KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player

Our plain-English summary of KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player, by L. Trassl, G.T. Stathopoulos (Cancers, 2022).

The study

• Authors: L. Trassl, G.T. Stathopoulos
• Journal: Cancers
• Published: 2022;14(17)
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare, incurable cancer of the mesothelial cells lining the lungs and the chest wall that is mainly caused by asbestos inhalation. The molecular mechanisms of mesothelial carcinogenesis are still unclear despite comprehensive studies of the mutational landscape of MPM, and the most frequently mutated genes BAP1, NF2, CDKN2A, TP53, and TSC1 cannot cause MPM in mice in a standalone fashion. Although KRAS pathway alterations were sporadically detected in older studies employing targeted sequencing, they have been largely undetected by next generation sequencing. We recently identified KRAS mutations and copy number alterations in a significant proportion of MPM patients. Here, we review and analyze multiple human datasets and the published literature to show that, in addition to KRAS, multiple other genes of the KRAS pathway are perturbed in a significant proportion of patients with MPM.

In plain English

This article is a review of published research on changes in the KRAS gene pathway in malignant pleural mesothelioma (MPM), combined with the authors' own reanalysis of public genetic databases. It did not study asbestos exposure. Across the studies reviewed, the authors noted that mutations in KRAS and related pathway genes were found more often when targeted methods were used than in large sequencing studies. The authors reanalyzed 13 KRAS pathway genes in The Cancer Genome Atlas (82 patients) and found alterations in 44 patients (54%). In a second database (COSMIC, 775 patients), the combined mutation frequency of the pathway increased gradually in biphasic and sarcomatoid MPM compared with epithelioid MPM. In gene-activity data from 55 MPM and 41 normal lung tissues, the two most significantly altered pathways involved PI3K-AKT signaling, and a set of these genes separated malignant from benign samples. The review also described the authors' own earlier study, which found KRAS mutations in 3 of 12 human MPM samples (25%). The authors concluded that KRAS pathway alterations have an underestimated role in MPM and warrant further investigation.

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: Review of published literature combined with the authors' reanalysis of publicly available genetic datasets
• Who was studied: No new patients were recruited. The authors used public data: The Cancer Genome Atlas (TCGA) MPM dataset (82 patients with full data), the COSMIC MPM dataset (775 patients) and GEO microarray dataset GSE51024 (55 MPM and 41 normal lung tissues), together with published studies found through PubMed.
• Exposure: Asbestos exposure was not studied; it is mentioned only as background. The analysis concerned genetic alterations in 13 KRAS/TP53 pathway genes (EGFR, KRAS, NF2, BRAF, PIK3CA, RASSF1, MAP2K1, AKT1, STK3, MAPK1, LATS1, MDM2, TP53).
• Main results:
  • In the TCGA MPM dataset (82 patients), KRAS pathway mutations, copy number alterations and three fusions were found in 44 patients (54% alteration frequency).
  • In the COSMIC MPM dataset (775 patients), the cumulative mutation frequency of the KRAS pathway increased gradually in biphasic and sarcomatoid MPM compared with epithelioid MPM.
  • Reanalysis of microarray data from 55 MPM and 41 normal lung tissues found 2204 gene probes that were differentially regulated, and 14 WikiPathways perturbed in MPM.
  • The two most significantly altered pathways involved PI3K-AKT signaling. This PI3K-AKT signature was overrepresented in all three histologic subtypes and separated malignant from benign samples on clustering.
  • Across the reviewed studies, mutations of KRAS and its pathway genes were detected more often with targeted approaches than in large next generation sequencing cohorts.
  • In the authors' own earlier published study (not the analysis in this review), digital droplet PCR detected KRAS mutations in 25% (3/12) of human MPM samples.
• The authors' conclusion: The authors concluded that the literature, their recent work and the public data analyzed indicate a thus-far underestimated role for KRAS pathway alterations in MPM, and that these warrant further investigation.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Carcinogenesis, BAP1, CDKN2A.

Related studies

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• Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions — D.L. Jardim, S.Z. Millis, et al. (2021)
• Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations — T. Sato, K. Akao, et al. (2023)
• Asbestos in Belgium: an underestimated health risk. The evolution of mesothelioma mortality rates (1969-2009) — L. Van den Borre, P. Deboosere (2014)
• Asbestos ingestion and gastrointestinal cancer: a possible underestimated hazard — A. Di Ciaula (2017)
• The importance of FISH signal cut-off values for 9p21 deletion in malignant pleural mesothelioma: Is it underestimated? — G. Kulduk, Ö. Ekinci, et al. (2019)

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