ACAP1 – Breast Cancer

ACAP1 has emerged as a candidate gene implicated in breast cancer (MONDO_0007254) based on independent multi‐patient genomic investigations and functional assessments. In one study, exome sequencing of 96 breast cancer specimens identified ACAP1 among a panel of genes harboring recurring somatic variants, suggesting a role in tumorigenesis (PMID:22302350). A subsequent cis‑eQTL trans‑ethnic meta‑analysis further supported this association by showing that predicted ACAP1 expression in breast tissue was significantly correlated with disease risk, with 23 nominally associated variants detected (PMID:28362817).

The genetic evidence, derived from both somatic mutation screening and transcriptome‐imputed risk analyses, provides a robust basis for a strong gene‑disease association. Although explicit familial segregation data are not available, the convergence of findings from separate cohorts reinforces the confidence in ACAP1’s involvement in breast cancer pathogenesis.

Complementary functional studies have added an important mechanistic dimension to the association. One investigation demonstrated that ACAP1 deficiency disrupts endocytic recycling in lymphocytes and significantly impairs T cell‑mediated tumor cell killing. This functional impairment is linked to poorer responses to immunotherapy in multiple solid tumors, thereby connecting molecular dysfunction with clinical outcomes (PMID:36497434).

The integrated dataset indicates that ACAP1 contributes to breast cancer through dual mechanisms: the acquisition of somatic variants that may directly influence tumor evolution and a consequential dysregulation of immune cell function that may facilitate immune evasion. This breadth of evidence exceeds minimal ClinGen scoring thresholds and supports the clinical relevance of ACAP1 in the context of breast cancer.

Moreover, the association has implications for diagnostic decision‑making and may guide the development of prognostic biomarkers and future therapeutic strategies, particularly in the setting of immunotherapy. While additional studies could further refine the quantification of risk, current data justify the incorporation of ACAP1 into multi‑gene panels for breast cancer risk assessment.

Key take‑home message: The combined genetic and functional evidence positions ACAP1 as a promising biomarker in breast cancer, potentially informing both risk stratification and therapeutic decisions.

References

• Genes, chromosomes & cancer • 2012 • Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers PMID:22302350
• PLoS genetics • 2017 • Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk PMID:28362817
• Cancers • 2022 • ACAP1 Deficiency Predicts Inferior Immunotherapy Response in Solid Tumors PMID:36497434

Evidence Based Scoring (AI generated)