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This summary evaluates the association between ACTR1A (HGNC:167) and malignant pleural mesothelioma (MONDO_0005112). Evidence is drawn from multi‐patient sequencing studies and functional assays. The genetic data originate from tumor profiling studies while functional experiments in yeast provide mechanistic insights into the role of ACTR1A in essential cellular processes.
The clinical validity of the association is currently classified as Limited. In one study, point mutations in ACTR1A were identified in 4 malignant pleural mesothelioma tumors (PMID:18303113), and a targeted gene panel study of 164 patients further supported the presence of mutations in a broader cohort (PMID:33065998). However, no familial segregation data or evidence from unrelated germline probands is available, reducing the overall strength of the gene‑disease association.
The genetic evidence stems from somatic alterations observed within tumor samples. In these studies, mutations were discovered as part of a multi‐gene screening effort and, although recurrent in a subset of samples, the lack of extended segregation analysis limits the weight of the genetic component. The inheritance mode in this context is best described as Somatic with no affected relatives demonstrating germline segregation.
Functional experiments have provided moderate support for ACTR1A’s role in disease pathogenesis. In a yeast model, a detailed dissection of Arp1p, the homolog of human ACTR1A, revealed that specific mutations can uncouple the cell wall integrity checkpoint from nuclear migration functions (PMID:16415535). These findings offer mechanistic insights that are biologically plausible for cancer pathogenesis even though they are derived from a non‐mammalian system.
There is some conflicting context since the observed mutations in ACTR1A occur in a small fraction of cases and without supporting familial data, the association remains tentative. The genetic evidence is limited by the absence of segregation and recurrence in multiple independent cohorts, while the functional evidence is derived from a yeast system that may not fully recapitulate human tumor biology.
In conclusion, while the genetic findings in multi‐patient studies provide an initial link between ACTR1A and malignant pleural mesothelioma, the overall evidence remains limited despite supportive mechanistic data from functional assays. Key take‑home: ACTR1A represents a potential biomarker that merits further investigation in larger, well‐characterized cohorts to clarify its role in malignant pleural mesothelioma.
Gene–Disease AssociationLimitedAssociation based on limited genetic evidence with 4 tumor samples showing mutations (PMID:18303113) and inclusion in a targeted sequencing panel of 164 patients (PMID:33065998); no familial segregation data available. Genetic EvidenceLimitedGenetic findings include sporadic point mutations in ACTR1A detected in multi‐patient studies, lacking confirmed germline or segregation analysis, which reduces overall confidence. Functional EvidenceModerateYeast functional assays demonstrate that mutations in ACTR1A (Arp1p) disrupt cell wall integrity checkpoint and nuclear migration (PMID:16415535), supporting a plausible pathogenic mechanism. |