Altered oncomodules underlie chromatin regulatory factors driver mutations

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Chromatin regulatory factors (CRFs) are implicated in tumorigenesis across various cancers.
• The precise molecular mechanisms by which driver alterations in CRFs contribute to cancer development are not fully understood.

Purpose of the Study:

• To develop and apply a novel computational approach for discovering gene sets (oncomodules) associated with driver mutations in CRFs.
• To identify potential molecular pathways and therapeutic targets affected by CRF alterations in human cancers.

Main Methods:

• Developed the CRFs Oncomodules Discovery approach, integrating cancer genomics and perturbation data.
• Applied the approach to eleven TCGA tumor cohorts to identify significantly dysregulated gene sets in tumors with driver CRF mutations.
• Conducted experimental validation for identified associations, specifically investigating MLL2 mutations and mTOR pathway sensitivity.

Main Results:

• Identified oncomodules potentially associated with mutations in five driver CRFs across three cancer types.
• Revealed a potential link between loss-of-function mutations in MLL2 and the mTOR pathway in head and neck squamous cell carcinomas.
• Experimental validation confirmed that MLL2 loss-of-function enhances cancer cell line sensitivity to mTOR inhibition.

Conclusions:

• The CRFs Oncomodules Discovery approach effectively identifies potential oncogenic modules linked to driver CRF mutations.
• These findings suggest novel therapeutic strategies targeting pathways like mTOR to indirectly address the impact of specific CRF driver mutations.
• The identified oncomodules can guide future experimental research for understanding and targeting CRF-driven cancers.