KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma

Our plain-English summary of KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma, by M. Vannucchi, V. Pennati, C. Mencaroni, et al (Cancers, 2023).

The study

• Authors: M. Vannucchi, V. Pennati, C. Mencaroni, C. Defraia, L. Bardhi, F. Castiglione, C. Bellan, C.E. Comin
• Journal: Cancers
• Published: 2023;15(7)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface that includes three major histologic subtypes, epitheliod, sarcomatoid and biphasic. Epithelioid mesothelioma is usually associated with better prognosis. The genetic mechanisms driving MPM, the possible target mutations and the correlation with overall survival remain largely unsettled. We performed target exome sequencing in 29 cases of MPM aimed at identifying somatic mutations and, eventually, their correlation with phenotypic traits and prognostic significance. We found that KRAS mutations, occurring in 13.7% of cases, were associated with shortened median survival (7.6 versus 32.6 months in KRAS wild-type; p = 0.005), as it was the occurrence of any ≥3 mutations (7.6 versus 37.6 months; p = 0.049). Conversely, the presence of KDR single nucleotide polymorphism p.V297I (rs2305948) resulted in a favorable variable for survival (NR versus 23.4 months; p = 0.026). With the intrinsic limitations of a small number of cases and patient heterogeneity, results of this study contribute to the characterization of the mutation profile of MPM and the impact of selected somatic mutations, and possibly KDR polymorphism, on prognosis.

In plain English

This retrospective study tested stored tumor tissue for gene mutations: 29 of 54 malignant pleural mesothelioma samples from patients first diagnosed in Florence between January 2013 and December 2017. All 29 tumors were epithelioid; 25 patients were men and 4 were women. Asbestos exposure was "certain" in 18 patients, "possible" in 3, "probable" in 1 and "unknown" in 7. Sequencing found 36 somatic mutations, with at least one in 23 of 29 samples. KRAS mutations were found in 4 of 29 patients (13.7%), all with certain occupational asbestos exposure. These patients had shorter median survival: 7.6 months versus 32.6 months without KRAS mutations (hazard ratio 5.1, 95% confidence interval 1.5 to 17.9, p = 0.005). Patients with a KDR gene variant, p.V297I (5 of 29), survived longer (median not reached versus 23.4 months, p = 0.026). No survival link was detected for EGFR or TP53 mutations in this small cohort. The authors called the KRAS result a possible correlation. They noted the small, retrospective series and that treatment data existed for only a few patients and went unanalyzed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of archived tumor tissue using targeted next-generation sequencing (a panel covering 48 genes), with Kaplan-Meier and Cox survival analysis
• Who was studied: 29 patients first diagnosed with malignant pleural mesothelioma, all epithelioid subtype, at the University-Hospital of Florence, Careggi, Italy, January 2013 to December 2017. The 29 were chosen from 54 samples because they had enough tissue for testing. 25 were male and 4 female, with a median age at diagnosis of 74.2 years (range 63 to 84).
• Exposure: The study examined tumor gene mutations, not exposure levels. Asbestos exposure was taken from chart records and graded by Italian National Mesothelioma Registry (ReNaM) criteria: certain in 18 patients (62.0%), possible in 3 (10.3%), probable in 1 (3.4%), unknown in 7 (24.1%). Fiber types were not specified.
• Main results:
  • Sequencing found 36 somatic mutations in total, with at least one mutation in 23 of 29 samples (79.3%).
  • KRAS mutations occurred in 4 of 29 patients (13.7%).
  • Median overall survival was 7.6 months (range 4.6 to 10.4) in patients with a KRAS mutation and 32.6 months (range 26.7 to 38.5) in KRAS wild-type patients (hazard ratio 5.1, 95% CI 1.5 to 17.9, p = 0.005).
  • All four patients with KRAS mutations had a recorded certain previous occupational asbestos exposure. The authors found no correlation between KRAS mutation and clinical features.
  • Patients with three or more mutations had a median overall survival of 7.6 months (range 6 to 9.1), compared with 37.6 months (range 19.2 to 56.0) in patients without mutations (p = 0.004 in the results section).
  • The KDR polymorphism p.V297I was found in 5 of 29 cases (17.2%).
  • Patients with the KDR p.V297I polymorphism had longer overall survival (median not reached) than patients without it (median 23.4 months, range 0.3 to 48.9; hazard ratio 0.32, 95% CI 0.02 to 0.95; p = 0.026).
  • Eight EGFR mutations were found in 5 of 29 patients, two of them not previously reported. The statistical analysis did not detect a correlation between EGFR mutations and clinical characteristics or survival in this cohort.
  • Six TP53 mutations were found in 4 of 29 patients. Kaplan-Meier analysis did not detect a significant correlation between TP53 mutations and overall survival in this cohort.
• The authors' conclusion: The authors concluded that they had found a possible correlation between KRAS mutations and shortened overall survival compared with wild-type cases. They concluded that the KDR p.V297I polymorphism seemed to confer a survival advantage in their cohort. They said the findings remain to be validated in broader studies and in other mesothelioma subtypes.
• Limitations the authors state:
  • The study was retrospective.
  • Treatment information was available for only a few patients, so it was not included in the analysis and the impact of treatment on survival could not be assessed.
  • The number of cases was relatively small, and only the epithelioid subtype was included.
  • Tumor grade and specimen type showed no significant link with survival, which the authors said may reflect the small number of patients.

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Pleural Mesothelioma, Histological Subtype, Sarcomatoid, Biphasic Mesothelioma, Mesothelioma, Prognosis, Overall Survival.

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