link somatic mutations
with cancer-specific splicing events. We identi-
fied more than 40,000 driver variant candidates and
their 80,000 putative splicing targets deregulated in
33 cancer types and inferred their functional impact.
Strikingly, tumors with splicing perturbations show
reduced expression of immune system-related
genes and increased expression of cell proliferation
markers. Tumors harboring different mutations in
the same gene often exhibit distinct splicing perturbations.
Further stratification of 10,000 patients based
on their mutation-splicing relationships identifies
subtypes with distinct clinical features, including survival
rates. Our work reveals how single-nucleotide
changes can alter the repertoires of splicing isoforms,
providing insights into oncogenic mechanisms for
precision medicine.

The paper by Li et al can be found here.