Case Report: Novel mutation in CHD4 triggers occult breast cancer with bone metastases

TL;DR

A new mutation in the CHD4 gene is linked to a rare case of breast cancer that spreads to the bones and responds to hormone therapy.

Contribution

A novel CHD4 truncation mutation is identified in occult breast cancer with bone metastases, not previously reported in other cancers.

Findings

The CHD4 p.Trp736Ter mutation disrupts ATPase activity and NuRD complex assembly.

The cancer was classified as luminal-A subtype and showed response to endocrine therapy.

The mutation may shift CHD4's regulatory balance, promoting metastatic progression.

Abstract

Chromatin domain-binding protein 4 (CHD4), the ATPase core component of the NuRD complex, exerts dual roles in epigenetic regulation—mediating both gene silencing and activation. We report a case of occult breast cancer with extensive bone metastasis harboring a novel somatic truncation mutation in the catalytic SNF2 domain (CHD4 p.Trp736Ter). This mutation, unreported in other cancers to date, abolishes ATPase activity and disrupts NuRD complex assembly. Multimodal analysis (PET/CT, biomarkers, pathology) confirmed the case as luminal-A subtype and revealed a significant response to endocrine therapy. We hypothesize that this CHD4 mutation may alter the protein’s dual regulatory balance, particularly enhancing its potential gene-activating functions, and propose that impaired chromatin remodeling driven by such mutations is associated with metastatic progression of breast cancer.

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