Genomic analysis in short- and long-term patients with malignant pleura mesothelioma treated with palliative chemotherapy.

BACKGROUND

Malignant pleural mesothelioma (MPM) is an aggressive tumour with poor prognosis. The aim of this study was to identify genetic mutations associated with poor or extended survival in patients who received palliative chemotherapy.

METHODS

A total of 720 patients diagnosed with MPM between 2005 and 2015 were identified. Overall survival (OS) was longer than 30 months from diagnosis for 27 patients. Twelve of 27 (44%) of the pleural biopsies from long-term survivors were retrieved and matched with 12 biopsies from patients who survived less than 12 months; one biopsy was then excluded for poor DNA quality.

RESULTS

A total of 11 patients had a mean OS of 5.5 months, whereas 12 patients lived more than 30 months (mean OS: 55.8 ± 25). Mutational analysis identified 428 alterations; of which, 148, classified as somatic and functional, were considered further. Among these, 85% were missense variants, 8% were variants causing a stop gain and 6% were splice variants. Loss-of-function mutations in UQCRC1 were significantly associated with reduced survival in patients with MPM (p = 0.027), while a higher frequency of mutations in MXRA5 and RAPGEF6 was registered in long-term survivors.

CONCLUSION

This is the first study evaluating the relationship between the mutational profile and outcome in patients with MPM after palliative chemotherapy. UQCRC1 codes for cytochrome b-c1 complex subunit 1 which plays a fundamental role in normal mitochondrial functions and in cell metabolism. Recent studies described UQCRC1 deregulation in other cancers. Our results suggest a possible role for mitochondrial metabolism in the biology of mesothelioma.