MXRA5 – Malignant Pleural Mesothelioma

The current evidence indicates that somatic alterations in MXRA5 (HGNC:7539) have been observed in malignant pleural mesothelioma (MONDO_0005112). In several multi‐patient studies, MXRA5 mutations were recurrently identified, with one cohort reporting a mutation frequency of 23% in a group of 164 patients (PMID:33065998), and another deep sequencing study associating MXRA5 mutations with the biphasic histological subtype of mesothelioma in a cohort of 69 patients (PMID:32872534). Furthermore, case‐based evidence noted that a higher frequency of MXRA5 alterations was present in long‐term survivors compared to short‑term survivors, suggesting potential prognostic value (PMID:32339978).

Given that these studies are observational and derived from tumor sequencing with no accompanying functional assays or familial segregation data, the overall genetic evidence supporting the role of MXRA5 in malignant pleural mesothelioma remains limited. The variant spectrum is primarily defined by missense changes and rare loss‐of‐function events; however, no specific, recurrent HGVS‐described variant has been reported for MXRA5 in these studies.

The genetic data are derived exclusively from somatic analyses, and there is currently no established mode of Mendelian inheritance applicable for MXRA5 in this context. As such, standard segregation analysis is not relevant for this acquired somatic event.

While further functional studies are required to elucidate the precise mechanism by which MXRA5 alterations contribute to the pathogenesis or progression of mesothelioma, the observed association does inform diagnostic stratification in a clinical setting. This emerging association, despite being based on limited genetic evidence, supports the potential incorporation of MXRA5 screening in molecular profiling panels for malignant pleural mesothelioma.

Key Take‑home: Recurrent somatic MXRA5 alterations, although supported by limited evidence, offer a promising molecular marker for patient stratification in malignant pleural mesothelioma.

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 • Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma PMID:32872534
• Cancers • 2020 • Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study PMID:33065998

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