Identification of actionable mutations in malignant pleural mesothelioma

Our plain-English summary of Identification of actionable mutations in malignant pleural mesothelioma, by T. Shukuya, M. Serizawa, M. Watanabe, et al (Lung Cancer, 2014).

The study

• Authors: T. Shukuya, M. Serizawa, M. Watanabe, H. Akamatsu, M. Abe, H. Imai, T. Tokito, A. Ono, T. Taira, H. Kenmotsu, T. Naito, H. Murakami, T. Takahashi, M. Endo, Y. Ohde, T. Nakajima, N. Yamamoto, Y. Koh
• Journal: Lung Cancer
• Published: 2014;86(1):35-40
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood.

Patients And Methods: Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes.

Results: Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing.

Conclusions: Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

In plain English

This study looked for gene changes in tumor samples from 42 patients with malignant pleural mesothelioma treated at the Shizuoka Cancer Center in Japan between 2003 and 2012. Asbestos exposure was recorded as definite for 21 patients and not definite for 21. The article gives no fiber types or other exposure details. The authors tested all samples for changes in genes that have targeted drugs in other cancers. They also tested 21 samples with a broader sequencing panel of 48 cancer-related genes. In the first testing, 4 of 42 patients had a change: three PIK3CA amplifications and one KRAS mutation. Median overall survival was 103 days for patients with these changes and 527 days for those without (p = 0.0009). The authors note this comparison was univariate only, because of the small number of patients. The broader panel found 16 mutations in 9 of the 21 patients, including TP53, APC, PIK3CA and VHL. Patient characteristics, including asbestos exposure, did not differ significantly between patients with and without changes. The authors concluded that potential drug targets were found and that larger studies are needed.

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: Laboratory genetic analysis of stored tumor samples from consecutive patients at one hospital, with comparison of survival by gene status
• Who was studied: 42 patients with malignant pleural mesothelioma (33 male, 9 female; median age 63.5; 30 epithelioid, 7 sarcomatoid, 2 biphasic, 3 not otherwise specified) treated at the Shizuoka Cancer Center, Japan, 2003 to 2012. 21 of them also had broader sequencing.
• Exposure: Not an asbestos exposure study. The study examined gene mutations and amplifications in tumors. Asbestos exposure was recorded only as definite (21 patients, 50%) or not definite (21 patients, 50%), with no fiber types or doses given.
• Main results:
  • Among the 42 patients, 3 had PIK3CA amplifications and 1 had a KRAS mutation (G12D).
  • No mutations were found in EGFR, BRAF, NRAS, MEK1, AKT1, PTEN or HER2, and no amplifications in EGFR, MET, FGFR1 or FGFR2, among the 42 samples.
  • Median survival time for all 42 patients was 527 days.
  • Median overall survival was 103 days in patients with genetic alterations and 527 days in patients without (log rank p = 0.0009, hazard ratio printed as 0.120).
  • Median overall survival was 103 days in patients with PIK3CA amplifications and 527 days in patients without them (log rank p = 0.0299, hazard ratio printed as 0.197).
  • Broader sequencing of 21 patients' samples found 16 mutations in 9 patients: 4 cases with TP53, 3 with APC, 3 with PIK3CA and 2 with VHL mutations, plus mutations in ALK, FGFR3, KRAS and PTPN11.
  • Both VHL mutations found among the 21 sequenced samples were the same change (N131Y).
  • Gender, age, histological subtype, performance status, asbestos exposure and stage showed no statistically significant difference between patients with and without genetic alterations, in both the 42-patient testing and the sequencing group.
• The authors' conclusion: The authors concluded that genetic alterations that are potential targets for molecular targeted therapy were detected in malignant pleural mesothelioma. They said further study in a larger cohort is needed to evaluate these alterations as therapeutic targets and predictive markers.
• Limitations the authors state:
  • The survival comparison by genetic alteration status was analyzed by univariate analysis only, because of the small number of patients.
  • Patients with genetic alterations tended to have advanced stage and sarcomatoid histology.
  • The analysis did not include NF2 and BAP1, genes already known to be altered in mesothelioma.
  • One type of base change (C:G to T:A substitutions) had to be removed because it is often an artifact of preserved tissue, so some mutation information was lost.
  • The study size was limited, so the prevalence of the genetic alterations remains uncertain.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, EGFR, HER2, Targeted Therapy.

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