RAPGEF6 – Malignant Pleural Mesothelioma

This summary evaluates the association between RAPGEF6 and malignant pleural mesothelioma. Two independent multi‐patient studies have identified alterations in RAPGEF6 in MPM cohorts, with one study noting that mutations in RAPGEF6 were significantly associated with the non‑epithelioid subtype (p = 0.03 (PMID:33065998)) and another reporting a higher mutation frequency in long‑term survivors (PMID:32339978). The overall clinical validity is therefore assessed as moderate based on the recurrence of alterations in modest-sized cohorts and statistically significant associations with disease subtypes.

Genetic evidence supporting this association is derived from targeted sequencing analyses of MPM tissue samples. Although no specific RAPGEF6 variant with full HGVS annotation was reported in these studies, the gene inclusion in mutational panels and its correlation with histologic differences suggest an underlying mutational spectrum. The analyses involved extensive cohorts (e.g., 720 patients in one report and 164 in another) (PMID:32339978; PMID:33065998), and while detailed segregation data is not available, the recurrence across independent studies strengthens the gene–disease link.

In terms of variant spectrum, reports indicate that the majority of identified mutations in the MPM panels were missense in nature, with no single recurrent variant explicitly defined for RAPGEF6. As such, no specific HGVS variant could be isolated from the provided evidence. This highlights an area for future research where more granular variant-level data may enhance diagnostic utility.

The inheritance mode for these alterations is best characterized as somatic, as the evidence arises from tumor sequencing data in malignant pleural mesothelioma cases rather than from a germline perspective. Additionally, segregation analysis is not applicable in this context, with affected tissue rather than familial transmission driving the observed associations.

Functional evidence for RAPGEF6 comes from a study evaluating its role in cellular adhesion, where experiments demonstrated that RAPGEF6 interacts in complexes that modulate cell adhesion and migration (PMID:20800573). It is important to note, however, that this functional assessment was performed in the context of metastatic malignant neoplasm (MONDO_0024880) and may not fully recapitulate the pathogenic mechanisms in malignant pleural mesothelioma. As such, while supportive, the experimental data provide limited direct evidence linking RAPGEF6 dysfunction to MPM specifically.

In conclusion, the integration of multi‐patient genetic data and complementary functional assays supports a moderate association between RAPGEF6 and malignant pleural mesothelioma. The evidence suggests a potential role for RAPGEF6 alterations in defining tumor subtype and patient prognosis, underscoring the clinical utility of incorporating RAPGEF6 analysis into molecular diagnostic strategies in MPM.

Key Take‑home: Genetic profiling for RAPGEF6 mutations may offer valuable prognostic insights in malignant pleural mesothelioma, but additional variant‐level and functional studies in this specific disease context are warranted.

References

• European journal of cancer • 2020 • Genomic analysis in short- and long-term patients with malignant pleura mesothelioma treated with palliative chemotherapy PMID:32339978
• Cancers • 2020 • Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study PMID:33065998
• Biochemical and biophysical research communications • 2010 • BAG3 directly associates with guanine nucleotide exchange factor of Rap1, PDZGEF2, and regulates cell adhesion PMID:20800573

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