# Pan-Cancer Analysis of Mutations Affecting Protein Liquid–Liquid Phase Separation Revealing Clinical Implications

## TL;DR

This study identifies mutations affecting protein phase separation in 16 cancer types, linking them to cancer pathways and poor patient outcomes.

## Contribution

The first pan-cancer analysis of mutations affecting protein liquid–liquid phase separation and their clinical implications.

## Key findings

- Nearly 10% of mutations across 1,267,908 affect protein phase separation in 16 cancer types.
- Mutations affecting phase separation are enriched in cancer-related pathways like TGF-beta signaling.
- Patients with mutations enhancing phase separation have worse outcomes in melanoma and lung cancer.

## Abstract

Identifying mutations affecting protein phase separation is important for understanding cancer development. This research provided a pan-cancer landscape of mutations affecting protein liquid–liquid phase separation. The researchers calculated the phase separation scores alterations for 1,267,908 mutations across 16 cancer types using the TCGA dataset. Nearly 10% of the mutations were phase separation-affecting mutations in pan-cancer dataset. Proteins carrying these mutations were enriched in cancer-related pathways, including TGF-beta signaling pathways and polycomb repressive complex. Phase separation of these proteins would be regulated by kinases, including CDK1, CDK2, and EGFR, and transcription factors, including ZNF407, ZNF318, and MGA proteins, to play functions in cancer. Protein–Protein Interaction Network revealed that these phase separation proteins are highly interconnected. Finally, patients carrying mutations that positively affect the protein phase separation are associated with poor prognosis in skin cutaneous melanoma (SKCM) and lung squamous cell carcinoma (LUSC). This research provided a pan-cancer landscape for depicting the association of phase separation and cancer mutations, revealing clinical implications for phase separation.

Phase separation is one of the mechanisms critical for protein function, and its aberrances are associated with cancer development. However, mutations that affect protein phase separation and cancer development have not been systematically identified and analyzed. In this study, we systematically identified the mutations affecting protein liquid–liquid phase separation in multiple cancers. We calculated the phase separation scores alterations for over 1,200,000 mutations across 16 cancer types using the TCGA dataset. We then performed pathway enrichment, kinase, TF enrichment, and survival analysis to identify related biological processes and clinical implications. Nearly 10% of the mutations were defined to affect phase separation in pan-cancer. These mutations occupied a consistent percentage in each cancer type. Extremely influencing mutations accumulate on stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC), and skin cutaneous melanoma (SKCM). Moreover, proteins carrying these mutations are enriched in cancer-related pathways, including TGF-beta signaling pathways and polycomb repressive complex. Phase separation of these proteins would be regulated by kinases, including CDK1, CDK2, and EGFR, and transcription factors, including ZNF407, ZNF318, and MGA proteins, to play functions in cancer. Protein–Protein Interaction Network revealed that these phase separation proteins are highly interconnected. Finally, patients carrying mutations that positively affect the protein phase separation are associated with poor prognosis in skin cutaneous melanoma (SKCM) and lung squamous cell carcinoma (LUSC), which could be partially explained by the pathogenicity of these mutations. The study provided a pan-cancer landscape for depicting the association of phase separation and cancer mutations, which would be a rich data resource for understanding the association of cancer mutations and phase separation.