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The association between CHD1 and prostate cancer is supported by multiple lines of evidence from case series, multi‐patient cohort analyses, and functional studies. Recent studies have identified recurrent deletions and point mutations in CHD1 in lethal and metastatic prostate cancer, suggesting that alterations in this chromatin remodeler contribute to tumor progression (PMID:22722839).
Clinical studies have reported CHD1 disruptions in several cohorts of prostate cancer patients. In one comprehensive analysis of lethal, castration‑resistant cases, CHD1 deletions were recurrently observed in over 20 probands (PMID:22722839), and similar findings were replicated in additional studies involving multi‐sample genomic analyses (PMID:27148588) and detailed imaging of tumor foci (PMID:25175909). These data justify a ClinGen gene–disease association strength in the Strong range.
Genetic evidence indicates that somatic alterations in CHD1—comprising deletions and point mutations such as c.5113T>C (p.Trp1705Arg)—are frequently observed in prostate cancer. While most alterations are acquired, the genetic profiles in affected tumor tissues have been corroborated with genomic and transcriptomic analyses, revealing robust segregation of CHD1 loss with aggressive disease phenotypes (PMID:22722839). The reported genetic events have been observed in numerous probands across independent studies.
Functional assays further support the pathogenicity of CHD1 alterations. In vitro studies have demonstrated that CHD1 disruption impairs chromatin remodeling and transcription regulation, impacting the expression of key androgen receptor target genes (PMID:17620414). Additionally, animal and cell‐based models have confirmed that CHD1 loss can mimic molecular features of aggressive prostate cancer (PMID:30728766), and clinical correlations of CHD1 status with therapeutic response (e.g. abiraterone sensitivity) further solidify its functional relevance (PMID:30068710).
The integration of genetic and functional studies provides a coherent narrative that CHD1 plays a critical role in prostate cancer pathogenesis. Genomic analyses across diverse cohorts have revealed recurrent CHD1 deletions and mutations, while experimental models have illuminated the mechanistic underpinnings by which CHD1 loss dysregulates transcriptional programs essential for prostate tumor maintenance and progression.
Although additional evidence exists that exceeds the ClinGen scoring maximum, the available data are robust enough to support the clinical utility of CHD1 testing in the diagnostic work‐up of aggressive prostate cancer. Key to‐take home: CHD1 functions as a critical regulator of chromatin structure whose disruption is strongly associated with adverse prostate cancer outcomes, thereby representing a significant biomarker for both diagnosis and targeted therapy.
Gene–Disease AssociationStrongMultiple independent studies in >20 probands (PMID:22722839) and concordant functional findings justify a Strong gene–disease association for CHD1 in prostate cancer. Genetic EvidenceStrongRecurrent CHD1 deletions and variants, including c.5113T>C (p.Trp1705Arg), have been identified in aggressive prostate cancer cohorts, with robust segregation in multiple multi‑patient studies (PMID:27148588). Functional EvidenceModerateFunctional experiments demonstrate that CHD1 loss disrupts chromatin remodeling and transcriptional regulation, with supportive in vitro and in vivo models (PMID:17620414; PMID:30728766). |